Kenneth D. Carr, Ph.D.

Food restriction increases acquisition, persistence and drug prime-induced expression of a cocaine-conditioned place preference in rats
Zheng, Danielle; de Vaca, Soledad Cabeza; Carr, Kenneth D
2012 Jan;100(3):538-544, Pharmacology biochemistry & behavior
Cocaine conditioned place preference (CPP) is more persistent in food-restricted than ad libitum fed rats. This study assessed whether food restriction acts during conditioning and/or expression to increase persistence. In Experiment 1, rats were food-restricted during conditioning with a 7.0mg/kg (i.p.) dose of cocaine. After the first CPP test, half of the rats were switched to ad libitum feeding for three weeks, half remained on food restriction, and this was followed by CPP testing. Rats tested under the ad libitum feeding condition displayed extinction by the fifth test. Their CPP did not reinstate in response to overnight food deprivation or a cocaine prime. Rats maintained on food restriction displayed a persistent CPP. In Experiment 2, rats were ad libitum fed during conditioning with the 7.0mg/kg dose. In the first test only a trend toward CPP was displayed. Rats maintained under the ad libitum feeding condition did not display a CPP during subsequent testing and did not respond to a cocaine prime. Rats tested under food-restriction also did not display a CPP, but expressed a CPP following a cocaine prime. In Experiment 3, rats were ad libitum fed during conditioning with a 12.0mg/kg dose. After the first test, half of the rats were switched to food restriction for three weeks. Rats that were maintained under the ad libitum condition displayed extinction by the fourth test. Their CPP was not reinstated by a cocaine prime. Rats tested under food-restriction displayed a persistent CPP. These results indicate that food restriction lowers the threshold dose for cocaine CPP and interacts with a previously acquired CPP to increase its persistence. In so far as CPP models Pavlovian conditioning that contributes to addiction, these results suggest the importance of diet and the physiology of energy balance as modulatory factors
— id: 147686, year: 2012, vol: 100, page: 538, stat: Journal Article,

Food scarcity, neuroadaptations, and the pathogenic potential of dieting in an unnatural ecology: Binge eating and drug abuse
Carr, Kenneth D
2011 Jul 25;104(1):162-167, Physiology & behavior
In the laboratory, food restriction has been shown to induce neuroadaptations in brain reward circuitry which are likely to be among those that facilitate survival during periods of food scarcity in the wild. However, the upregulation of mechanisms that promote foraging and reward-related learning may pose a hazard when food restriction is self-imposed in an ecology of abundant appetitive rewards. For example, episodes of loss of control during weight-loss dieting, use of drugs with addictive potential as diet aids, and alternating fasting with alcohol consumption in order to avoid weight gain, may induce synaptic plasticity that increases the risk of enduring maladaptive reward-directed behavior. In the present mini-review, representative basic research findings are outlined which indicate that food restriction alters the function of mesoaccumbens dopamine neurons, potentiates cellular and behavioral responses to D-1 and D-2 dopamine receptor stimulation, and increases stimulus-induced synaptic insertion of AMPA receptors in nucleus accumbens. Possible mechanistic underpinnings of increased drug reward magnitude, drug-seeking, and binge intake of sucrose in food-restricted animal subjects are discussed and possible implications for human weight-loss dieting are considered
— id: 134091, year: 2011, vol: 104, page: 162, stat: Journal Article,

Enhanced cocaine-conditioned place preference and associated brain regional levels of BDNF, p-ERK1/2 and p-Ser845-GluA1 in food-restricted rats
Liu S; Zheng D; Peng XX; Cabeza de Vaca S; Carr KD
2011 Jul 11;1400:31-41, Brain research
Previously, a learning-free measure was used to demonstrate that chronic food restriction (FR) increases the reward magnitude of a wide range of abused drugs. Moreover, a variety of striatal neuroadaptations were detected in FR subjects, some of which are known to be involved in synaptic plasticity but have been ruled out as modulators of acute drug reward magnitude. Little is known about effects of FR on drug-conditioned place preference (CPP) and brain regional mechanisms that may enhance CPP in FR subjects. The purpose of the present study was to compare the expression and persistence of a conditioned place preference (CPP) induced by a relatively low dose of cocaine (7.0mg/kg, i.p.) in ad libitum fed (AL) and FR rats and take several brain regional biochemical measures following the first CPP conditioning session to probe candidate mechanisms that may underlie the more robust CPP observed in FR subjects. Behaviorally, AL subjects displayed a CPP upon initial testing which extinguished rapidly over the course of subsequent test sessions while CPP in FR subjects persisted. Despite previous reports of elevated BDNF protein in forebrain regions of FR rats, the FR protocol used in the present study did not alter BDNF levels in dorsal hippocampus, nucleus accumbens or medial prefrontal cortex. On the other hand, FR rats, whether injected with cocaine or vehicle, displayed elevated p-ERK1/2 and p-Ser845-GluA1 in dorsal hippocampus. FR rats also displayed elevated p-ERK1/2 in medial prefrontal cortex and elevated p-ERK1 in nucleus accumbens, with further increases produced by cocaine. The one effect observed exclusively in cocaine-treated FR rats was increased p-Ser845-GluA1 in nucleus accumbens. These findings suggest a number of avenues for continuing investigation with potential translational significance
— id: 134090, year: 2011, vol: 1400, page: 31, stat: Journal Article,

A food restriction protocol that increases drug reward decreases tropomyosin receptor kinase B in the ventral tegmental area, with no effect on brain-derived neurotrophic factor or tropomyosin receptor kinase B protein levels in dopaminergic forebrain regions
Pan, Y; Chau, L; Liu, S; Avshalumov, M V; Rice, M E; Carr, K D
2011 Dec 1;197:330-338, Neuroscience
Food restriction (FR) decreases brain-derived neurotrophic factor (BDNF) expression in hypothalamic and hindbrain regions that regulate feeding and metabolic efficiency, while increasing expression in hippocampal and neocortical regions. Drugs of abuse alter BDNF expression within the mesocorticolimbic dopamine (DA) pathway, and modifications of BDNF expression within this pathway alter drug-directed behavior. Although FR produces a variety of striatal neuroadaptations and potentiates the rewarding effects of abused drugs, the effects of FR on BDNF expression and function within the DA pathway are unknown. The primary purpose of the present study was to examine the effect of FR on protein levels of BDNF and its tropomyosin receptor kinase B (TrkB) receptor in component structures of the mesocorticolimbic pathway. Three to four weeks of FR, with stabilization of rats at 80% of initial body weight, did not alter BDNF or TrkB levels in nucleus accumbens, caudate-putamen, or medial prefrontal cortex. However, FR decreased TrkB levels in the ventral tegmental area (VTA), without change in levels of BDNF protein or mRNA. The finding that FR also decreased TrkB levels in substantia nigra, with elevation of BDNF protein, suggests that decreased TrkB in VTA could be a residual effect of increased BDNF during an earlier phase of FR. Voltage-clamp recordings in VTA DA neurons indicated decreased glutamate receptor transmission. These data might predict lower average firing rates in FR relative to ad libitum fed subjects, which would be consistent with previous evidence of decreased striatal DA transmission and upregulation of postsynaptic DA receptor signaling. However, FR subjects also displayed elevated VTA levels of phospho-ERK1/2, which is an established mediator of synaptic plasticity. Because VTA neurons are heterogeneous with regard to neurochemistry, function, and target projections, the relationship(s) between the three changes observed in VTA, and their involvement in the augmented striatal and behavioral responsiveness of FR subjects to drugs of abuse, remains speculative
— id: 141070, year: 2011, vol: 197, page: 330, stat: Journal Article,

Effects of food restriction and sucrose intake on synaptic delivery of AMPA receptors in nucleus accumbens
Peng XX; Ziff EB; Carr KD
2011 Oct;65(10):1024-31 L, Synapse
Insertion and removal of AMPA receptors from the synaptic membrane underlie dynamic tuning of synaptic transmission and enduring changes in synaptic strength. Preclinical addiction research suggests that AMPA receptor trafficking plays an important role in nucleus accumbens (NAc) neuroplasticity underlying the compulsive and persistent quality of drug-seeking. Considering the parallels between drug addiction and compulsive eating, plus the supranormal reward properties of sucrose, and the role of dieting as a risk factor in development of binge pathology, the present study used a biochemical subcellular fractionation approach to determine whether brief intake of a 10% sucrose solution increases synaptic delivery of AMPA receptors in NAc of chronically food-restricted (FR) relative to ad libitum fed (AL) rats. FR, alone, produced a small but significant increase in synaptic expression of AMPA receptors. This may contribute to NAc integrative mechanisms that mediate the enhanced behavioral responsiveness of FR subjects to phasic reward stimuli, including food and drugs. Brief intake of sucrose increased GluR1 in the PSD, regardless of dietary condition, though the net effect was greater in FR than AL subjects. A marked increase in GluR2 was also observed, but only in FR rats. This set of results suggests that in FR subjects, sucrose may have primarily increased delivery of GluR1/GluR2 heteromers to the PSD, while in AL subjects sucrose increased delivery of GluR2-lacking channels. The functional consequences of these possible differences in subunit composition of trafficked AMPA receptors between diet groups remain to be determined. Nevertheless, the present set of results suggest a promising new avenue to pursue in the effort to understand synaptic plasticity involved in adaptive and pathological food-directed behavior and the mechanistic basis of severe dieting as a risk factor for the latter. Synapse, 2011. (c) 2011 Wiley-Liss, Inc
— id: 134092, year: 2011, vol: 65, page: 1024, stat: Journal Article,

SKF-83566, a D(1) -dopamine receptor antagonist, inhibits the dopamine transporter
Stouffer, Melissa A; Ali, Solav; Reith, Maarten E A; Patel, Jyoti C; Sarti, Federica; Carr, Kenneth D; Rice, Margaret E
2011 Sep;118(5):714-720, Journal of neurochemistry
J. Neurochem. (2011) 118, 714-720. ABSTRACT: Dopamine (DA) is an important transmitter in both motor and limbic pathways. We sought to investigate the role of D(1) -receptor activation in axonal DA release regulation in dorsal striatum using a D(1) -receptor antagonist, SKF-83566. Evoked DA release was monitored in rat striatal slices using fast-scan cyclic voltammetry. SKF-83566 caused a concentration-dependent increase in peak single-pulse evoked extracellular DA concentration, with a maximum increase of approximately 65% in 5 muM SKF-83566. This was accompanied by a concentration-dependent increase in extracellular DA concentration clearance time. Both effects were occluded by nomifensine (1 muM), a dopamine transporter (DAT) inhibitor, suggesting that SKF-83566 acted via the DAT. We tested this by examining [(3) H]DA uptake into LLc-PK cells expressing rat DAT, and confirmed that SKF-83566 is a competitive DAT inhibitor with an IC(50) of 5.7 muM. Binding studies with [(3) H]CFT, a cocaine analog, showed even more potent action of SKF-83566 at the DAT cocaine binding site (IC(50) = 0.51 muM). Thus, data obtained using SKF-83566 as a D(1) DA-receptor antagonist may be confounded by concurrent DAT inhibition. More positively, however, SKF-83566 might be a candidate to attenuate cocaine effects in vivo because of the greater potency of this drug at the cocaine versus DA binding site of the DAT
— id: 136635, year: 2011, vol: 118, page: 714, stat: Journal Article,

AMPA receptor subunit GluR1 downstream of D-1 dopamine receptor stimulation in nucleus accumbens shell mediates increased drug reward magnitude in food-restricted rats
Carr, K D; Chau, L S; Cabeza de Vaca, S; Gustafson, K; Stouffer, M; Tukey, D S; Restituito, S; Ziff, E B
2010 Feb 17;165(4):1074-1086, Neuroscience
Previous findings suggest that neuroadaptations downstream of D-1 dopamine (DA) receptor stimulation in nucleus accumbens (NAc) are involved in the enhancement of drug reward by chronic food restriction (FR). Given the high co-expression of D-1 and GluR1 AMPA receptors in NAc, and the regulation of GluR1 channel conductance and trafficking by D-1-linked intracellular signaling cascades, the present study examined effects of the D-1 agonist, SKF-82958, on NAc GluR1 phosphorylation, intracranial electrical self-stimulation reward (ICSS), and reversibility of reward effects by a polyamine GluR1 antagonist, 1-NA-spermine, in ad libitum fed (AL) and FR rats. Systemically administered SKF-82958, or brief ingestion of a 10% sucrose solution, increased NAc GluR1 phosphorylation on Ser845, but not Ser831, with a greater effect in FR than AL rats. Microinjection of SKF-82958 in NAc shell produced a reward-potentiating effect that was greater in FR than AL rats, and was reversed by co-injection of 1-NA-spermine. GluR1 abundance in whole cell and synaptosomal fractions of NAc did not differ between feeding groups, and microinjection of AMPA, while affecting ICSS, did not exert greater effects in FR than AL rats. These results suggest a role of NAc GluR1 in the reward-potentiating effect of D-1 DA receptor stimulation and its enhancement by FR. Moreover, GluR1 involvement appears to occur downstream of D-1 DA receptor stimulation rather than reflecting a basal increase in GluR1 expression or function. Based on evidence that phosphorylation of GluR1 on Ser845 primes synaptic strengthening, the present results may reflect a mechanism via which FR normally facilitates reward-related learning to re-align instrumental behavior with environmental contingencies under the pressure of negative energy balance
— id: 106493, year: 2010, vol: 165, page: 1074, stat: Journal Article,

Reward-potentiating effects of D-1 dopamine receptor agonist and AMPAR GluR1 antagonist in nucleus accumbens shell and their modulation by food restriction
Carr, Kenneth D; Cabeza de Vaca, Soledad; Sun, Yanjie; Chau, Lily S
2009 Mar;202(4):731-743, Psychopharmacology
RATIONALE: Previous studies have suggested that chronic food restriction (FR) increases sensitivity of a neural substrate for drug reward. The neuroanatomical site(s) of key neuroadaptations may include nucleus accumbens (NAc) where changes in D-1 dopamine (DA) receptor-mediated cell signaling and gene expression have been documented. OBJECTIVES: The purpose of the present study was to begin bridging the behavioral and tissue studies by microinjecting drugs directly into NAc medial shell and assessing behavioral effects in free-feeding and FR subjects. MATERIALS AND METHODS: Rats were implanted with microinjection cannulae in NAc medial shell and a subset were implanted with a stimulating electrode in lateral hypothalamus. Reward-potentiating effects of the D-1 DA receptor agonist, SKF-82958, AMPAR antagonist, DNXQ, and polyamine GluR1 antagonist, 1-na spermine, were assessed using the curve-shift method of self-stimulation testing. Motor-activating effects of SKF-82958 were also assessed. RESULTS: SKF-82958 (2.0 and 5.0 mug) produced greater reward-potentiating and motor-activating effects in FR than ad libitum fed (AL) rats. DNQX (1.0 mug) and 1-na spermine (1.0 and 2.5 mug) selectively decreased the x-axis intercept of rate-frequency curves in FR subjects, reflecting increased responding for previously subthreshold stimulation. CONCLUSIONS: Results suggest that FR may facilitate reward-directed behavior via multiple neuroadaptations in NAc medial shell including upregulation of D-1 DA receptor function involved in the selection and expression of goal-directed behavior, and increased GluR1-mediated activation of cells that inhibit nonreinforced responses
— id: 96114, year: 2009, vol: 202, page: 731, stat: Journal Article,

Effects of the MEK inhibitor, SL-327, on rewarding, motor- and cellular-activating effects of D-amphetamine and SKF-82958, and their augmentation by food restriction in rat
Carr, Kenneth D; de Vaca, Soledad Cabeza; Sun, Yanjie; Chau, Lily S; Pan, Yan; Dela Cruz, Julie
2009 Jan;201(4):495-506, Psychopharmacology
RATIONALE: Food restriction (FR) enhances learned and unlearned behavioral responses to drugs of abuse and increases D-1 dopamine (DA) receptor-mediated activation of extracellular signal-regulated kinases (ERK) 1/2 MAP kinase in nucleus accumbens (NAc). While a role has been established for ERK signaling in drug-mediated associative learning, it is not clear whether ERK regulates unconditioned behavioral effects of abused drugs. OBJECTIVES: The purpose of this study was to determine whether blockade of ERK signaling, using the brain-penetrant MEK inhibitor, SL-327, decreases behavioral or NAc cellular responses to acute drug treatment and their augmentation by FR. MATERIALS AND METHODS: Separate experiments assessed the effects of SL-327 (50 mg/kg, intraperitoneally) on (1) the reward-potentiating effect of D-amphetamine in an intracranial self-stimulation protocol, (2) the locomotor-activating effect of the D-1 agonist, SKF-82958, and (3) Fos-immunostaining induced in the NAc by SKF-82958. RESULTS: FR rats displayed enhanced responses to drug treatment on all measures. SL-327 had no effect on sensitivity to rewarding brain stimulation or the reward-potentiating effect of D-amphetamine. The MEK inhibitor, U0126, microinjected into the NAc was also without effect. The locomotor-activating effect of SKF-82958 was unaffected by SL-327. In contrast, SL-327 decreased NAc Fos-immunostaining and abolished the difference between feeding groups. CONCLUSIONS: These results support the conclusion that ERK signaling does not mediate unlearned behavioral responses to drug treatment. However, the upregulation of ERK and downstream transcriptional responses to acute drug treatment may underlie the reported enhancement of reward-related learning in FR subjects
— id: 111779, year: 2009, vol: 201, page: 495, stat: Journal Article,

The adenosine A2A receptor agonist, CGS-21680, blocks excessive rearing, acquisition of wheel running, and increases nucleus accumbens CREB phosphorylation in chronically food-restricted rats
Cabeza de Vaca, Soledad; Kannan, Pavitra; Pan, Yan; Jiang, Nancy; Sun, Yanjie; Carr, Kenneth D
2007 Apr 20;1142:100-109, Brain research
Adenosine A(2A) receptors are preferentially expressed in rat striatum, where they are concentrated in dendritic spines of striatopallidal medium spiny neurons and exist in a heteromeric complex with D(2) dopamine (DA) receptors. Behavioral and biochemical studies indicate an antagonistic relationship between A(2A) and D(2) receptors. Previous studies have demonstrated that food-restricted (FR) rats display behavioral and striatal cellular hypersensitivity to D(1) and D(2) DA receptor stimulation. These alterations may underlie adaptive, as well as maladaptive, behaviors characteristic of the FR rat. The present study examined whether FR rats are hypersensitive to the A(2A) receptor agonist, CGS-21680. In Experiment 1, spontaneous horizontal motor activity did not differ between FR and ad libitum fed (AL) rats, while vertical activity was greater in the former. Intracerebroventricular (i.c.v.) administration of CGS-21680 (0.25 and 1.0 nmol) decreased both types of motor activity in FR rats, and returned vertical activity levels to those observed in AL rats. In Experiment 2, FR rats given access to a running wheel for a brief period outside of the home cage rapidly acquired wheel running while AL rats did not. Pretreatment with CGS-21680 (1.0 nmol) blocked the acquisition of wheel running. When administered to FR subjects that had previously acquired wheel running, CGS-21680 suppressed the behavior. In Experiment 3, CGS-21680 (1.0 nmol) activated both ERK 1/2 and CREB in caudate-putamen with no difference between feeding groups. However, in nucleus accumbens (NAc), CGS-21680 failed to activate ERK 1/2 and selectively activated CREB in FR rats. These results indicate that FR subjects are hypersensitive to several effects of an adenosine A(2A) agonist, and suggest the involvement of an upregulated A(2A) receptor-linked signaling pathway in NAc. Medications targeting the A(2A) receptor may have utility in the treatment of maladaptive behaviors associated with FR, including substance abuse and compulsive exercise.
— id: 72863, year: 2007, vol: 1142, page: 100, stat: Journal Article,

Chronic food restriction: Enhancing effects on drug reward and striatal cell signaling
Carr, Kenneth D
2007 ;91(5):459-472, Physiology & behavior
Chronic food restriction (FR) increases behavioral sensitivity to drugs of abuse in animal models and is associated with binge eating, which shares comorbidity with drug abuse, in clinical populations. Behavioral, biochemical and molecular studies conducted in this laboratory to elucidate the functional and mechanistic bases of these phenomena are briefly reviewed. Results obtained to date indicate that FR increases the reward magnitude and locomotor-activating effects of abused drugs, and direct dopamine (DA) receptor agonists, as a result of neuroadaptations rather than changes in drug disposition. Changes in striatal DA dynamics, and postsynaptic cell signaling and gene expression in response to D-1 DA receptor stimulation have been observed. Of particular interest is an upregulation of NMDA receptor-dependent MAP kinase and CaM Kinase II signaling, CREB phosphorylation, and immediate-early and neuropeptide gene expression in nucleus accumbens (NAc) which may facilitate reward-related learning, but also play a role in the genesis of maladaptive goal-directed behaviors. Covariation of altered drug reward sensitivity with body weight loss and recovery suggests a triggering role for one of the endocrine adiposity hormones. However, neither acute nor chronic central infusions of leptin or the melanocortin 3/4 receptor agonist, MTII, have attenuated d-amphetamine reward or locomotor activation in FR rats. Interestingly, chronic intracerebroventricular leptin infusion in ad libitum fed (AL) rats produced a sustained decrease in food intake and body weight that was accompanied by a reversible potentiation of rewarding and locomotor-activating effects of d-amphetamine. This raises the interesting possibility that rapid progressive weight loss is sufficient to increase behavioral sensitivity to drugs of abuse. Whether weight loss produced by leptin infusion produces the same neuroadaptations as experimenter-imposed FR, and whether any of the observed neuroadaptations are necessary for expression of increased behavioral responsiveness to acute drug challenge remain to be investigated
— id: 69632, year: 2007, vol: 91, page: 459, stat: Journal Article,

Role of alpha(1)-Adrenoceptors of the Locus Coeruleus in Self-Stimulation of the Medial Forebrain Bundle
Lin, Yan; de Vaca, Soledad Cabeza; Carr, Kenneth D; Stone, Eric A
2007 Apr;32(4):835-841, Neuropsychopharmacology
The present experiments were undertaken to clarify the role of central alpha(1)-adrenoceptors in reward processes. Rats, trained to self-stimulate via electrodes in the medial forebrain bundle of the lateral hypothalamus, were administered alpha(1)-selective drugs near the locus coeruleus (LC), a site of a dense concentration of alpha(1)-receptors. Effects on reward potency were assessed from shifts in rate-frequency curves while effects on motor response capacity were judged from changes in the maximal rates of responding. It was found that local blockade of LC alpha(1)-receptors with terazosin produced a significant dose-dependent and site-dependent rightward shift of 0.08 log units and a significant decrease of 16.3% in the maximum response rate. Both effects were completely reversed by coadministration of the alpha(1)-agonist, phenylephrine and were not attributable to terazosin's weak action at alpha(2)-adrenoceptors. It is concluded that LC alpha(1)-adrenoceptors are involved both in reward/motivational processes and operant response elaboration which are postulated to work together to facilitate goal attainment.Neuropsychopharmacology advance online publication, 5 July 2006; doi:10.1038/sj.npp.1301145
— id: 69634, year: 2007, vol: 32, page: 835, stat: Journal Article,

Effects of central leptin infusion on the reward-potentiating effect of D-amphetamine
Hao, Joy; Cabeza de Vaca, Soledad; Pan, Yan; Carr, Kenneth D
2006 May 4;1087(1):123-133, Brain research
It was previously reported that chronic food restriction and maintenance of rats at 75-80% of initial body weight enhanced the reward-potentiating effect of D-amphetamine in the lateral hypothalamic self-stimulation (LHSS) paradigm. Moreover, the enhancement reversed in parallel with body weight recovery when ad libitum access to food was reinstated. The present study tested the hypothesis that hypoleptinemia during food restriction is necessary for expression of enhanced drug reward. In Experiment 1, intracerebroventricular (i.c.v.) infusion of leptin (0.5 microg/0.5 microl/hr for 8 days) in food-restricted rats did not alter the rewarding effect of D-amphetamine (0.5 mg/kg, i.p.). Considering that i.c.v. leptin may not diffuse into deep brain regions where direct effects on drug reward sensitivity may be exerted, effects of acute bilateral microinjection of leptin (0.5 microg) in ventral tegmental area and nucleus accumbens were tested in Experiment 2 and found to have no effect. In Experiment 3, chronic i.c.v. leptin infusion in ad libitum fed rats decreased food intake and body weight and enhanced the rewarding effect of D-amphetamine. Sensitivity to D-amphetamine returned to normal as body weight recovered following cessation of leptin infusion. This result suggests that weight loss, whether from hormone-induced appetite suppression or experimenter-imposed food restriction, is sufficient to enhance drug reward sensitivity. Experiment 4 tested whether food restriction in the absence of body weight loss alters drug reward sensitivity. Rats received chronic i.c.v. infusion of the orexigenic melanocortin receptor antagonist, SHU9119 (0.02 microg/0.5 microl/hr for 12 days), and a subset were pair-fed to vehicle-infused controls. Although these subjects ingested approximately 50% of the amount of food ingested by free-feeding SHU9119-infused rats, they displayed no weight loss and no change in sensitivity to D-amphetamine. Together, results of this study support the importance of weight loss, but not leptin, in the enhancement of drug reward sensitivity
— id: 67847, year: 2006, vol: 1087, page: 123, stat: Journal Article,

Synthesis, protein levels, activity, and phosphorylation state of tyrosine hydroxylase in mesoaccumbens and nigrostriatal dopamine pathways of chronically food-restricted rats
Pan, Yan; Berman, Yemiliya; Haberny, Sandra; Meller, Emanuel; Carr, Kenneth D
2006 Nov 29;1122(1):135-142, Brain research
Chronic food restriction (FR) enhances the rewarding and motor-activating effects of abused drugs, and is accompanied by changes in dopamine (DA) dynamics and increased D-1 DA receptor-mediated cell signaling and transcriptional responses in nucleus accumbens (NAc). However, little is known about effects of FR on DA synthetic activity in the mesoaccumbens and nigrostriatal pathways. In Experiment 1 of the present study, tyrosine hydroxylase (TH) gene expression was measured in ventral tegmental area and substantia nigra, using real-time RT-PCR and in situ hybridization; no differences were observed between FR and ad libitum fed (AL) rats. In Experiment 2, TH protein levels, determined by Western blot, were found to be elevated in NAc and caudate-putamen (CPu) of FR relative to AL rats. In the absence of increased transcription, this may reflect a slowing of TH degradation. In Experiments 3 and 4, DA synthetic activity was assessed by Western blot measurement of TH phosphorylation at Ser40, and HPLC measurement of in vivo tyrosine hydroxylation rate, as reflected by DOPA accumulation following administration of a decarboxylase inhibitor (NSD-1015; 100 mg/kg, i.p.). Basal phospho-(Ser40)-TH levels did not differ between groups but DOPA accumulation was decreased by FR. Decreased DOPA synthesis, despite increased levels of TH protein, may reflect the inhibitory effect of increased DA binding to TH protein or decreased concentrations of cofactor tetrahydrobiopterin. Finally, in response to D-amphetamine (0.5 and 5.0 mg/kg, i.p.), phospho-(Ser40)-TH was selectively decreased in NAc of FR rats. This suggests increased feedback inhibition of DA synthesis-a possible consequence of postsynaptic receptor hypersensitivity, or increased extracellular DA concentration. These results indicate that FR increases TH protein levels, but may decrease the capacity for DA synthesis by decreasing TH activity. According to this scheme, the previously observed upregulation of striatal cell signaling and transcriptional responses to DA receptor agonist administration may include compensatory neuroadaptations
— id: 69633, year: 2006, vol: 1122, page: 135, stat: Journal Article,

Striatal cell signaling in chronically food-restricted rats under basal conditions and in response to brief handling
Pan, Yan; Siregar, Ermanda; Carr, Kenneth D
2006 Jan 30;393(2-3):243-248, Neuroscience letters
Chronic food restriction increases exploratory behavior, cognitive function, and the rewarding effects of abused drugs. Recently, striatal neuroadaptations that may be involved in these effects were observed. Specifically, D-1 dopamine (DA) receptor agonist challenge produced stronger activation of extracellular signal-regulated kinase (ERK), calcium-calmodulin-dependent kinase II (CaMKII), and the nuclear transcription factor cAMP response element binding protein (CREB) in nucleus accumbens (NAc) of food-restricted (FR) relative to ad libitum fed (AL) rats. Further, when FR rats were injected intracerebroventricularly (i.c.v.) with vehicle (saline) they displayed stronger activation of c-Jun N-terminal protein kinase (JNK), ERK and CaMKII than did AL rats. It is not known to what extent the latter effects represent the basal state of FR rats or an amplified response to the brief handling involved in the i.c.v. injection procedure. Using Western blotting it was found that basal phospho-JNK is higher in caudate-putamen (CPu) and NAc of FR relative to AL rats. Interestingly, brief handling decreased phospho-JNK levels in FR subjects. Basal phospho-ERK1/2 also tended to be elevated in CPu and NAc of FR rats but the elevation was not significant. However, phospho-MEK--the activated kinase upstream of ERK1/2--was significantly elevated in NAc of FR rats. Neither ERK1/2 nor MEK were activated by brief handling. CaMKII was selectively activated by handling in NAc of FR rats, suggesting a state-dependent response to a salient event. Given the established involvement of mitogen-activated protein kinase (MAPK) and CaMKII in synaptic plasticity, learning and memory, the increase in basal phospho-MEK and hyperresponsiveness of CaMKII in NAc may represent adaptive cellular responses to persistent negative energy balance that facilitate associative learning in connection with food-seeking
— id: 62808, year: 2006, vol: 393, page: 243, stat: Journal Article,

Chronic food restriction and dopamine transporter function in rat striatum
Zhen, Juan; Reith, Maarten E A; Carr, Kenneth D
2006 Apr 12;1082(1):98-101, Brain research
The present communication reports on DA uptake in rat striatum in a model of chronic food restriction. The K(m) for DA uptake was unaltered, but the V(max) was reduced by 32%, not supporting the idea that the enhanced behavioral sensitivity to cocaine or d-amphetamine upon chronic food restriction is due to a greater density of DAT at the plasma membrane for drug interaction. Chronic food restriction did not alter the potency of cocaine or D-amphetamine in inhibiting DA uptake in the striatum, suggesting that the enhanced behavioral sensitivity to these drugs upon chronic food restriction is not due to their enhanced affinity for DAT. These results point to factors other than DAT density or affinity underlying the sensitized response to psychostimulants in food restriction
— id: 68807, year: 2006, vol: 1082, page: 98, stat: Journal Article,

Feeding, body weight, and sensitivity to non-ingestive reward stimuli during and after 12-day continuous central infusions of melanocortin receptor ligands
Cabeza de Vaca, S; Hao, J; Afroz, T; Krahne, L L; Carr, K D
2005 Nov;26(11):2314-2321, Peptides
The brain melanocortin system mediates downstream effects of hypothalamic leptin and insulin signaling. Yet, there have been few studies of chronic intracerebroventricular (i.c.v.) melanocortin receptor (MCR) agonist or antagonist infusion. Although there is evidence of interaction between melanocortin and dopamine (DA) systems, effects of chronic MCR ligand infusion on behavioral sensitivity to non-ingestive reward stimuli have not been investigated. The objective of this study was to investigate effects of chronic i.c.v. infusion of the MCR agonist, MTII, and the MCR antagonist, SHU9119, on food intake, body weight, and sensitivity to rewarding lateral hypothalamic electrical stimulation (LHSS) and the reward-potentiating (i.e., threshold-lowering) effect of D-amphetamine. The MCR antagonist, SHU9119 (0.02 microg/h) produced sustained hyperphagia and weight gain during the 12-day infusion period, followed by compensatory hypophagia and an arrest of body weight gain during the 24-day post-infusion period. At no point during the experiment was sensitivity to LHSS or D-amphetamine (0.25mg/kg, i.p.) altered. The MCR agonist, MTII (0.02 microg/h) produced a brief hypophagia (3 days) followed by a return to control levels of daily intake, but with body weight remaining at a reduced level throughout the 12-day infusion period. This was followed by compensatory hyperphagia and weight gain during the 24-day post-infusion period. There was no change in sensitivity to non-ingestive reward stimuli during the infusion of MTII. However, sensitivity to D-amphetamine was increased during the 24-day post-infusion period. It therefore seems that changes in ingestive behavior that occur during chronic MCR ligand infusion may not affect the response to non-ingestive reward stimuli. However, it is possible that the drive to re-feed and restore body weight following MCR agonist treatment includes neuroadaptations that enhance the incentive effects of drug stimuli
— id: 62738, year: 2005, vol: 26, page: 2314, stat: Journal Article,

Food restriction increases NMDA receptor-mediated calcium-calmodulin kinase II and NMDA receptor/extracellular signal-regulated kinase 1/2-mediated cyclic amp response element-binding protein phosphorylation in nucleus accumbens upon D-1 dopamine receptor stimulation in rats
Haberny, S L; Carr, K D
2005 ;132(4):1035-1043, Neuroscience
Biological drive states exert homeostatic control in part by increasing the reinforcing effects of environmental incentive stimuli. An apparent by-product of this adaptive response is the enhanced acquisition of drug self-administration behavior in food-restricted (FR) animals. While previous research has demonstrated increased central sensitivity to rewarding effects of abused drugs and direct dopamine (DA) receptor agonists in FR subjects, the underlying neurobiology is not well understood. Recently, it was demonstrated that intracerebroventricular (i.c.v.) injection of the D-1 DA receptor agonist, SKF-82958 produces a stronger activation of striatal extracellular signal-regulated kinase (ERK) 1/2 and cyclic AMP response element-binding protein (CREB) in FR relative to ad libitum (AL) fed rats. The main purpose of the present study was to characterize the involvement and mechanisms of interaction between NMDA receptor function and the augmented cellular responses to D-1 DA receptor stimulation in nucleus accumbens (NAc) of FR rats. In experiment 1, Western immunoblotting was used to demonstrate that i.c.v. injection of SKF-82958 (20 microg) produces greater phosphorylation of the NMDA NR1 subunit and calcium-calmodulin kinase II (CaMK II) in NAc of FR as compared with AL rats. In experiment 2, pretreatment of subjects with the NMDA antagonist, MK-801 (1.0 mg/kg, i.p.) decreased SKF-82958-induced activation of CaMK II, ERK1/2 and CREB, and reversed the augmenting effect of FR on activation of all three proteins. In experiment 3, pretreatment with the mitogen-activated protein kinase/ERK kinase inhibitor SL-327 (60 mg/kg, i.p.) suppressed SKF-82958- induced activation of ERK1/2 and reversed the augmenting effect of FR on CREB activation. These results point to specific neuroadaptations in the NAc of FR rats whereby D-1 DA receptor stimulation leads to increased NMDA NR1 subunit phosphorylation and consequent increases in NMDA receptor-dependent CaMK II and ERK1/2 signaling, and increased NMDA receptor/ERK1/2-dependent phosphorylation of the nuclear transcription factor, CREB. The upregulated cellular responses to D-1 DA agonist challenge may play a role in the augmentation of drug reward and appetitive instrumental learning during periods of food restriction
— id: 56355, year: 2005, vol: 132, page: 1035, stat: Journal Article,

Comparison of basal and D-1 dopamine receptor agonist-stimulated neuropeptide gene expression in caudate-putamen and nucleus accumbens of ad libitum fed and food-restricted rats
Haberny, Sandra L; Carr, Kenneth D
2005 Nov 30;141(2):121-127, Brain research. Molecular brain research
Behavioral studies have demonstrated that chronic food restriction augments the rewarding and motor-activating effects of centrally injected psychostimulants and direct dopamine (DA) receptor agonists. Recently, it has been shown that intracerebroventricular (i.c.v.) injection of the D-1 DA receptor agonist, SKF-82958, produces an enhanced locomotor-activating effect as well as increased activation of striatal ERK 1/2 MAP kinase, CaM kinase II, CREB, and c-fos in food-restricted (FR) relative to ad libitum fed (AL) rats. Striatal neurons that express the D-1 DA receptor coexpress dynorphin and substance P, and CREB is known to couple D-1 DA receptor stimulation to preprodynorphin (ppD) gene expression. The purpose of the present study was to examine possible genomic consequences of FR using real-time quantitative RT-PCR to measure striatal neuropeptide gene expression 3 h after i.c.v. injection of SKF-82958 (20 microg). Results indicate that, in nucleus accumbens (NAc), basal levels of ppD and preprotachykinin (ppT) mRNA are lower in FR than AL rats. This may reflect a decrease in tonic DA transmission during FR which precedes the compensatory upregulation of postsynaptic D-1 DA receptor-mediated cell signaling. In response to SKF-82958 challenge, however, FR subjects displayed greater levels of ppD and ppT mRNA in NAc than did AL subjects. A similar trend was seen in caudate-putamen (CPu). SKF-82958 also increased preproenkephalin (ppE) mRNA in Nac, but not CPu, with no difference between feeding groups. The present findings regarding ppD and ppT are consistent with prior findings of increased behavioral and cellular responses to acute D-1 DA agonist challenge in FR rats. The functional consequences of increased neuropeptide gene expression in response to acute drug challenge remain to be investigated but may include modulation of behavioral effects that emerge with repeated drug exposure, including sensitization, tolerance, and addiction
— id: 69635, year: 2005, vol: 141, page: 121, stat: Journal Article,

A progressive ratio schedule of self-stimulation testing in rats reveals profound augmentation of d-amphetamine reward by food restriction but no effect of a "sensitizing" regimen of d-amphetamine
Cabeza de Vaca, Soledad; Krahne, Lisa L; Carr, Kenneth D
2004 Aug;175(1):106-113, Psychopharmacology
RATIONALE: Prior research indicates that psychostimulant-induced sensitization is not expressed in lateral hypothalamic electrical self-stimulation (LHSS)-based measures of drug reward, although the augmenting effect of chronic food restriction is. Neuroadaptations within the brain dopamine system have been identified in both psychostimulant-sensitized and food-restricted animals. Consequently, a variant of the LHSS paradigm in which responding is particularly sensitive to changes in dopaminergic tone may be best suited to detect and compare effects of chronic d-amphetamine and food restriction. Instrumental responding on a progressive ratio (PR) schedule is more sensitive to dopaminergic manipulations than is responding on a continuous reinforcement (CRF) schedule, but has not previously been used to examine chronic psychostimulant and food restriction effects on LHSS-based measures of drug reward. OBJECTIVE: The first aim of this study was to determine whether a regimen of d-amphetamine treatment, that produces locomotor sensitization (5 mg/kg per day x5 days), increases the reward-potentiating effect of d-amphetamine in a PR LHSS protocol. The second aim, was to determine whether chronic food restriction produces a marked increase in the reward-potentiating effect of d-amphetamine in the PR LHSS protocol and, if so, whether it is reversible in parallel with body weight recovery when free feeding is restored. METHOD: Reward-potentiating effects of a challenge dose of d-amphetamine (0.25 mg/kg, IP) were measured in terms of the break point of LHSS responding on a PR schedule of reinforcement, in ad libitum fed and food-restricted rats. RESULTS: A regimen of d-amphetamine treatment that produced locomotor sensitization did not increase the break point for LHSS in the presence or absence of d-amphetamine. Chronic food restriction produced a marked increase in the break point-increasing effect of d-amphetamine (3-fold), which returned to baseline in parallel with body weight recovery over a 4-week period of restored free-feeding. CONCLUSIONS: A locomotor-sensitizing regimen of d-amphetamine treatment does not increase the rewarding effect of LH electrical stimulation or the reward-potentiating effect of d-amphetamine in a PR LHSS protocol. The augmenting effect of chronic food restriction on drug reward is mechanistically and functionally different from psychostimulant sensitization and may be controlled by signals associated with adipose depletion and repletion
— id: 48099, year: 2004, vol: 175, page: 106, stat: Journal Article,

Chronic food restriction increases D-1 dopamine receptor agonist-induced phosphorylation of extracellular signal-regulated kinase 1/2 and cyclic AMP response element-binding protein in caudate-putamen and nucleus accumbens
Haberny, S L; Berman, Y; Meller, E; Carr, K D
2004 ;125(1):289-298, Neuroscience
Results of behavioral and c-fos immunohistochemical studies have suggested that chronic food restriction and maintenance of animals at 75-80% of free-feeding body weight may increase d-1 dopamine (DA) receptor function. The purpose of the present study was to determine whether D-1 DA receptor binding and/or mitogen-activated protein kinase (MAPK) signaling in caudate-putamen (CPu) and nucleus accumbens (NAc) are increased in food-restricted subjects. In the first experiment, saturation binding of the D-1 DA receptor antagonist [3H]SCH-23390 indicated no difference between food-restricted and ad libitum fed rats with regard to density or affinity of d-1 binding sites in CPu or NAc. In the second experiment, activation of extracellular signal-regulated kinases (ERK1/2) and cyclic AMP response element-binding protein (CREB) by i.c.v. injection of the D-1 DA receptor agonist SKF-82958 (20 microg) were markedly greater in food-restricted than ad libitum fed rats. Given a prior finding that SKF-82958 does not differentially stimulate adenylyl cyclase in CPu or NAc of food-restricted versus ad libitum fed subjects, the present results suggest that increased D-1 DA receptor-mediated ERK1/2 MAP kinase signaling may mediate the enhanced downstream activation of CREB, c-fos, and behavioral responses in food-restricted subjects. It is of interest that food restriction also increased the activation of c-Jun N-terminal protein kinase/stress-activated protein kinase, but this effect was no greater in rats injected with SKF-82958 than in those injected with saline vehicle. This represents additional evidence of increased striatal cell signaling in food-restricted subjects, presumably in response to the i.c.v. injection procedure, although the underlying receptor mechanisms remain to be determined. There were no differences between feeding groups in protein levels of the major phosphatases, MKP-2 and PP1. The upregulation of striatal MAP kinase signaling in food-restricted animals may adaptively serve to facilitate associative learning but, at the same time, increase vulnerability to the rewarding and addictive properties of abused drugs
— id: 46194, year: 2004, vol: 125, page: 289, stat: Journal Article,

Effects of chronic ICV leptin infusion on motor-activating effects of D-amphetamine in food-restricted and ad libitum fed rats
Hao, J; Cabeza de Vaca, S; Carr, K D
2004 Dec 15;83(3):377-381, Physiology & behavior
Recently, attention has turned to the possibility that endocrine adiposity hormones, such as leptin, may regulate appetitively motivated behavior by modulating brain dopamine function. By extension, it has been hypothesized that the increased behavioral sensitivity of food-restricted, underweight rats to psychostimulant challenge may be triggered by the accompanying hypoleptinemia. The purpose of the present study was to determine whether two weeks of continuous intracerebroventricular (ICV) infusion of leptin alters the motor-activating effect of D-amphetamine (0.75 mg/kg, IP) in food-restricted rats. Lateral ventricular infusion of leptin, using a regimen that decreases food intake and body weight in ad libitum fed rats (12 microg/day), had no effect on the locomotor response to D-amphetamine in food-restricted rats that were maintained at 80% of prerestriction body weight. This result may indicate that hypoleptinemia is not involved in the induction/maintenance of neuroadaptations that mediate enhanced behavioral sensitivity to psychostimulant challenge. Interestingly, ad libitum fed rats treated with leptin displayed an increased locomotor response to D-amphetamine that was most prominent 3-5 days after termination of the infusion. Body weights and D-amphetamine sensitivity of these subjects returned to control values by 8-10 days postinfusion. The enhanced behavioral sensitivity to D-amphetamine in leptin-treated ad libitum fed rats may be a by-product of adipose depletion and, if so, would further support involvement of a peripheral signal other than hypoleptinemia in the modulation of central sensitivity to psychostimulant challenge
— id: 47900, year: 2004, vol: 83, page: 377, stat: Journal Article,

Effects of the group I metabotropic glutamate receptor agonist, DHPG, and injection stress on striatal cell signaling in food-restricted and ad libitum fed rats
Pan, Yan; Berman, Yemiliya; Carr, Kenneth D
2004 Dec 3;5(1):50-50, BMC Neuroscience
BACKGROUND: Chronic food restriction augments the rewarding effect of centrally administered psychostimulant drugs and this effect may involve a previously documented upregulation of D-1 dopamine receptor-mediated MAP kinase signaling in nucleus accumbens (NAc) and caudate-putamen (CPu). Psychostimulants are known to induce striatal glutamate release, and group I metabotropic glutamate receptors (mGluR) have been implicated in the cellular and behavioral responses to amphetamine. The purpose of the present study was to evaluate whether chronic food restriction increases striatal MAP kinase signaling in response to the group I mGluR agonist, DHPG. RESULTS: Western immunoblotting was used to demonstrate that intracerebroventricular (i.c.v.) injection of DHPG (500 nmol) produces greater activation of ERK1/2 and CREB in CPu and NAc of food-restricted as compared to ad libitum fed rats. Fos-immunostaining induced by DHPG was also stronger in CPu and NAc core of food-restricted relative to ad libitum fed rats. However, i.c.v. injection of saline-vehicle produced greater activation of ERK1/2 and CREB in CPu and NAc of food-restricted relative to ad libitum fed rats, and this difference was not seen when subjects received no i.c.v. injection prior to sacrifice. In addition, although DHPG activated Akt, there was no difference in Akt activation between feeding groups. To probe whether the augmented ERK1/2 and CREB activation in vehicle-injected food-restricted rats are mediated by one or more GluR types, effects of an NMDA antagonist (MK-801, 100 nmol), AMPA antagonist (DNQX, 10 nmol), and group I mGluR antagonist (AIDA, 100 nmol) were compared to saline-vehicle. Antagonist injections did not diminish activation of ERK1/2 or CREB. CONCLUSIONS: These results indicate that a group I mGluR agonist induces phosphorylation of Akt, ERK1/2 and CREB in both CPu and NAc. However, group I mGluR-mediated signaling may not be upregulated in food-restricted rats. Rather, a physiological response to 'i.c.v. injection stress' is augmented by food restriction and appears to summate with effects of the group I mGluR agonist in activating ERK1/2 and CREB. While the augmented cellular response of food-restricted rats to i.c.v. injection treatment represents additional evidence of enhanced CNS responsiveness in these subjects, the functional significance and underlying mechanism(s) of this effect remain to be elucidated
— id: 55996, year: 2004, vol: 5, page: 50, stat: Journal Article,

Evidence of the receptor for cocaine and amphetamine regulated transcript ( CART ) in GH3 cells and bovine anterior pituitary
Berman, Y.; Lukyanov, Y. S.; Tkalych, O.; Fiallo, A.; Helmer, E.; Petrenko, A.; Carr, K. D.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Cocaine-and Amphetamine Regulated Transcript (CART) was first identified as a mRNA upregulated in striatum in response to acute injection of cocaine and amphetamine. The CART transcript encodes for a protein (Pro-CART) which is processed to smaller forms of bioactive peptides, CART 55-102 and CART 62-102. The subcellular localization of CART peptides within dense core vesicles of axon terminals suggests a neurotransmitter role for these peptides. However, CART receptors have not been identified. In the present study, saturable specific binding of (125I) CART was demonstrated in GH3 cells (a rat pituitary adenoma cell line) and bovine anterior pituitary. Further, it was shown by confocal microscopy in live cells that activation of these binding sites results in translocation of beta-arrestin2/green fluorescent protein (beta-arr2-GFP) to the plasma membrane, suggesting that CART binding sites are G-protein coupled receptors. Analysis of receptor-mediated signal transduction revealed that CART peptides inhibit forskolin-stimulated cAMP production in a pertussis toxin-sensitive manner, suggesting that the CART binding site is coupled to Gi/o proteins. CART peptides also activated Mitogen Activated Protein Kinase (MAPK) in a time and dose dependent manner, with significantly different time courses for the 55-102 and 62-102 fragments. Together, these results indicate that cellular effects of CART peptides are mediated by membrane G-protein coupled receptors with negative and positive coupling to cAMP and MAPK signaling pathways, respectively
— id: 92205, year: 2003, vol: 2003, page: ?, stat: Journal Article,

Effects of chronic ICV infusion of melanocortin receptor ligands on brain stimulation reward and the threshold - lowering effect of D - amphetamine
Cabeza de Vaca, S.; Krahne, L.; Carr, K. D.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Lateral hypothalamic self-stimulation (LHSS) and the threshold-lowering effects of abused drugs are increased by chronic food restriction. LHSS is also modulated by the endocrine adiposity hormones insulin and leptin. The endogenous melanocortin receptor (MCR) ligands, AGRP (antagonist) and alpha-MSH (agonist) mediate opponent physiological and behavioral actions in response to changes in mediobasal hypothalamic leptin and insulin exposure. The purpose of the present study was to evaluate whether chronic stimulation or blockade of central MCRs alters the rewarding effect of LH stimulation or the threshold-lowering effect of d-amphetamine. Thirty rats were trained in a rate-frequency LHSS paradigm and the threshold-lowering effect of d-amphetamine (0.25 mg/kg, i.p.) was determined. Rats were then divided into 3 groups of 10 and implanted with subcutaneous osmotic minipumps that delivered either the MCR agonist MTII (0.5 mug/12 mul/24 hr), the MCR antagonist SHU9119 (0.5 mug/12 mul/24 hr), or vehicle (12 mul/24 hr) via a lateral ventricular cannula for 12 days. LHSS and the threshold-lowering effect of d-amphetamine were tested again on days 3, 8 and 12 of icv infusions. MTII and SHU9119 produced a sustained decrease and increase, respectively, in food intake. SHU9119 had no effect on LHSS threshold or the threshold-lowering effect of d-amphetamine. MTII, however, lowered LHSS thresholds and augmented the threshold-lowering effect of d-amphetamine. It is not yet clear whether these effects result directly from MCR stimulation or arise secondarily as a consequence of the progressive weight loss produced by MTII infusion
— id: 92208, year: 2003, vol: 2003, page: ?, stat: Journal Article,

Evidence of increased dopamine receptor signaling in food-restricted rats
Carr, K D; Tsimberg, Y; Berman, Y; Yamamoto, N
2003 ;119(4):1157-1167, Neuroscience
It is well established that chronic food restriction enhances sensitivity to the rewarding and motor-activating effects of abused drugs. However, neuroadaptations underlying these behavioral effects have not been characterized. The purpose of the present study was to explore the possibility that food restriction produces increased dopamine (DA) receptor function that is evident in behavior, signal transduction, and immediate early gene expression. In the first two experiments, rats received intracerebroventricular (i.c.v.) injections of the D1 DA receptor agonist SKF-82958, and the D2/3 DA receptor agonist quinpirole. Both agonists produced greater motor-activating effects in food-restricted than ad libitum-fed rats. In addition, Fos-immunostaining induced by SKF-82958 in caudate-putamen (CPu) and nucleus accumbens (Nac) was greater in food-restricted than ad libitum-fed rats, as was staining induced by quinpirole in globus pallidus and ventral pallidum. In the next two experiments, neuronal membranes prepared from CPu and Nac were exposed to SKF-82958 and quinpirole. Despite the documented involvement of cyclic AMP (cAMP) signaling in D1 DA receptor-mediated c-fos induction, stimulation of adenylyl cyclase (AC) activity by SKF-82958 in CPu and Nac did not differ between groups. Food restriction did, however, decrease AC stimulation by the direct enzyme stimulant, forskolin, but not NaF or MnCl(2), suggesting a shift in AC expression to a less catalytically efficient isoform. Finally, food restriction increased quinpirole-stimulated [(35)S]guanosine triphosphate-gammaS binding in CPu, suggesting that increased functional coupling between D2 DA receptors and G(i) may account for the augmented behavioral and pallidal c-Fos responses to quinpirole. Results of this study support the hypothesis that food restriction leads to neuroadaptations at the level of postsynaptic D1 and D2 receptor-bearing cells which, in turn, mediate augmented behavioral and transcriptional responses to DA. The signaling pathways mediating these augmented responses remain to be fully elucidated
— id: 39172, year: 2003, vol: 119, page: 1157, stat: Journal Article,

Food restriction upregulates D-1 dopamine receptor-mediated MAP kinase signaling in caudate-putamen and nucleus accumbens
Haberny, S. L.; Berman, Y.; Meller, E.; Carr, K. D.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Chronic food restriction increases the rewarding, motor-activating and immediate-early gene responses to centrally injected psychostimulants and direct dopamine (DA) receptor agonists. The purpose of the present study was to determine whether the food restriction regimen that produces these effects causes adaptive changes in D-1 DA receptors and their intracellular signaling pathways. In all experiments, rats were fed 10 grams of chow each day until a 20-25% weight loss was achieved. This was followed by maintenance of the target body weight for at least one additional week. D-1 receptor binding: saturation curves were obtained for specific 3H-SCH23390 binding in caudate-putamen (CPU) and nucleus accumbens (NAC). There were no differences in Kd or Bmax between food-restricted and control subjects. cA
— id: 92207, year: 2003, vol: 2003, page: ?, stat: Journal Article,

Chronic cocaine administration alters immunoreactive cocaine and amphetamine regulated transcript levels in specific rat brain regions
Lukyanov, Y. S.; Tkalych, O.; Helmer, E.; Fiallo, A.; Carr, K. D.; Berman, Y.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Cocaine and amphetamine regulated transcript (CART) was originally discovered as a novel up-regulated mRNA in a drug abuse paradigm. CART is one of the most abundantly expressed mRNA in the hypothalamus and nucleus accumbens. In rat, differential splicing gives rise to two different CART mRNAs encoding precursors of either 116 or 129 amino acids. CART precursor processing is tissue dependent and two forms of peptide predominate in the brain, CART 55-102 and CART 62-102. Aside from the first report on amphetamine and cocaine as inducers of CART mRNA expression, other studies found modest gender-dependent effects on expression level or no changes at all. The aim of the present study was to re-investigate effects of cocaine on ir-CART peptide levels in the brain using a 'binge' cocaine paradigm. Male rats were treated with 'binge' cocaine for 14 days (3x15 mg/kg/day, i.p.) . One hour after the final injection, levels of ir-CART were quantified by RIA and immunofluorescence. CART immunoreactivity was detected using polyclonal CART antibody as primary and Cy-3-conjugated donkey anti-rabbit secondary antibody. High levels of expression were found in hypothalamic areas and nucleus accumbens and very low levels in caudate putamen, frontal cortex and cerebellum. 'Binge' cocaine caused an increase in the cerebellum, pons, medulla and paraventricular hypothalamic nucleus. Pro-CART processing in 'binge' cocaine treated rats was compared with controls by Western blot analysis. In untreated rats the dominant peptide in all brain structures is CART 55-102. Data on the ratio between the two forms of peptides in cocaine treated rats will be presented
— id: 92206, year: 2003, vol: 2003, page: ?, stat: Journal Article,

THE THRESHOLD - LOWERING EFFECT OF COCAINE ON LATERAL HYPOTHALAMIC SELF - STIMULATION IS ENHANCED BY THE MELANOCORTIN RECEPTOR AGONIST, MTII
Cabeza de Vaca, S.; Krahne, L. L.; Carr, K. D.
2002 ;2002:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Numerous forms of evidence support a functional association between drug-seeking and ingestive behavior. We recently demonstrated that lateral ventricular injections of the melanocortin receptor agonist, MTII, potentiate the rewarding effect of amphetamine in rats (Cabeza de Vaca, et al., Psychopharm, 2002, 161:77-85). The objective of the present study was to explore the effect of MTII on the rewarding effect of cocaine (3.0 mg/kg, i.p.). Rewarding effects were measured in terms of the lowering of threshold for lateral hypothalamic self-stimulation (LHSS) using a psychophysical rate-frequency method. Results: MTII at 0.5 mg and 1.0 mg doses decreased overnight food intake by 61% and 80%, respectively. These same doses had no effect on LHSS thresholds when administered alone but potentiated the threshold-lowering effect of cocaine by approximately 53% and 67%, respectively. Initial experiments in a microinjection mapping study cast doubt on nucleus accumbens (NAC) as the site of MTII action on cocaine reward. The present results parallel the findings previously reported for another psychostimulant, d-amphetamine
— id: 92209, year: 2002, vol: 2002, page: ?, stat: Journal Article,

The melanocortin receptor agonist MTII augments the rewarding effect of amphetamine in ad-libitum-fed and food-restricted rats
Cabeza de Vaca, Soledad; Kim, Gye-Young; Carr, Kenneth D
2002 Apr;161(1):77-85, Psychopharmacology
RATIONALE: Numerous forms of evidence support a functional association between drug-seeking and ingestive behavior. One example is the augmentation of rewarding and cellular-activating effects of abused drugs by chronic food restriction. Within the past several years, a variety of orexigenic and anorexigenic neuropeptides that mediate adaptive responses to changes in energy balance and body weight have been identified. The involvement of these neuropeptidergic signaling systems in the modulation of drug reward has received little experimental attention. alpha-Melanocyte-stimulating hormone (alpha-MSH) and agouti-related protein, which act as agonist and antagonist, respectively, at melanocortin receptors (MCRs), are of particular interest because of their neuroanatomical distribution and opponent actions at a common receptor type. OBJECTIVES: The objective of this study was to determine whether lateral ventricular (i.c.v.) injections of the MCR agonist MTII and MCR antagonist SHU9119 at doses that decrease and increase food intake, respectively, modify the rewarding effect of amphetamine. METHODS: The rewarding effect of amphetamine was measured in terms of its ability to lower the threshold for lateral hypothalamic self-stimulation (LHSS) using a rate-frequency method. The modulatory effects of MTII and SHU9119 were evaluated by preceding i.c.v. amphetamine injection with i.c.v. injection of one of these MCR ligands or vehicle. Tests were conducted in both ad-libitum-fed and food-restricted subjects. RESULTS: SHU9119, the agouti-related protein-like antagonist, markedly increased overnight food intake of ad-libitum-fm-fed rats following i.c.v. injection of 1.0 microg and 0.5 microg. However, these injections had no effect on thresholds for LHSS tested 25 min or 60 min post-injection, nor did they alter the threshold-lowering effect of amphetamine (50 microg) tested 25 min, 100 min, or 24 h post-injection. MTII, the alpha-MSH-like agonist, suppressed overnight food intake of ad-libitum-fed rats following i.c.v. injection of 1.0 microg. MTII had no effect on thresholds for LHSS tested 60 min post-injection. However, this MCR agonist potentiated the threshold-lowering effect of amphetamine tested 100 min but not 24 h post-injection. This effect was evident in both ad-libitum-fed and food-restricted rats. CONCLUSIONS: These results indicate that agonist activity at MCRs potentiates amphetamine reward and that the anorexigenic neuropeptide alpha-MSH may exert this effect physiologically
— id: 39670, year: 2002, vol: 161, page: 77, stat: Journal Article,

Effects of the D(3) dopamine receptor antagonist, U99194A, on brain stimulation and d-amphetamine reward, motor activity, and c-fos expression in ad libitum fed and food-restricted rats
Carr, K D; Yamamoto, N; Omura, M; Cabeza de Vaca, S; Krahne, L
2002 Aug;163(1):76-84, Psychopharmacology
RATIONALE: Previous studies indicate that the D(3) dopamine (DA) receptor is preferentially expressed in limbic forebrain DA terminal areas and may mediate functional effects opposite those of the D(1) and D(2) receptor types. However, the locations of the D(3) receptors that regulate behavior, and the range of behavioral functions regulated, are not clear. OBJECTIVE: The objective of this study was to evaluate behavioral and cellular effects of the preferential D(3) dopamine receptor antagonist, U99194A. METHODS: In experiment 1, the rewarding effect of U99194A (5.0, 10.0 and 20.0 mg/kg, SC) was measured in terms of its ability to lower the threshold for lateral hypothalamic self-stimulation (LHSS) in ad libitum fed rats. To amplify a possibly weak reward signal, testing was also conducted in food-restricted rats. The ability of U99194A to alter the threshold-lowering effect of d-amphetamine was also assessed. In experiment 2, effects of U99194A on horizontal and vertical motor activity were compared in ad libitum fed and food-restricted rats. In experiment 3, effects of a behaviorally active dose of U99194A (5.0 mg/kg) on brain c-fos expression were measured and compared to those produced by d-amphetamine (0.5 mg/kg, IP). In experiment 4, the motor and cellular activating effects of U99194A were challenged with the D(1) dopamine receptor antagonist, SCH-23390 (0.1 mg/kg). RESULTS: U99194A displayed no rewarding efficacy in the LHSS paradigm. U99194A did, however, augment the rewarding effect of d-amphetamine. U99194A also produced a motor activating effect, reversible by SCH-23390, which was greater in food-restricted than ad libitum fed rats. The pattern and intensity of fos-like immunoreactivity (FLI) induced by U99194A was similar to that produced by d-amphetamine and was blocked, in caudate-putamen and nucleus accumbens, by SCH-23390. CONCLUSIONS: These results indicate that U99194A has psychostimulant-like effects on motor activity and striatal c-fos expression that are dependent upon the D(1) DA receptor. However, doses of U99194A that are adequate to stimulate motor activity and c-fos expression in striatal and limbic structures do not possess direct rewarding effects in the LHSS paradigm. Overall, these results seem consistent with the hypothesis that D(3) antagonism enhances D(1)/D(2) mediated signaling with behavioral effects dependent on both the density of D(3) receptors and the prevailing level of DA transmission in particular brain regions
— id: 39605, year: 2002, vol: 163, page: 76, stat: Journal Article,

Augmentation of drug reward by chronic food restriction. Behavioral evidence and underlying mechanisms
Carr, Kenneth D
2002 Jul;76(3):353-364, Physiology & behavior
Chronic food restriction and maintenance of low body weight have long been known to increase the self-administration and motor-activating effects of abused drugs. Using a lateral hypothalamic self-stimulation (LHSS) rate-frequency method, it is shown that chronic food restriction augments the rewarding (i.e., threshold lowering) effect of diverse drugs of abuse. Further, the effect is attributed to increased sensitivity of a neural substrate, rather than a change in drug bioavailability or pharmacokinetics, because it is preserved when drugs are injected directly into the lateral cerebral ventricle (intracerebroventricularly). The food restriction regimen that augments drug reward also increases the induction of c-fos, by intracerebroventricular amphetamine, in limbic forebrain dopamine (DA) terminal areas. The possibility of increased DA receptor function is suggested by findings that rewarding and motor-activating effects of direct DA receptor agonists are augmented by food restriction, and the augmented behavioral effects of amphetamine are reversed by an otherwise subthreshold dose of D-1 antagonist. Initial studies of DA receptor-mediated signal transduction, that are focused on the D-2 receptor, suggest increased functional coupling between receptor and G-protein (i.e., quinpirole-stimulated [35S]GTPgammaS binding) in dorsal striatum. Unlike behavioral sensitization induced by intermittent stress or psychostimulant treatment, which persist indefinitely following induction, the augmenting effect of food restriction abates within 1 week of restored ad libitum feeding and weight gain. The possible involvement of endocrine hormones and/or 'feeding-related' neuropeptides, whose levels change dynamically with depletion and repletion of adipose stores, is therefore under investigation. Initial tests have been limited to acute treatments aimed at attenuating the effects of hypoinsulinemia, hypoleptinemia and elevated corticosterone levels in food-restricted rats. None of these treatments has attenuated the behavioral effect of food restriction. While a melanocortin receptor agonist has been found to enhance drug reward, melanocortin receptors do not seem to mediate the augmenting effect of food restriction. Continuing investigations of endocrine adiposity signals, 'feeding-related' neuropeptides and dopaminergic signal transduction may further elucidate the way in which drugs of abuse exploit mechanisms that mediate survival-related behavior, and help explain the high comorbidity of drug abuse and eating disorders
— id: 32240, year: 2002, vol: 76, page: 353, stat: Journal Article,

EFFECT OF CHRONIC FOOD RESTRICTION ON QUINPIROLE-STIMULATED (35S)GTPgammaS BINDING IN RAT STRIATUM
Tsimberg, Y.; Berman, Y.; Carr, K.
2002 ;2002:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Chronic food restriction augments the rewarding, motor-and cellular-activating effects of direct and indirect dopamine (DA) agonists injected directly into the brain ventricular system. Neuroadaptations within the brain DA system that may be involved in these effects have yet to be demonstrated. In the present study, rats had ad libitum access to food or were restricted to a single 10 g meal per day until body weight decreased by 20% (approximately 2 weeks). Rats were then maintained for an additional week with body weight of the food-restricted group clamped at this value. Caudate-putamen (CPU) and nucleus accumbens (NAC) were micropunched from frozen coronal brain sections. Stimulation of (35S)GTPgammaS binding in membranes, by the D2/3 DA agonist, quinpirole, was measured using quinpirole concentrations ranging from 30nM to 100muM. The maximal stimulation observed in CPU membranes of ad libitum fed rats was 33.9% over the basal level. In CPU membranes of food-restricted rats, the concentration-response curve was shifted to the left and maximal stimulation increased to 43.9% over the basal level (p<.05). Although quinpirole also produced a concentration-related stimulation of (35S)GTPgammaS binding in NAC membranes, there was no difference between groups. These results suggest that an amplification of D2-mediated signal transduction in CPU may be involved in the augmented behavioral effects of quinpirole and various indirect DA agonists in chronically food-restricted rats
— id: 92210, year: 2002, vol: 2002, page: ?, stat: Journal Article,

Rewarding and locomotor-activating effects of direct dopamine receptor agonists are augmented by chronic food restriction in rats
Carr KD; Kim GY; Cabeza de Vaca S
2001 Apr;154(4):420-428, Psychopharmacology
RATIONALE: Previous studies indicate that chronic food restriction augments the rewarding and motor-activating effects of diverse drugs of abuse. The drugs that have so far proved susceptible to the augmenting effect of food restriction all increase synaptic concentrations of dopamine (DA). It is not known whether behavioral effects of selective, direct DA receptor agonists are also subject to the augmenting effect of food restriction. OBJECTIVES: The first objective of this study was to investigate whether the rewarding and locomotor-activating effects of the D1 agonist, A77636, and the D2 agonist, quinpirole are augmented by chronic food restriction. The second purpose was to investigate whether the augmented rewarding and locomotor-activating effects of d-amphetamine in food-restricted rats are reversed by the D1 antagonist, SCH23390. METHODS: Rewarding effects of drugs were measured in terms of their ability to lower the threshold for lateral hypothalamic self-stimulation (LHSS) using a rate-frequency method. Locomotor-activating effects were measured in terms of the number of midline crossings exhibited by rats in a shuttle apparatus. RESULTS: A77636 (1.0 and 2.5 mg/kg, i.p.) produced a greater threshold-lowering effect in food-restricted than ad libitum fed rats but produced variable effects on locomotor activity with no difference between groups. Quinpirole (0.2 and 0.5 mg/kg, i.p.) produced a marginally greater threshold-lowering effect in food-restricted rats and a dramatic locomotor response that was exclusive to food-restricted rats. The D1 antagonist, SCH23390, at a dose of 0.01 mg/kg (i.p.), had no effect on the lowering of LHSS threshold by amphetamine (0.5 mg/kg, i.p.) in ad libitum fed rats but blocked the augmentation otherwise observed in food-restricted rats. SCH23390, at a dose of 0.025 mg/kg, had no effect on locomotor activity induced by amphetamine (0.5 mg/kg) in ad libitum fed rats but blocked the augmentation otherwise observed in food-restricted rats. CONCLUSIONS: These results indicate that the augmentation of reward by food restriction extends to drugs that bypass the DA terminal and act postsynaptically. When taken together with prior immunohistochemical and behavioral findings, these results suggest that food restriction may increase the 'enabling' effect of the D1 receptor on DA-mediated behaviors
— id: 20668, year: 2001, vol: 154, page: 420, stat: Journal Article,

Repeated treatment with antidepressants differentially alters 5-HT1A agonist-stimulated (35S)GTPgammaS binding in rat brain regions
Shen, C. P.; Carr, K. D.; Meller, E.
2001 ;27(1):995-995, Abstracts (Society for Neuroscience)
Electrophysiological studies suggest that drug therapy of anxiety/depression involves regionally-specific changes in 5-HT1A receptor sensitivity. Furthermore, the purported net effect of clinically-relevant repeated drug treatment is enhancement of hippocampal 5-HT neurotransmission. Depending on the drug, decreased sensitivity of inhibitory somatodendritic autoreceptors, increased sensitivity of postsynaptic hippocampal receptors, or both, occurs after 2-3 weeks of treatment. This hypothesis was tested using autoradiographic analysis of agonist-stimulated (35S)GTPgammaS binding. Groups of rats were treated with saline, fluoxetine, 10; imipramine, 10; clorgyline, 1; or ipsapirone, 2X20 mg/kg for 21 days and sacrificed on day 22. Quadruplicate serial sections were incubated under standard conditions as described previously (JPET 292:684, 2000) in the presence or absence of 3 muM N,N-dipropyl-5-carboxamidotryptamine. Three brain regions were examined: dorsal raphe (DR; somatodendritic), and dorsal hippocampus (DH) and lateral septum (LS) (postsynaptic). Only imipramine (+17%) and (unexpectedly) fluoxetine (+54%) significantly increased agonist-stimulated binding in DH. All drugs except imipramine decreased binding in DR (-20 to -40%). While the results support the concept of net enhancement of hippocampal 5-HT neurotransmission, the pattern of changes in receptor sensitivity differed somewhat from the results of electrophysiological studies. The most consistent and striking effect, however, was a decrease in (35S)GTPgammaS binding in the LS by all four drug treatments (-14 to -23%), a finding previously reported also after chronic buspirone treatment
— id: 92211, year: 2001, vol: 27, page: 995, stat: Journal Article,

Hypoinsulinemia may mediate the lowering of self-stimulation thresholds by food restriction and streptozotocin-induced diabetes
Carr KD; Kim G; Cabeza de Vaca S
2000 Apr 28;863(1-2):160-168, Brain research
7 days beyond cessation of insulin treatment) elevation of threshold in ad libitum fed rats and, more transiently, reversed the threshold-lowering effect of food restriction. Acute insulin treatment (3 mU, 15 min prior) also elevated threshold in food-restricted rats. These results are consistent with the hypothesis that insulin modulates sensitivity of a brain reward system and that hypoinsulinemia may be the common factor in food restriction and diabetes that accounts for the enhancement of perifornical LHSS
— id: 11742, year: 2000, vol: 863, page: 160, stat: Journal Article,

Chronic food restriction in rats augments the central rewarding effect of cocaine and the delta1 opioid agonist, DPDPE, but not the delta2 agonist, deltorphin-II
Carr KD; Kim GY; Cabeza de Vaca S
2000 Oct;152(2):200-207, Psychopharmacology
RATIONALE: Chronic food restriction augments the self-administration and locomotor stimulating effects of opiates, psychostimulants and NMDA antagonists. The extent to which these effects can be attributed to changes in drug pharmacokinetics and bioavailability versus sensitivity of the neuronal circuits that mediate the affected behavioral functions, has not been established. Recent studies point to central adaptive changes insofar as rewarding, locomotor and c-fos-inducing effects of amphetamine and MK-801, injected directly into the lateral ventricle, are greater in food-restricted than ad libitum fed rats. The increased expression of c-fos in nucleus accumbens (NAC) shell, in particular, suggests that food restriction may augment drug reward by modulating dopamine (DA) synaptic function in this area. OBJECTIVES: The first purpose of this study was to investigate whether the rewarding effects of cocaine and the delta1 opioid agonist DPDPE, both of which increase DA synaptic transmission, are augmented by food restriction. The second purpose was to determine whether the delta2 opioid agonist, deltorphin-II, which has been reported to exert DA-independent rewarding effects, is subject to the potentiating effect of food restriction. METHODS: Rewarding effects of drugs were measured in terms of their ability to lower the threshold for lateral hypothalamic self-stimulation (LHSS) using a rate-frequency method. RESULTS: In separate experiments, cocaine (50, 100 and 150 microg, ICV) and DPDPE (10 and 25 microg, ICV) produced greater threshold-lowering effects in food-restricted than ad libitum fed rats. Deltorphin-II (5.0, 10 and 25 microg, ICV) had no effect on reward thresholds, regardless of feeding regimen. CONCLUSIONS: While the reported DA-independence of deltorphin-II rewarding effects seemed to offer a means of testing the hypothesis that DA transmission is the critical modulated variable in food-restricted subjects, rewarding effects of this compound could not be demonstrated in the LHSS paradigm. The present results do, however, confirm and extend prior findings indicating that the enhanced self-administration of abused drugs by food-restricted subjects is due to enhanced sensitivity of a final common pathway for drug reward
— id: 39527, year: 2000, vol: 152, page: 200, stat: Journal Article,

Chronic food restriction increases fos-like immunoreactivity (FLI) induced in rat forebrain by intraventricular amphetamine
Carr KD; Kutchukhidze N
2000 Apr 7;861(1):88-96, Brain research
Chronic food restriction enhances behavioral responsiveness to amphetamine and other abused drugs. Because this effect is evident when drugs are administered intracerebroventricularly (i.c.v.) as well as systemically, it would seem to reflect increased sensitivity of a neural substrate rather than a change in drug disposition. In the present study, c-Fos immunohistochemistry was used to evaluate whether the magnitude and pattern of cellular activation induced by i.c.v. amphetamine is altered by a regimen of food restriction previously shown to potentiate amphetamine reward. In the absence of amphetamine challenge, there was generally no difference in brain Fos-like immunoreactivity (FLI) between ad libitum fed and food-restricted rats. In response to amphetamine (50 microg), both groups displayed increased FLI in caudate-putamen, nucleus accumbens, bed nucleus of the stria terminalis, ventral pallidum, central nucleus of the amygdala, and cingulate cortex. With the exception of cingulate cortex and caudal caudate-putamen, a significantly greater response was observed in brain regions of food-restricted rats. These results indicate that food restriction augments a cellular immediate early gene (IEG) response to acute amphetamine in brain regions known to mediate rewarding and other behavioral effects of psychostimulants. The difference between these results and those produced by sensitizing regimens of psychostimulant exposure are discussed, as are possible endocrine factors that could be involved in the modulatory effect of food restriction on cellular and behavioral responses to amphetamine
— id: 11773, year: 2000, vol: 861, page: 88, stat: Journal Article,

Effect of chronic food restriction on Fos-like immunoreactivity (FLI) induced in rat brain regions by intraventricular MK-801
Carr KD; Kutchukhidze N
2000 Aug 11;873(2):283-286, Brain research
The noncompetitive NMDA antagonist, MK-801, produces stimulant and rewarding effects that are mediated by a combination of dopamine-dependent and -independent mechanisms. It was recently demonstrated that, similar to amphetamine, the rewarding and locomotor effects of intraventricular (i.c.v.) MK-801 are potentiated by chronic food restriction. Because food restriction also increases c-Fos expression induced by i.c.v. amphetamine in several subcortical dopamine (DA) terminal areas, Fos-like immunoreactivity (FLI) induced by i.c.v. MK-801 was evaluated in an effort to identify responses that are common to amphetamine and MK-801 and similarly augmented by food restriction. Unlike amphetamine, MK-801 did not increase FLI in caudate-putamen, bed nucleus of the stria terminalis, or ventral pallidum. Similar to amphetamine, MK-801 increased FLI in cingulate cortex, central nucleus of the amygdala and nucleus accumbens (NAC) core, but in none of these areas was the response augmented by food restriction. In medial prefrontal cortex, retrosplenial cortex, and NAC shell, however, MK-801 induced FLI that was augmented by food restriction. An effect that is common to amphetamine and MK-801 is the augmentation of FLI by food restriction in NAC shell. It is therefore suggested that increased releasability of DA, or upregulation of the D-1 receptor linked signal transduction pathway, in NAC shell may mediate the enhanced behavioral sensitivity of food-restricted subjects to drugs of abuse
— id: 11562, year: 2000, vol: 873, page: 283, stat: Journal Article,

Effects of chronic food restriction on locomotion, reward and c-fos expression induced by D-1 and D-2 dopamine agonists
Carr, K. D.; Cabeza de Vaca, S.; Kutchukhidze, N.; Kim, G. Y.
2000 ;26(1-2):?-?, Abstracts (Society for Neuroscience)
Chronic food restriction (FR) augments the locomotor and rewarding effects of abused drugs (Cabeza de Vaca and Carr, J. Neurosci. 18:7502,1998). FR also augments the induction of c-fos by amphetamine in nucleus accumbens, central nucleus of the amygdala (CEA) and bed nucleus of the stria terminalis (BNST) (Carr and Kutchukhidze, Brain Res. 861:88, 2000). Because all drugs tested to date, whose rewarding effects are augmented by FR, directly or indirectly stimulate dopamine (DA) release, the c-fos findings suggest that FR may augment behavioral responses by enhancing DA releasability in one or more DA terminal regions. The purpose of this study was to test whether direct DA receptor agonists are exempt from the effect of FR. In Exp. 1, the D-2 agonist quinpirole (0.2 and 0.5 mg/kg, i.p.) produced a dramatic locomotor response in FR rats and no response in ad libitum fed controls. The D-1 agonist A77636 (1.0 and 2.5 mg/kg, i.p.) did not differentially affect the two groups. In Exp. 2, the rewarding effect of A77636 (1.0 and 2.5 mg/kg, i.p.), assessed in a self-stimulation rate-frequency paradigm, was greater in FR rats than controls. The rewarding effect of quinpirole (0.2 and 0.5 mg/kg, i.p.) displayed only a trend in that direction. In Exp. 3, quinpirole (0.5 mg/kg, i.p.) induced fos-like immunoreactivity (FLI) in globus pallidus, BNST, and CEA; the response in CEA was augmented by FR. The behavioral results indicate that augmentation of rewarding/stimulant drug effects by FR may be mediated, at least in part, by postsynaptic DA mechanisms. The immunohistochemical results suggest that augmented transsynaptic effects of quinpirole on cellular activity in CEA may be involved in the locomotor response to this drug in FR rats
— id: 92212, year: 2000, vol: 26, page: ?, stat: Journal Article,

5-Hydroxytryptamine(1A) receptor-stimulated [(35)S]GTPgammaS binding in rat brain: absence of regional differences in coupling efficiency
Meller E; Li H; Carr KD; Hiller JM
2000 Feb;292(2):684-691, Journal of pharmacology & experimental therapeutics
In hippocampal membranes, the selective 5-hydroxytryptamine (5-HT(1A)) receptor agonists 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) and N,N-dipropyl-5-carboxamidotryptamine (N,N-DP-5-CT) stimulated guanosine-5'-O-(3-thio)triphosphate ([(35)S]GTPgammaS) binding by 130 to 140%; binding stimulated by nonselective agonists (5-HT and 5-CT) was approximately 30% greater. However, the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohex anecarboxamide (WAY100,635) completely abolished the increases produced by 8-OH-DPAT and N,N-DP-5-CT but only eliminated 70% of that elicited by 5-CT. The rank potency order of the tested agonists was identical with their rank order of affinity for 5-HT(1A) receptors [5-CT congruent with N,N-DP-5-CT > R-(+)-8-OH-DPAT > 5-HT > ipsapirone]. Racemic 8-OH-DPAT and the partial agonist ipsapirone exhibited lower intrinsic activity than R-(+)-8-OH-DPAT. R-(+)-8-OH-DPAT also stimulated [(35)S]GTPgammaS binding in cortex, but not in striatum, which lacks 5-HT(1A) receptors. Partial irreversible inactivation of 5-HT(1A) receptors, in vitro with phenoxybenzamine (0.3 or 1 microM) or in vivo with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (1 mg/kg), reduced the maximal response produced by R-(+)-8-OH-DPAT but did not alter its EC(50). In autoradiographic sections, R-(+)-8-OH-DPAT stimulated [(35)S]GTPgammaS binding in 5-HT(1A) receptor-rich regions (dorsal hippocampus, 123%; lateral septum, 111%; midhippocampus, 110%; dorsal raphe nucleus, 83%; medial prefrontal cortex, approximately 60%). The EC(50) of R-(+)-8-OH-DPAT did not vary significantly among brain regions (46-96 nM). Partial irreversible blockade of 5-HT(1A) receptors in brain sections (phenoxybenzamine, 10 microM) reduced the maximal response without altering the EC(50) in both the hippocampus and dorsal raphe. Despite prior evidence that dorsal raphe somatodendritic 5-HT(1A) autoreceptors exhibit high receptor/effector coupling efficiency (receptor reserve) compared with postsynaptic receptors in hippocampus, there was no evidence of a difference at the level of receptor/G protein coupling
— id: 11861, year: 2000, vol: 292, page: 684, stat: Journal Article,

CRF antagonist reverses the potentiation of amphetamine reward by food restriction
Cabeza de Vaca, S.; Carr, K. D.
1999 ;25(1-2):2082-2082, Abstracts (Society for Neuroscience)
— id: 92213, year: 1999, vol: 25, page: 2082, stat: Journal Article,

Differential effects of mu and kappa opioid antagonists on Fos-like immunoreactivity in extended amygdala
Carr KD; Kutchukhidze N; Park TH
1999 Mar 20;822(1-2):34-42, Brain research
It was previously reported that systemic administration of the nonselective opioid antagonist, naltrexone, induces Fos-like immunoreactivity (FLI) within the central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (lateral-dorsal division; BSTLD), nucleus accumbens shell (NACshell) and ventral tegmental area (VTA) of free-feeding rats. These findings suggest that cellular activity in these brain regions is subject to opioid-mediated inhibitory control under basal conditions. Considering the involvement of mesoaccumbens dopamine neurons and components of the 'extended amygdala' in motivated behavior and reward, it was hypothesized that the induction of c-Fos by naltrexone accounts for the motivational-affective consequences of opioid antagonism. In Experiment 1, naltrexone was administered intracerebroventricularly (i.c.v.; 100 microg) to determine whether results obtained in the prior immunohistochemical studies could be attributed to blockade of opioid receptors in brain as opposed to peripheral tissues that convey visceral sensory inputs to the CeA and BSTLD. Naltrexone produced a marked increase in FLI within the CeA and BSTLD, and a moderate increase in NACshell. In Experiment 2, the kappa opioid antagonist, nor-binaltorphimine (Nor-BNI; 20.0 microg, i.c.v.) reproduced the effect of naltrexone in BSTLD and CeA, suggesting that the induction of c-Fos in these two structures is a consequence of kappa receptor blockade. The selective mu antagonist, CTAP (2.0 microg, i.c.v.), reproduced the effect of naltrexone in NACshell, suggesting that the induction of c-Fos in this structure is a consequence of mu receptor blockade. The functional implications of these results are discussed in terms of the known functions of these brain regions and opioid receptor types, and the prior observation that chronic food restriction eliminates the FLI induced by naltrexone in CeA and BSTLD. It is suggested that tonic mu opioid-mediated inhibition in NACshell has a predisposing effect on goal-approach behavior in general while kappa opioid-mediated inhibition in CeA and BSTLD has a predisposing effect on palatability-driven feeding in particular. Finally, a possible relationship between food restriction-induced suppression of the kappa opioid mechanism in CeA/BSTLD, local CRH function, and sensitization of the neural substrate for incentive-motivating effects of abused drugs is discussed.
— id: 6063, year: 1999, vol: 822, page: 34, stat: Journal Article,

Increased site-specific phosphorylation of tyrosine hydroxylase accompanies stimulation of enzymatic activity induced by cessation of dopamine neuronal activity
Lew JY; Garcia-Espana A; Lee KY; Carr KD; Goldstein M; Haycock JW; Meller E
1999 Feb;55(2):202-209, Molecular pharmacology
Activation of striatal dopamine (DA) neurons by neuroleptic treatment or by electrical stimulation of the nigrostriatal pathway increases the activity of tyrosine hydroxylase (TH). The increase is mediated by phosphorylation of the enzyme. However, abolition of DA neuronal activity [by gamma-butyrolactone (GBL) treatment or transection of the nigrostriatal pathway] also increases TH activity. Quantitative blot immunolabeling experiments using site- and phosphorylation state-specific antibodies to TH demonstrated that GBL treatment (750 mg/kg, 35 min) significantly increased phosphorylation at Ser19 (+40%) and Ser40 (+217%) without altering Ser31 phosphorylation. Concomitantly, GBL treatment [along with the 3,4-dihydroxyphenylalanine (dopa) decarboxylase inhibitor NSD-1015, 100 mg/kg, 30 min] increased in vivo striatal dopa accumulation and in vitro TH activity 3-fold. Likewise, cerebral hemitransection of the nigrostriatal pathway significantly increased phosphorylation of TH at Ser19 (+89%) and Ser40 (+158%) but not at Ser31; dopa levels were increased accordingly (+191%). Kinetic analysis of TH activity established that GBL treatment and hemitransection primarily decreased the Km for the cofactor tetrahydrobiopterin (3-fold). The effects of GBL and hemitransection were abolished or attenuated by pretreatment with the DA agonist R-(-)-N-n-propylnorapomorphine (NPA; 30 microgram/kg, 40 min), presumably via stimulation of inhibitory presynaptic DA autoreceptors. NPA dose-response curves for reversal of GBL-induced dopa accumulation and Ser40 phosphorylation were identical; however, only the highest dose of NPA reversed the small and variable increase in Ser19 phosphorylation. Thus, TH activity seems to be regulated by phosphorylation in both hyper- and hypoactive striatal DA neurons; in the latter case, activation seems to be caused by selective phosphorylation of Ser40
— id: 7388, year: 1999, vol: 55, page: 202, stat: Journal Article,

Cloning and characterization of a mu opioid receptor from bovine brain
Onoprishvili, I.; Andria, M. L.; Vilim, S. S.; Hiller, J. M.; Carr, K. D.; Simon, E. J.
1999 ;25(1-2):1476-1476, Abstracts (Society for Neuroscience)
— id: 92214, year: 1999, vol: 25, page: 1476, stat: Journal Article,

Food restriction enhances the central rewarding effect of abused drugs
Cabeza de Vaca S; Carr KD
1998 Sep 15;18(18):7502-7510, Journal of neuroscience
Chronic food restriction increases the systemic self-administration and locomotor-stimulating effect of abused drugs. However, it is not clear whether these behavioral changes reflect enhanced rewarding potency or a CNS-based modulatory process. The purpose of this study was to determine whether food restriction specifically increases the rewarding potency of drugs, as indexed by their threshold-lowering effect on lateral hypothalamic self-stimulation, and whether any such effect can be attributed to an enhanced central response rather than changes in drug disposition. When drugs were administered systemically, food restriction potentiated the threshold-lowering effect of amphetamine (0.125, 0.25, and 0.5 mg/kg, i.p.), phencyclidine (1.0, 2.0, and 3.0 mg/kg, i.p.), and dizocilpine (MK-801) (0.0125, 0.05, and 0.1 mg/kg, i.p.) but not nicotine (0.15, 0.3, 0.45 mg/kg, s.c.). When amphetamine (25.0, 50.0, and 100.0 microgram) and MK-801 (5.0, 10.0, and 20.0 microgram) were administered via the intracerebroventricular route, food restriction again potentiated the threshold-lowering effects and increased the locomotor-stimulating effects of both drugs. These results indicate that food restriction increases the sensitivity of neural substrates for rewarding and stimulant effects of drugs. In light of work that attributes rewarding effects of MK-801 to blockade of NMDA receptors on medium spiny neurons in nucleus accumbens, the elements affected by food restriction may lie downstream from the mesoaccumbens dopamine neurons whose terminals are the site of amphetamine-rewarding action. Possible metabolic-endocrine triggers of this effect are discussed, as is the likelihood that mechanisms mediating the modulatory effect of food restriction differ from those mediating sensitization by intermittent drug exposure
— id: 8024, year: 1998, vol: 18, page: 7502, stat: Journal Article,

A search for the metabolic signal that sensitizes lateral hypothalamic self-stimulation in food-restricted rats
Cabeza De Vaca S; Holiman S; Carr KD
1998 Jun 1;64(3):251-260, Physiology & behavior
Food deprivation and restriction increase the rewarding potency of food, drugs of abuse, and electrical brain stimulation. Based on evidence that the rewarding effects of these stimuli are mediated by the same neuronal circuitry, lateral hypothalamic self-stimulation (LHSS) was used to investigate the involvement of various metabolic signals in the sensitization of reward. In Experiment 1, glucoprivation with 2-deoxy-d-glucose (150 mg/kg, intraperitoneally (i.p.)) and lipoprivation with nicotinic acid (150 mg/kg, subcutaneously (s.c.)), individually and in combination, failed to affect the LHSS threshold in ad lib.-fed rats. These results suggest that signals associated with acute shortage of metabolic substrate do not sensitize reward. Because numerous responses to more prolonged negative energy balance are mediated by neuropeptide Y (NPY), the effect of exogenous neuropeptide Y upon LHSS was investigated in Experiment 2. Intraventricular infusion of orexigenic neuropeptide Y doses (2.0, 5.0, and 12.5 g), in ad lib.-fed rats, had no effect on LHSS threshold. In Experiment 3, other concomitants of prolonged negative energy balance--high circulating levels of free fatty acids (FFA) and beta-hydroxybutyrate (HDB)-were investigated. Nicotinic acid (250 mg/kg, s.c.), which suppressed serum HDB and FFA levels, had no effect on LHSS in food-restricted or ad lib.-fed rats. Mercaptoacetate (68.4 mg/kg, i.p.), which suppressed serum HDB levels and exacerbated the elevation of FFA levels, also had no effect. Thus, the brain reward system, if modulated by these substances, is not affected by transient, though marked, changes in their levels. To investigate the effect of a sustained increase in levels of FFA and HDB, a 'ketogenic' diet was employed. Although this diet produced a fourfold increase in serum HDB levels, it had no effect on LHSS thresholds. Moreover, the failure of mercaptoacetate (68.4 mg/kg, i.p.) to decrease LHSS thresholds in these rats supports the conclusion that acute shortage of metabolic substrate does not sensitize reward. Other possible mechanisms of reward sensitization, including sustained decreases in circulating insulin and leptin and increases in corticosterone, are discussed
— id: 8025, year: 1998, vol: 64, page: 251, stat: Journal Article,

Food restriction sensitizes the neural substrate for drug reward
Cabeza De Vaca, S.; Carr, K. D.
1998 ;24(1-2):1964-1964, Abstracts (Society for Neuroscience)
— id: 92215, year: 1998, vol: 24, page: 1964, stat: Journal Article,

Effect of adrenalectomy on cocaine facilitation of medial prefrontal cortex self-stimulation
Carr KD; Abrahamsen GC
1998 Mar 23;787(2):321-327, Brain research
Adrenalectomy (ADX) is known to block the acquisition of intravenous cocaine self-administration. A previous study therefore examined whether ADX decreases sensitivity of the 'brain reward system' in general, or its response to cocaine in particular, by measuring thresholds for intracranial self-stimulation with and without concurrent cocaine administration. ADX had no effect on thresholds for lateral hypothalamic self-stimulation (LHSS) and did not alter the cocaine dose-response curve for lowering the LHSS threshold. This result suggested that ADX does not affect sensitivity of the brain reward system. However, medial prefrontal cortex (MPFC) appears to be an important site in the mediation of cocaine reinforcing effects, and MPFC self-stimulation (MPFCSS) is mediated by a neural substrate that is largely independent of that which mediates LHSS. The present study therefore assessed whether ADX diminishes cocaine facilitation of MPFCSS. It was found that the threshold-lowering effect of cocaine (5.0, 10.0 and 20.0 mg/kg, i.p. ) did not differ between ADX rats maintained on 0.7% saline, ADX rats maintained on corticosterone (50 microg/ml) in 0.7% saline, and sham-operated controls. However, there was a trend toward desensitization of MPFCSS, itself, following ADX in the group that did not receive corticosterone supplementation. Based on this observation, and the similar responses of MPFCSS and cocaine self-administration to noncontingent priming stimulation, stress, and NMDA receptor antagonism, it is speculated that acquisition of MPFCSS and cocaine self-administration may be dependent upon a common sensitization process that is regulated by corticosterone.
— id: 7523, year: 1998, vol: 787, page: 321, stat: Journal Article,

Neuroanatomical patterns of Fos-like immunoreactivity induced by naltrexone in food-restricted and ad libitum fed rats
Carr KD; Park TH; Zhang Y; Stone EA
1998 Jan 1;779(1-2):26-32, Brain research
Chronic food restriction produces a variety of adaptive changes in physiology and behavior aimed at the preservation of energy homeostasis. The brain opioid system may be involved in the adaptation to food restriction since regional levels of opioid peptides, precursor mRNA, and receptor binding have previously been observed. In the present study, c-Fos immunohistochemistry was used to localize cells that are released from opioid-mediated inhibition by naltrexone under conditions of food restriction and ad libitum feeding. In the majority of hypothalamic and forebrain areas examined, Fos-like immunoreactivity (FLI) was higher in food-restricted rats regardless of injection treatment. This may reflect the persistent stress of underfeeding or the synchronizing effect of afternoon feeding on spontaneous c-fos mRNA expression in food-restricted rats. In two brain regions, bed nucleus of the stria terminalis (BNST) and central amygdala (CEA), naltrexone increased FLI in ad libitum fed rats, exclusively. This result suggests the presence of tonic opioid secretion under basal conditions that is suppressed by food restriction. Interestingly, work in other laboratories indicates that anorectic agents consistently increase FLI in BNST and CEA. In three brain regions--lateral (LH), dorsomedial (DMH) and arcuate hypothalamus (ARC)--naltrexone increased FLI in food-restricted rats, exclusively. This result suggests the presence of opioid secretion that is unique to the state of food restriction. The hypothalamic pattern of FLI is discussed in terms of NPY-opioid interactions that result from the ARC response to changes in circulating insulin, corticosterone and leptin levels during food restriction
— id: 7524, year: 1998, vol: 779, page: 26, stat: Journal Article,

Effects of an intrahypothalamic injection of antisense oligonucleotides for preproenkephalin mRNA in female rats: evidence for opioid involvement in lordosis reflex (vol 777, pg 60, 1997)
Nicot, A; Ogawa, S; Berman, Y; Carr, KD; Pfaff, DW
1998 NOV 2 ;809(2):337-337, Brain research
— id: 53680, year: 1998, vol: 809, page: 337, stat: Journal Article,

Neuroanatomical patterns of fos-like immunoreactivity induced by a palatable meal and meal-paired environment in saline- and naltrexone-treated rats
Park TH; Carr KD
1998 Sep 14;805(1-2):169-180, Brain research
Opioid antagonists block the positive hedonic response to food taste and are potent inhibitors of palatability-driven feeding. However, the specific brain regions within which opioid peptide secretion contributes to the maintenance of palatability-driven feeding have not been clearly established. In the present study, c-Fos immunohistochemistry was used to identify regions rostral to the hindbrain that display cellular activation in response to a palatable meal and the meal-paired environment. Further, it was determined whether any of the cellular responses could be prevented by pretreating animals with naltrexone. Twenty brain regions known to be involved in gustation, appetite and reward functions were examined. Ingestion of the palatable meal (3.0 g of 30% shortening, 20% sucrose and 50% powdered Purina rat chow) increased Fos-like immunoreactivity (FLI) in lateral hypothalamus (LH), ventral tegmentum (VTA) and medial preoptic area (MPOA), and decreased FLI in the habenula (Hab). The meal-paired environment increased FLI in the VTA and nucleus accumbens shell (NAC shell). Naltrexone (1.0 mg/kg, i.p.) did not block consumption of the small meal but did prevent all of the distinctive increases in FLI induced by the meal and meal-paired environment. Since naltrexone, alone, increased FLI in VTA, NAC shell, central amygdala (ceA) and laterodorsal bed nucleus of the stria terminalis (BSTLD), the blunting of ingestion reward by naltrexone may result from direct or transsynaptic activating effects on opponent neuronal activity within this highly interconnected set of structures that mediate and modulate reward.
— id: 7422, year: 1998, vol: 805, page: 169, stat: Journal Article,

Neuroanatomical patterns of Fos-like immunoreactivity induced by a palatable meal and meal-paired environment in saline- and naltrexone-treated rats
Park, T. H.; Carr, K. D.
1998 ;24(1-2):706-706, Abstracts (Society for Neuroscience)
— id: 92216, year: 1998, vol: 24, page: 706, stat: Journal Article,

Effect of adrenalectomy on cocaine facilitation of lateral hypothalamic self-stimulation
Abrahamsen GC; Carr KD
1997 Apr 25;755(1):156-161, Brain research
An emerging body of evidence indicates that the adrenal hormone corticosterone modulates behavioral effects of abused drugs. Recently, it was reported that the self-administration and locomotor stimulatory effect of cocaine are blocked by adrenalectomy (ADX). In order to evaluate the effect of ADX on the brain reward system in general, and cocaine reward in particular, the effect of ADX on lateral hypothalamic self-stimulation (LHSS) and its facilitation by cocaine were investigated. Using curve-shift methodology, effects of cocaine (1.0, 3.0 and 10.0 mg/kg, i.p.) on the rewarding efficacy of brain stimulation were determined in ADX rats, with and without corticosterone supplementation, and compared with sham-operated controls. Results indicate that ADX does not affect LHSS or the facilitatory effect of cocaine. The divergence between these results and the results of cocaine self-administration studies is discussed in terms of the neuroanatomical and psychological processing of reward
— id: 7097, year: 1997, vol: 755, page: 156, stat: Journal Article,

Aminoglutethimide, a corticosteroid synthesis inhibitor, facilitates brain stimulation reward in food-restricted rats: an investigation of underlying mechanisms
Abrahamsen GC; Kandawire MJ; Carr KD
1997 Oct;133(4):405-412, Psychopharmacology
It was previously observed that the corticosteroid synthesis inhibitor, aminoglutethimide (AG), markedly facilitates lateral hypothalamide (AG), markedly facilitates lateral hypothalamic self-stimulation (LHSS) in food-restricted rats. This effect is not present 30 min after injection when plasma corticosterone levels are suppressed, but rather at 2 h when corticosterone has recovered from suppression. In experiment 1, it was confirmed that AG (50.0 mg/kg, s.c.) lowers the threshold for LHSS in food-restricted rats but not in control rats that have ad libitum access to food. This effect occurred independently of whether food restriction, by itself, lowered threshold. Experiment 2 examined whether the facilitation of LHSS coincides with biosynthetic rebound of corticosteroid precursors. While a pregnenolone surge was demonstrated by radioimmunoassay, dose-response testing with exogenous pregnenolone and progesterone (0.1, 1.0 and 10.0 mg/kg, s.c.) failed to confirm the prediction that one of these precursors facilitates reward. Therefore, a general test of the involvement of adrenocortical biosynthetic events was conducted in experiment 3 where rats were adrenalectomized (ADX) or sham-operated prior to food restriction. Surprisingly, ADX did not diminish the effect of AG. This finding raises the possibility of a CNS, rather than adrenal, site of action. AG is known to penetrate the blood-brain barrier and exert weak anticonvulsant effects. The facilitation of reward may result from central inhibitory effects of the drug and share a common basis with the enhanced reinforcing potency of other CNS depressants in food-restricted rats
— id: 12179, year: 1997, vol: 133, page: 405, stat: Journal Article,

Effect of adrenalectomy on cocaine's facilitation of medial prefrontal cortex self-stimulation
Abrahamsen, G. C.; Ladigoski, J. M.; Carr, K. D.
1997 ;23(1-2):2146-2146, Abstracts (Society for Neuroscience)
— id: 92217, year: 1997, vol: 23, page: 2146, stat: Journal Article,

Chronic food restriction and streptozotocin-induced diabetes differentially alter prodynorphin mRNA levels in rat brain regions
Berman Y; Devi L; Spangler R; Kreek MJ; Carr KD
1997 Jun;46(1-2):25-30, Brain research. Molecular brain research
It was previously reported that chronic food restriction and streptozotocin-induced diabetes lead to brain region-specific changes in levels of Prodyn-derived peptides. These changes parallel behavioral adaptations that are reversed by opioid antagonists. In the present study, effects of food restriction and diabetes on Prodyn gene expression were measured in rat brain regions using a quantitative solution hybridization mRNA assay. Picogram amounts of Prodyn mRNA were determined in extracts of five brain regions. The highest density of Prodyn mRNA was observed in extracts of nucleus accumbens (4.68 pg/microg total RNA), bed nucleus of the stria terminalis (4.18 pg/microg), and in caudate nucleus (3.51 pg/microg). Lower levels were observed in the lateral hypothalamus (1.87 pg/microg) and central nucleus of the amygdala (1.22 pg/microg). Food restriction and diabetes both markedly increased the levels of Prodyn mRNA in the central amygdala (163% and 93%, respectively). Levels in the lateral hypothalamus were also increased (35% and 29%, respectively), though only the food-restriction effect was statistically significant. Neither treatment altered prodynorphin mRNA levels in the caudate nucleus, nucleus accumbens or bed nucleus of the stria terminalis. These results suggest that dynorphin neurons in central amygdala and lateral hypothalamus may be involved in behavioral or physiological adaptations to sustained metabolic need
— id: 7114, year: 1997, vol: 46, page: 25, stat: Journal Article,

C-fos activation by naltrexone in food-restricted and ad libitum fed rats
Carr, K. D.; Park, T. H.; Zhang, Y.; Stone, E. A.
1997 ;23(1-2):517-517, Abstracts (Society for Neuroscience)
— id: 92218, year: 1997, vol: 23, page: 517, stat: Journal Article,

Effects of an intrahypothalamic injection of antisense oligonucleotides for preproenkephalin mRNA in female rats: evidence for opioid involvement in lordosis reflex [published erratum appears in Brain Res 1998 Nov 2;809(2):337]
Nicot A; Ogawa S; Berman Y; Carr KD; Pfaff DW
1997 Nov 28;777(1-2):60-68, Brain research
Previous studies in female rats have shown that estrogen increases preproenkephalin (PPE) mRNA levels in the ventrolateral part of the ventromedial nucleus of the hypothalamus (VMHVL), an area implicated in the modulation of sexual behavior. In order to assess the physiological role of hypothalamic opioid expression in lordosis reflex 16-mer oligodeoxynucleotide (ODN) directed towards the PPE mRNA were acutely microinjected above the VMH of estradiol-primed ovariectomized rats. Estradiol-induced lordosis behavior was observed in response to a stud male 2 days thereafter. Antisense (without or with 4 mismatches) ODN injections near the VMHVL resulted in a significant reduction in lordosis quotient compared to control (reverse sense) ODN treatment or to antisense ODN injections targeted anterior or posterior to the VMHVL. In contrast, locomotor activity of these animals in the open-field test was not affected by ODN treatments. Enkephalin immunoreactive levels were determined by radioimmunoassay in the preoptic area, a major terminal field of the VMHVL. Estradiol-induced enkephalin levels were greatly reduced in antisense-treated groups. Using the in situ hybridization technique, PPE mRNA levels in the VMHVL were also determined. A 1.5-2-fold increase in PPE mRNA levels was observed in estradiol-treated rats compared to ovariectomized rats as previously described. This increase in PPE mRNA levels was not affected by ODN treatment, suggesting that the reduction of enkephalin expression was mainly due to physical blockade of PPE mRNA translation and not to its degradation. Taken together, these data further support the behavioral role of PPE expressing VMHVL neurons. They also highlight the in vivo potency of acute administration of antisense phosphorothioate ODNs in blocking neuronal target gene expression
— id: 7710, year: 1997, vol: 777, page: 60, stat: Journal Article,

Blockade of estradiol-induced hypothalamic enkephalin expression by antisense oligonucleotides reduces lordosis reflex in female rats
Nicot, A.; Ogawa, S.; Berman, Y.; Carr, K. D.; Pfaff, D. W.
1997 ;23(1-2):124-124, Abstracts (Society for Neuroscience)
— id: 92219, year: 1997, vol: 23, page: 124, stat: Journal Article,

Effects of corticosteroid synthesis inhibitors on the sensitization of reward by food restriction
Abrahamsen GC; Carr KD
1996 Jul 8;726(1-2):39-48, Brain research
Chronic food restriction sensitizes animals to the rewarding effects of food, drugs and lateral hypothalamic electrical stimulation. The present study employed a curve-shift analysis of lateral hypothalamic self-stimulation (LHSS) to evaluate whether the elevated plasma corticosterone levels that accompany food restriction mediate the sensitization of reward. In Experiment 1, two adrenocorticoid synthesis inhibitors, aminoglutethimide and metyrapone, were administered to food-restricted rats and the magnitude of plasma corticosterone suppression was determined at two post-administration time points. In Experiment 2, these compounds were administered to ad libitum fed and food-restricted rats whose LHSS behavior was evaluated at a time coincident with suppression of corticosterone. It was found that neither compound reversed the sensitizing effect of food-restriction on the rewarding efficacy of brain stimulation. However, aminoglutethimide (50 mg/kg) produced an increase in maximal response rates (a performance factor) across groups while metyrapone (100 mg/kg) produced a decrease. The most interesting result of this study was that 2 h after aminoglutethimide administration, when corticosterone levels had recovered from suppression, the rewarding efficacy of LHSS increased markedly in food-restricted rats. Possible explanations for this effect, including adrenocortical rebound, alterations in neurosteroid synthesis, and exacerbation of metabolic need are discussed
— id: 12580, year: 1996, vol: 726, page: 39, stat: Journal Article,

Examination of aminoglutethimide induced sensitization of lateral hypothalamic self-stimulation (LHSS) in food restricted rats
Abrahamsen, G. C.; Kandawire, M.; Carr, K. D.
1996 ;22(1-3):685-685, Abstracts (Society for Neuroscience)
— id: 92220, year: 1996, vol: 22, page: 685, stat: Journal Article,

Haloperidol antagonism of cue-elicited cocaine craving
Berger, S P; Hall, S; Mickalian, J D; Reid, M S; Crawford, C A; Delucchi, K; Carr, K; Hall, S
1996 Feb 24;347(9000):504-508, Lancet
BACKGROUND: Studies of cocaine-dependent subjects have shown that re-exposure to environmental cues previously associated with cocaine use produces a strong conditioned response characterised by autonomic hyperarousal and increases in subjective measures of cocaine craving. METHODS: To evaluate the role of dopamine release by such cues, 20 cocaine-dependent inpatients were randomised in a single-dose, crossover, placebo-controlled design, to haloperidol (4 mg by mouth) and placebo. Plasma homovanillic acid (HVA, a dopamine metabolite), adrenocorticotropic hormone (ACTH), and cortisol were assayed before and after cue exposure. Craving and anxiety were measured before and after cues with visual analogue scales for desire to use cocaine now and for mood changes. FINDINGS: Cocaine cues significantly increased anxiety, ACTH, cortisol, and HVA. Increases in anxiety and craving resulting from cue exposure were significantly antagonised by pretreatment with haloperidol. INTERPRETATION: It has long been hypothesised that increases in extracellular concentrations of dopamine mediate the acute reinforcing effects of cocaine. Our data suggest that dopamine release may also mediate some of the conditioned responses to cocaine cues
— id: 109300, year: 1996, vol: 347, page: 504, stat: Journal Article,

Feeding, drug abuse, and the sensitization of reward by metabolic need
Carr KD
1996 Nov;21(11):1455-1467, Neurochemical research
The incentive-motivating effects of external stimuli are dependent, in part, upon the internal need state of the organism. The increased rewarding efficacy of food as a function of energy deficit, for example, has obvious adaptive value. The enhancement of food reward extends, however, to drugs of abuse and electrical brain stimulation, probably due to a shared neural substrate. Research reviewed in this paper uses lateral hypothalamic electrical stimulation to probe the sensitivity of the brain reward system and investigate mechanisms through which metabolic need, induced by chronic food restriction and streptozotocin-induced diabetes, sensitizes this system. Results indicate that sensitivity to rewarding brain stimulation varies inversely with declining body weight. The effect is not mimicked by pharmacological glucoprivation or lipoprivation in ad libitum fed animals; sensitization appears to depend on persistent metabolic need or adipose depletion. While the literature suggests elevated plasma corticosterone as a peripheral trigger of reward sensitization, sensitization was not reversed by meal-induced or pharmacological suppression of plasma corticosterone. Centrally, reward sensitization is mediated by opioid receptors, since the effect is reversed by intracerebroventricular (i.c.v.) infusion of naltrexone, TCTAP (mu antagonist) and nor-binaltorphimine (kappa antagonist). The fact that these same treatments, as well as i.c.v. infusion of dynorphin A antiserum, block the feeding response to lateral hypothalamic stimulation suggests that feeding and reward sensitization are mediated by a common opioid mechanism. Using in vitro autoradiography, radioimmunoassays and a solution hybridization mRNA assay, brain regional mu and kappa opioid receptor binding, levels of prodynorphin-derived peptides, and prodynorphin mRNA, respectively, were measured in food-restricted and diabetic rats. Changes that could plausibly be involved in reward sensitization are discussed, with emphasis on the increased dynorphin A1-3 and prodynorphin mRNA levels in lateral hypothalamic neurons that innervate the pontine parabrachial nucleus, where mu binding decreased and kappa binding increased. Finally, the possible linkage between metabolic need and activation of a brain opioid mechanism is discussed, as is evidence supporting the relevance of these findings to drug abuse
— id: 12487, year: 1996, vol: 21, page: 1455, stat: Journal Article,

Opioid receptor types and stimulation-induced feeding
Carr KD
Drug receptor subtypes and ingestive behavior London : Academic Press, 1996,
— id: 3428, year: 1996, vol: , page: 167, stat: Chapter,

Diabetes alters mu and kappa opioid binding in rat brain regions: comparison with effects of food restriction
Wolinsky TD; Abrahamsen GC; Carr KD
1996 Oct 28;738(1):167-171, Brain research
Diabetic rats display changes in opioid pharmacology and brain regional levels of opioid peptides and prodynorphin mRNA. Previous investigations of opioid receptor binding, carried out in whole-brain homogenates, have, however, failed to detect changes. In the present study, quantitative autoradiography was used to measure mu and kappa opioid receptor binding in discrete brain regions of streptozotocin-treated diabetic rats. Measurement was limited to regions that previously displayed opioid binding changes in chronically food-restricted rats, since our primary aim is to identify brain mechanisms that mediate adaptive responses to persistent metabolic need and adipose depletion. Diabetics displayed strong trends or statistically significant changes which matched seven of the thirteen binding changes observed in food-restricted rats. In no case did diabetics display changes in the opposite direction. The two statistically significant changes common to food-restricted and diabetic rats are increased kappa binding in the medial preoptic area and decreased mu binding in the lateral habenula. The possible functional significance of these changes is discussed
— id: 12511, year: 1996, vol: 738, page: 167, stat: Journal Article,

Chronic food restriction alters mu and kappa opioid receptor binding in the parabrachial nucleus of the rat: a quantitative autoradiographic study
Wolinsky TD; Carr KD; Hiller JM; Simon EJ
1996 Jan 15;706(2):333-336, Brain research
Using quantitative autoradiography, it was previously observed that chronic food restriction alters mu and kappa receptor binding in several regions of the rat forebrain. The present autoradiographic study was designed to investigate whether food restriction affects regional mu and kappa binding in the brainstem. [3H]DAGO (mu) and-mu/delta blocked [3H]BMZ (kappa) binding were analyzed in 21 brainstem regions. A significant decrease in mu binding was observed in the external lateral and external medial subnuclei of the parabrachial nucleus while a significant increase in kappa binding was observed in the external lateral subnucleus. The possible functional significance of these changes is discussed
— id: 8089, year: 1996, vol: 706, page: 333, stat: Journal Article,

Curve-shift analysis of self-stimulation in food-restricted rats: relationship between daily meal, plasma corticosterone and reward sensitization
Abrahamsen GC; Berman Y; Carr KD
1995 Oct 16;695(2):186-194, Brain research
Chronic food restriction lowers the threshold for lateral hypothalamic electrical self-stimulation (LHSS). This effect has previously been interpreted to reflect a sensitization of reward. In the present study a curve-shift method was used to explicitly differentiate effects of food restriction on brain stimulation rewarding efficacy and performance. Food restriction consistently shifted rate-frequency curves to the left, lowering the M-50 and Theta-0 parameters of rewarding efficacy. Asymptotic rates of reinforcement and slopes of rate-frequency functions were unaffected, confirming that food restriction does not facilitate LHSS by enhancing performance. In this and previous studies, LHSS in food-restricted rats was measured in the period immediately preceding the daily meal when hunger (i.e., period since last meal) and plasma corticosterone are at peak levels. In the light of evidence that corticosterone may regulate sensitivity of the mesolimbic dopamine pathway and account for the sensitizing effect of stress on psychomotor effects of opiates and stimulants, LHSS and corticosterone were measured in the immediate pre-and post-meal periods. While all food-restricted rats displayed elevated corticosterone levels in the pre-meal period and generally displayed a decline to control levels in the post-meal period, the sensitization of reward was not reversed in the post-meal period. These results indicate that chronic food restriction produces a sensitization of reward that does not depend upon the acute state of hunger that precedes the daily meal and does not vary with dynamic changes in plasma corticosterone level
— id: 6882, year: 1995, vol: 695, page: 186, stat: Journal Article,

Effects of streptozotocin-induced diabetes on prodynorphin-derived peptides in rat brain regions
Berman Y; Devi L; Carr KD
1995 Jul 10;685(1-2):129-134, Brain research
Pharmacological studies suggest that diabetes produces changes in the brain opioid system, affecting several behavioral functions including analgesia, feeding and self-stimulation. Previous investigations of opioid receptor binding have failed to explain the unusual opioid pharmacology of the diabetic animal. In the present study, the effects of streptozotocin-induced diabetes on levels of three immunoreactive (ir)-prodynorphin-derived peptides, ir-dynorphin A1-17 (A1-17), ir-dynorphin A1-8 (A1-8) and ir-dynorphin B1-13 (B1-13), were determined in eleven brain regions known to be involved in appetite, taste and reward. Diabetes was found to increase levels of A1-17 in the ventromedial and dorsomedial hypothalamic nuclei (+60% and +25%, respectively) and levels of A1-8 in the dorsomedial and lateral hypothalamus (+45% and +35%, respectively). The possible significance of these results is discussed in relation to (i) diabetic hyperphagia, (ii) medial hypothalamic transduction of circulating insulin levels, and (iii) the potentiation of reward by metabolic need states
— id: 6887, year: 1995, vol: 685, page: 129, stat: Journal Article,

Repeated inescapable stress produces a neuroleptic-like effect on the conditioned avoidance response
Friedhoff AJ; Carr KD; Uysal S; Schweitzer J
1995 Oct;13(2):129-138, Neuropsychopharmacology
This study tests the hypothesis that the dopaminergic system mediates a restitutive response by decreasing its own activity in the face of events like persistent inescapable stress that threaten to interrupt organized mental activity. It is well established that neuroleptic drugs inhibit the conditioned avoidance response (CAR), but not the escape response, probably via a reduction in subcortical dopaminergic activity. We trained rats to perform the CAR and then subjected them to acute and chronic stress to determine whether this would result in inhibition of the CAR. Rats subjected to twice daily tailshock stress for 8 days showed inhibition of the CAR and a reduction in dopamine (DA) utilization in the nucleus accumbens. These findings are compatible with the hypothesis that an endogenous DA-dependent mechanism exists that mimics neuroleptic effects in the face of repeated stress. In humans this response may serve as a protection against psychotic decompensation from chronic endogenous or exogenous insult
— id: 6826, year: 1995, vol: 13, page: 129, stat: Journal Article,

Massive activation of c-fos in forebrain after mechanical stimulation of the locus coeruleus
Stone EA; Zhang Y; Carr KD
1995 ;36(1):77-80, Brain research bulletin
Brief implantation of a 33-ga cannula in the locus coeruleus (LC) of the rat caused widespread and intense ipsilateral activation of c-fos throughout the forebrain. Areas showing heavy staining included the cingulate, piriform, parietal, frontal cortex, and the olfactory tubercle. Prior lesion of the LC with 6-hydroxydopamine (6-OHDA) abolished the response. It is concluded that the mechanical stimulation and/or trauma involved in the implantation of a cannula in the LC is sufficient to cause widespread activation of noradrenergic neurotransmission throughout the forebrain. The use of this procedure for drug delivery should therefore be reevaluated
— id: 12831, year: 1995, vol: 36, page: 77, stat: Journal Article,

Effects of chronic food restriction on prodynorphin-derived peptides in rat brain regions
Berman Y; Devi L; Carr KD
1994 Nov 21;664(1-2):49-53, Brain research
Chronic food restriction produces a variety of physiological and behavioral adaptations including a potentiation of the reinforcing effect of food, drugs and lateral hypothalamic electrical stimulation. Previous work in this laboratory has revealed that the lowering of self-stimulation threshold by food restriction is reduced by mu- and kappa-selective opioid antagonists. In the present study, the effect of chronic food restriction on levels of three prodynorphin-derived peptides, namely dynorphin A1-17 (A1-17), dynorphin A1-8 (A1-8) and dynorphin B1-13 (B1-13) were measured in eleven brain regions known to be involved in appetite, taste and reward. Food restriction increased levels of A1-17 in dorsal medial (+19.6%), ventral medial (+24.2%) and medial preoptic (+82.9%) hypothalamic areas. Levels of A1-17 decreased in the central nucleus of the amygdala (-35.1%). Food restriction increased levels of A1-8 in nucleus accumbens (+34.4%), bed nucleus of the stria terminalis (+24.5%) and lateral hypothalamus (+41.9%). Food restriction had no effect on levels of B1-13. A1-17 is highly kappa-preferring and the brain regions in which levels increased all have a high ratio of kappa: mu and delta receptors. A1-8 is less discriminating among opioid receptor types and the brain regions in which levels increased have a low ratio of kappa: mu and delta receptors. The present results suggest that food restriction alters posttranslational processing within the dynorphin A domain of the prodynorphin precursor, possibly leading to a change in the balance between kappa and non-kappa opioid receptor stimulation in specific brain regions
— id: 6573, year: 1994, vol: 664, page: 49, stat: Journal Article,

Regional distribution of neuropeptide processing endopeptidases in adult rat brain
Berman YL; Rattan AK; Carr K; Devi L
1994 ;76(3-4):245-250, Biochimie
Many peptide hormone and neuropeptide precursors undergo post-translational processing at mono- and/or dibasic residues. An enzymatic activity capable of processing prodynorphin at a monobasic processing site designated 'dynorphin converting enzyme' has been previously reported in rat rain and bovine pituitary. In this study the distribution of dynorphin converting enzyme activity in ten regions of rat brain has been compared with the distribution of subtilisin-like processing enzymes and with the immuno-reactive dynorphin peptides. The distribution of dynorphin converting enzyme activity generally matches the distribution of immuno-reactive dynorphin B-13 in most but not all brain regions. The regions that are known to have a relatively large number of immuno-reactive dynorphin-neurons also contain high levels of dynorphin converting enzyme activity. The distribution of dynorphin converting enzyme activity does not match the distribution of subtilisin-like processing enzyme or carboxypeptidase E activities. Taken together the data support the possibility that the dynorphin converting enzyme is involved in the maturation of dynorphin, as well as other neuropeptides, and peptide hormones
— id: 6574, year: 1994, vol: 76, page: 245, stat: Journal Article,

Effects of chronic food restriction on prodynorphin-derived peptides in rat brain regions
Berman, Y.; Devi, L.; Carr, K. D.
1994 ;20(1-2):752-752, Abstracts (Society for Neuroscience)
— id: 92222, year: 1994, vol: 20, page: 752, stat: Journal Article,

Endogenous opioid modulation of reward in food-restricted and diabetic rats
Carr KD
1994 ;54(1):43-44, Regulatory peptides
— id: 8100, year: 1994, vol: 54, page: 43, stat: Journal Article,

Streptozotocin-induced diabetes produces a naltrexone-reversible lowering of self-stimulation threshold
Carr KD
1994 Nov 21;664(1-2):211-214, Brain research
Stimulation frequency thresholds for lateral hypothalamic self-stimulation were monitored for 3 weeks following the induction of diabetes with streptozotocin (STZ). In each of the 3 weeks following STZ treatment, thresholds of diabetic rats were significantly lower than their pre-STZ baseline while thresholds of control animals did not change. Naltrexone (5.0 mg/kg, s.c.) increased thresholds of diabetic rats while having no effect on thresholds of control rats. These results suggest that STZ-induced diabetes is associated with an opioid-mediated lowering of self-stimulation threshold. The possible relationship between this finding and similar findings obtained in food-restricted animals is discussed
— id: 6588, year: 1994, vol: 664, page: 211, stat: Journal Article,

The role of multiple opioid receptors in the potentiation of reward by food restriction
Carr KD; Papadouka V
1994 Mar 14;639(2):253-260, Brain research
Chronic food restriction and weight loss were previously shown to produce a naltrexone-reversible facilitation of perifornical lateral hypothalamic self-stimulation. In the present study, high affinity receptor-selective antagonists were used to determine the particular opioid receptor type(s) that mediates the facilitation of reward by food restriction. Separate groups of food-restricted and ad libitum fed rats were used to conduct i.c.v. dose-response studies with TCTAP (mu), norbinaltorphimine (kappa), and naltrindole (delta). The highest dose of naltrindole (50.0 nmol) raised self-stimulation threshold independently of feeding condition. This suggests that delta opioid activity is involved in self-stimulation under basal conditions and may explain previous findings that high systemic doses of naloxone or naltrexone reduce self-stimulation. The highest doses of TCTAP and norbinaltorphimine (5.0 and 50.0 nmol, respectively) reversed the lowering of self-stimulation threshold produced by food restriction while having no effect on thresholds of ad libitum fed rats. These results suggest that state-dependent mu and kappa opioid activity facilitate reward. Since food restriction is known to increase the rewarding effect of food and drugs of abuse, the opioid mechanism identified in the present study may mediate adaptive behavior and, under some circumstances, pathological behavior. The possible relation of state-dependent opioid activity to Anorexia Nervosa, binge eating, and the high comorbidity of eating disorders and substance abuse is discussed
— id: 7881, year: 1994, vol: 639, page: 253, stat: Journal Article,

Regulation of feeding by multiple opioid receptors in cingulate cortex; follow-up to an in vivo autoradiographic study
Carr KD; Wolinsky TD
1994 Mar;26(3):207-213, Neuropeptides
A previous in vivo autoradiographic study demonstrated reduced 3H-diprenorphine binding in anterior cingulate cortex of rats that were injected (i.v.) with the radiolabeled opiate during lateral hypothalamic stimulation-induced feeding (SIF). This suggests that an opioid peptide is released in cingulate cortex during feeding and excludes binding of the tracer. The aim of the present study was to determine whether opioid activity in cingulate cortex contributes to the expression of SIF. Agonists and antagonists for multiple opioid receptors were microinjected into cingulate cortex and effects on stimulation frequency threshold for SIF were determined. Although the universal opioid antagonist naloxone (20.0 micrograms) increased threshold, high doses of selective antagonists for mu, delta, and kappa receptors--D-Tic-CTAP, natrindole and norbinaltorphimine, respectively--had no effect. The unique efficacy of naloxone may be due to this lipophilic compound's rapid diffusion throughout an extensive volume of anterior cingulate tissue. While high doses of the kappa agonist U50,488 and the delta agonist DPDPE had no effect, the mu agonist, DAGO (1.0 microgram), decreased the SIF threshold. Moreover, the threshold-lowering effect of DAGO was blocked by pretreatment with the irreversible mu antagonist beta-FNA. These results suggest that mu opioid activity in cingulate cortex can facilitate SIF but that under basal conditions endogenous opioid activity in this brain region makes only a small positive contribution, if any, to the expression of SIF
— id: 7880, year: 1994, vol: 26, page: 207, stat: Journal Article,

The role of multiple opioid receptors in the maintenance of stimulation-induced feeding
Papadouka V; Carr KD
1994 Mar 7;639(1):42-48, Brain research
Feeding induced by lateral hypothalamic electrical stimulation is sensitive to opioid antagonism and has previously been blocked by naloxone and antibodies to dynorphin A fragments. In the present study, high affinity receptor-selective antagonists were used to determine the particular opioid receptor type(s) that mediates stimulation-induced feeding (SIF). Separate groups of rats were used to conduct i.c.v. dose-response studies with TCTAP (mu), naltrindole (delta) and norbinaltorphimine (kappa). TCTAP, at the highest dose tested (i.e. 5.0 nmol) and norbinaltorphimine, at doses of 10.0 and 50.0 nmol, increased the brain stimulation frequency threshold for eliciting SIF. Naltrindole, at doses up to 50.0 nmol, had no effect. Results of another study, recently conducted in this laboratory, indicate that the present doses of TCTAP and norbinaltorphimine have no effect on thresholds for lateral hypothalamic self-stimulation. This suggests that mu and kappa opioid activity are associated with feeding, rather than the eliciting brain stimulation, and excludes non-specific performance deficits as an explanation of elevated SIF thresholds. In the SIF test, where 5 determinations of threshold are obtained in serial order, naloxone characteristically increases thresholds toward the end of a test while conventional appetite suppressants increase thresholds uniformly throughout a test. TCTAP and norbinaltorphimine produced a 'naloxone-like' pattern of threshold elevation, suggesting that mu and kappa receptors are involved in the process whereby endogenous opioid activity sustains feeding once initiated
— id: 6478, year: 1994, vol: 639, page: 42, stat: Journal Article,

Effects of chronic food restriction on mu and kappa opioid binding in rat forebrain: a quantitative autoradiographic study
Wolinsky TD; Carr KD; Hiller JM; Simon EJ
1994 Sep 12;656(2):274-280, Brain research
It was previously observed that chronic food restriction lowers the threshold for lateral hypothalamic self-stimulation in a manner that is reversible by mu- and kappa-selective opioid antagonists. The present quantitative autoradiographic study was designed to investigate whether chronic food restriction alters regional mu and kappa opioid binding in brain. [3H]DAGO (mu) and mu/delta blocked [3H]BMZ (kappa) binding were analyzed in 34 brain regions from the medial prefrontal cortex to posterior hypothalamus. Significant reductions in mu binding were observed in caudal portions of the medial and lateral habenula, and the basolateral and basomedial nuclei of the amygdala. kappa binding was similarly reduced in medial habenula. Large increases in kappa binding were observed in the bed nucleus of the stria terminalis, ventral pallidum, and medial preoptic area. The possible involvement of these changes in the sensitization of reward by food restriction is discussed
— id: 6781, year: 1994, vol: 656, page: 274, stat: Journal Article,

Effect of chronic food restriction on regional Kappa opioid receptor binding in the rat: A quantitative autoradiographic study
Wolinsky, T. D.; Carr, K. D.; Hiller, J. M.; Simon, E. J.
1994 ;20(1-2):752-752, Abstracts (Society for Neuroscience)
— id: 92221, year: 1994, vol: 20, page: 752, stat: Journal Article,

Distribution and characterization of a neuropeptide processing enzyme in adult rat brain
Berman, E.; Carr, K.; Fricker, L. D.; Devi, L.
1993 ;19(1-3):1362-1362, Abstracts (Society for Neuroscience)
— id: 92223, year: 1993, vol: 19, page: 1362, stat: Journal Article,

Norbinaltorphimine blocks the feeding but not the reinforcing effect of lateral hypothalamic electrical stimulation
Carr KD; Papadouka V; Wolinsky TD
1993 ;111(3):345-350, Psychopharmacology
The role of central kappa opioid receptors in the regulation of feeding and reward was evaluated using electrical brain stimulation paradigms in combination with the selective kappa antagonist, norbinaltorphimine (nor-BNI). Lateral ventricular injection of 10.0 and 50.0 nmol doses of nor-BNI increased the lateral hypothalamic stimulation frequency threshold for eliciting feeding behavior but had no effect on threshold for self-stimulation in the absence of food. This result is identical to those previously reported for naloxone and antibodies to dynorphin A and suggests that opioid activity is associated with feeding behavior rather than the eliciting brain stimulation. A further similarity between naloxone, dynorphin antiserum, and nor-BNI is their preferential effect on feeding threshold values obtained later, rather than initially, in a post-injection test session. This pattern of threshold elevation is shown to differ from that of the appetite suppressants, amphetamine and phenylpropanolamine, which elevate threshold uniformly throughout a post-injection test. The signature pattern of threshold elevation produced by opioid antagonism is consistent with the hypothesis that opioid activity is involved in the maintenance rather than the initiation of feeding. Specifically, it is hypothesized that a dynorphin A/kappa receptor mechanism is triggered by food taste and sustains feeding behavior by facilitating incentive reward
— id: 7879, year: 1993, vol: 111, page: 345, stat: Journal Article,

Chronic food restriction and weight loss produce opioid facilitation of perifornical hypothalamic self-stimulation
Carr KD; Wolinsky TD
1993 Apr 2;607(1-2):141-148, Brain research
Electrical stimulation frequency thresholds for lateral hypothalamic (LH) self-stimulation were monitored throughout a 3 week period of food restriction and a subsequent 3 week period of re-feeding. Rats with electrodes placed in the perifornical LH were sensitive to this dietary manipulation as evidenced by a high positive correlation between body weight and self-stimulation threshold. Rats with electrodes in the zona incerta/subincertal region or ventral hypothalamus displayed little or no change in threshold. Lateral ventricular injection of naltrexone (200.0 nM) reversed the decline in threshold that was otherwise present during food restriction in rats with perifornical placements. Naltrexone had no effect on thresholds of rats with placements outside the perifornical region. These findings suggest that food restriction and weight loss activate an opioid mechanism that facilitates perifornical LH self-stimulation. The documented association of perifornical LH with the phenomenon of stimulation-induced feeding, and the reciprocal connections between this region and gustatory structures, supports the hypothesis that facilitation of self-stimulation by food restriction is related to the natural phenomenon of positive alliesthesia (i.e. the hunger-dependency of food reward)
— id: 13189, year: 1993, vol: 607, page: 141, stat: Journal Article,

Chronic food restriction produces mu and kappa opioid facilitation of reward
Carr, K.; Papadouka, V.
1993 ;19(1-3):809-809, Abstracts (Society for Neuroscience)
— id: 92225, year: 1993, vol: 19, page: 809, stat: Journal Article,

The effect of chronic food restriction on mu opioid receptors in the rat: A quantitative autoradiographic study
Wolinsky, T. D.; Carr, K.; Hiller, J. M.; Simon, E. J.
1993 ;19(1-3):1154-1154, Abstracts (Society for Neuroscience)
— id: 92224, year: 1993, vol: 19, page: 1154, stat: Journal Article,

BRAIN OPIOID MECHANISMS THAT REGULATE INGESTIVE BEHAVIOR
CARR, KD
1992 DEC ;19(3):307-307, Appetite
— id: 54401, year: 1992, vol: 19, page: 307, stat: Journal Article,

MU OPIOID ACTIVITY IN MEDIAL THALAMUS EFFECTS ON BEHAVIOR AND DOPAMINE UTILIZATION
CARR K D; UYSAL S; SHWEITER J W; FRIEDHOFF A J
1991 ;17(1-2):1540-1540, Abstracts (Society for Neuroscience)
— id: 92226, year: 1991, vol: 17, page: 1540, stat: Journal Article,

Potentiation of reward by food deprivation is blocked by antibodies to dynorphin A
Carr KD
1991 ;105:551-552, NIDA research monograph series
— id: 14230, year: 1991, vol: 105, page: 551, stat: Journal Article,

Effects of parabrachial opioid antagonism on stimulation-induced feeding
Carr KD; Aleman DO; Bak TH; Simon EJ
1991 Apr 5;545(1-2):283-286, Brain research
The pontine parabrachial nucleus (PBN) contains gustatory relay neurons and a high concentration of opioid receptors. To investigate the involvement of PBN opioid activity in feeding behavior, antagonists were infused into the PBN bilaterally and effects on stimulation-induced feeding were determined. Naloxone, a mu-preferring antagonist, increased the lateral hypothalamic stimulation threshold for eliciting feeding behavior while nor-binaltorphimine, a kappa-selective antagonist, did not. Neither antagonist increased threshold when infused into dorsal pontine sites outside of the PBN or the fourth ventricle. In as much as PBN contains mu and kappa but no detectable delta receptors, the present results suggest that mu opioid activity within the PBN is involved in the mediation of feeding behavior
— id: 14069, year: 1991, vol: 545, page: 283, stat: Journal Article,

EFFECTS OF NOCICEPTIVE AND PSYCHOSOCIAL STRESSORS ON REGIONAL DOPAMINE UTILIZATION
UYSAL S; CARR K D; SCHWEITZER J W; FRIEDHOFF A J
1991 ;17(1-2):503-503, Abstracts (Society for Neuroscience)
— id: 92227, year: 1991, vol: 17, page: 503, stat: Journal Article,

MU OPIOID ACTIVITY IN ANTERIOR CINGULATE CORTEX MAY MEDIATE STIMULATION-INDUCED FEEDING
WOLINSKY T; GILADY D; CARR K D
1991 ;17(1-2):492-492, Abstracts (Society for Neuroscience)
— id: 92228, year: 1991, vol: 17, page: 492, stat: Journal Article,

PARABRACHIAL OPIOID ANTAGONISM BLOCKS STIMULATION-INDUCED FEEDING
CARR K D; ALEMAN D
1990 ;16(1):775-775, Abstracts (Society for Neuroscience)
— id: 92229, year: 1990, vol: 16, page: 775, stat: Journal Article,

Effects of antibodies to dynorphin A and beta-endorphin on lateral hypothalamic self-stimulation in ad libitum fed and food-deprived rats
Carr KD
1990 Nov 26;534(1-2):8-14, Brain research
Many laboratories have reported that systemically administered naloxone has little or no effect on lateral hypothalamic self-stimulation (LH ICSS). In the present study, lateral ventricular infusion of beta-endorphin antiserum and a high dose of naloxone (100 micrograms) produced small but significant increases in stimulation frequency threshold for LH ICSS. beta-Endorphin activity, mediated by a non-mu (e.g. delta or epsilon) receptor, may therefore be involved in the reinforcement of self-stimulation behavior. When rats are deprived of food for 24 h, LH ICSS thresholds decline. Under this condition, systemic naloxone elevates the LH ICSS threshold, often returning it to the pre-deprivation level. In the present study, lateral ventricular infusion of dynorphin A(1-13) antiserum similarly reversed the threshold-lowering effect of food deprivation. The effects of systemic naloxone and intraventricular dynorphin A antiserum on LH ICSS, which are specific to food-deprived animals, may be related to previous findings that these two treatments elevate LH stimulation threshold for eliciting feeding behavior. Results of the ICSS and stimulation-induced feeding studies suggest a model for the mediation of incentive stimuli by dynorphin A activity that is afferent to LH 'reward' neurons and positively gated by 'hunger'. An hypothesized role for 'hunger'-gated dynorphin A release in potentiating the hedonic response to alimentary stimuli and drugs of abuse is discussed
— id: 11479, year: 1990, vol: 534, page: 8, stat: Journal Article,

ROSTRAL AND CAUDAL VENTRICULAR INFUSION OF ANTIBODIES TO DYNORPHIN A(1-17) AND DYNORPHIN A(1-8) - EFFECTS ON ELECTRICALLY-ELICITED FEEDING IN THE RAT
Carr, KD; Bak, TH
1990 Jan 22;507(2):289-294, Brain research
— id: 31891, year: 1990, vol: 507, page: 289, stat: Journal Article,

Brain stimulation-induced feeding alters regional opioid receptor binding in the rat: an in vivo autoradiographic study
Stein EA; Carr KD; Simon EJ
1990 Nov 19;533(2):213-222, Brain research
Although opioid antagonists block feeding behavior in a variety of animal models, the number and identity of CNS regions in which the inferred endogenous opioid activity mediates feeding have yet to be established. Furthermore, it is not yet clear whether the opioid activity that sustains feeding is a concomitant of the appetitive motivational state or the consummatory response. In an effort to address these issues, an in vivo autoradiographic method was used to visualize CNS regional changes in opioid release during appetitively motivating electrical stimulation in the lateral hypothalamus (ESLH) and during consummatory behavior elicited by such stimulation. Regional decreases in [3H]diprenorphine [(3H]Dpr) binding, suggesting increased release of an endogenous opioid peptide, were observed in the medial prefrontal cortex, medial septum, gustatory cortex, zona incerta, mediodorsal thalamus, and hippocampus of rats receiving ESLH. Decreased binding in the latter 4 structures did not appear when animals were allowed to eat during ESLH, suggesting that the inferred opioid release is associated with appetitive behaviors elicited by ESLH which are suppressed when food is available and consummatory behavior predominates. When animals were allowed to eat during ESLH, [3H]Dpr binding in anterior cingulate cortex decreased substantially, suggesting that feeding behavior specifically triggers opioid release in this region. ESLH and feeding were found to increase [3H]Dpr binding in a number of CNS regions. Alternative explanations for increased binding, including inhibition of tonic opioid release, changes in cerebral blood flow, and opioid receptor up-regulation are discussed
— id: 62163, year: 1990, vol: 533, page: 213, stat: Journal Article,

Stimulus induced feeding alters regional opiate receptor binding in the rat: an in vivo audioradiographic study
Stein EA; Carr KD; Simon EJ
1990 ;328:187-190, Progress in clinical & biological research
— id: 63632, year: 1990, vol: 328, page: 187, stat: Journal Article,

Stereotypies elicited by injection of N-propylnorapomorphine into striatal subregions and nucleus accumbens
Bordi F; Carr KD; Meller E
1989 Jun 12;489(2):205-215, Brain research
Injection of the dopamine (DA) agonist R-(-)-N-n-propylnorapomorphine (NPA; 5-40 micrograms) into anterior ventral striatal sites (either lateral (VL) or medial (VM) elicited dose-dependent oral and sniffing stereotypies of rapid onset, long duration and high intensity. In contrast, injection into anterior dorsolateral (DL) or posterior ventral (lateral (PL) or medial (PM] sites produced little oral and moderate sniffing behavior of slower onset, shorter duration and low intensity. Injection into the dorsomedial (DM) striatum produced intermediate effects. Intra-accumbens NPA elicited weak oral activity and moderate sniffing which was similar in onset, duration and intensity to the least sensitive striatal sites (DL, PM and PL). In other experiments, DA receptors were inactivated with the irreversible blocking agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 6 mg/kg) and behavioral recovery was monitored by challenge with 20 micrograms NPA into the VL or the nucleus accumbens (NA) at various times after EEDQ. Sniffing behavior recovered rapidly (normal by day 4 in both regions), whereas oral activity required 8 (NA) and 12 days (VL) to return to control levels. The results are discussed in terms of a possible topographic distribution of behavior in the striatum. Alternatively, heterogeneity of DA receptor density may account for these findings
— id: 10586, year: 1989, vol: 489, page: 205, stat: Journal Article,

Effects of the selective kappa opioid antagonist, nor-binaltorphimine, on electrically-elicited feeding in the rat
Carr KD; Bak TH; Simon EJ; Portoghese PS
1989 ;45(19):1787-1792, Life sciences
Lateral ventricular injections of the 'nonspecific' opioid antagonist naloxone (100 micrograms) and the kappa-selective opioid antagonist nor-binaltorphimine (50 micrograms) elevated the electrical brain stimulation frequency threshold for eliciting feeding behavior. Mesopontine aqueductal injections of nor-binaltorphimine, on the other hand, lowered the feeding threshold while naloxone still elevated threshold. These findings suggest the existence of forebrain kappa receptors at which endogenous opioid activity results in a facilitation of feeding while kappa receptors in the brainstem seem to mediate an inhibitory effect
— id: 10828, year: 1989, vol: 45, page: 1787, stat: Journal Article,

CENTRAL-NERVOUS-SYSTEM OPIOID MECHANISMS THAT MEDIATE STIMULATION-INDUCED FEEDING IN THE RAT
Carr, KD
1989 Dec 18;575(4):503-505, Annals of the New York Academy of Sciences
— id: 31885, year: 1989, vol: 575, page: 503, stat: Journal Article,

Pharmacokinetics of [3H]-buprenorphine in the rat
Holland MJ; Carr KD; Simon EJ
1989 Apr;64(1):3-16, Research communications in chemical pathology & pharmacology
The present study was undertaken to evaluate the potential usefulness of 11C-buprenorphine (bup) as a ligand for investigating opioid receptors in living primates, including humans, using positron-emission transaxial tomography (PETT). Because PETT studies of receptor function are best carried out under conditions of low receptor occupancy, the pharmacokinetics, uptake into brain, and specific binding to opioid receptors within brain of 3H-bup were examined in rats under conditions in which occupancy of opioid receptors by 3H-bup never exceeded 2% of sites in the brain at any time point examined. Male Sprague Dawley rats (weight range 140-220 grams) were injected s.c. with either naloxone (10 mg/kg) or saline. Five min later, a saline solution containing [15, 16-3H] bup (39 Ci/mmole) was injected into tail veins at a dose of 0.4 microgram/kg body weight. At least 90-95% of radioactivity was cleared from the blood in the first 5 min. In saline pretreated rats, total brain uptake 15 min after injection of 3H-bup was about 0.4% of the administered dose. Ligand specifically bound to receptors may be estimated by comparing the amount of radioactivity in the brain following injection of labeled ligand alone to that obtained when a high concentration of an unlabeled competitor is pre- or co-administered. In the present study, average levels obtained in brain (excluding cerebellum) were higher in saline pretreated rats than in naloxone pretreated rats at all time points and the difference increased with time indicating specific binding to opioid receptors. Specific binding may also be estimated by comparing radioactivity accumulated in brain areas rich in opioid receptors with 'background' levels achieved in areas known to be low in opioid receptors, e.g., the cerebellum in rats. In the present study, ratios of the amount of radioactivity in brain (excluding cerebellum) to the amount in the cerebellum increased with time (to about 4 after 60 min) in saline pretreated rats, but remained close to 1 in naloxone pretreated rats. The effects of biological variation were less when specific binding was estimated by the latter method since each animal served as its own control. Tissue distribution of radioactivity to other tissues (blood, skin, muscle, fat, liver, kidney) was similar in naloxone and saline pretreated rats. The results presented here suggest that 11C-bup or an 18F-labeled fluorinated derivative would be a useful ligand for PETT studies
— id: 10690, year: 1989, vol: 64, page: 3, stat: Journal Article,

CNS REGIONAL CHANGES IN TRITIATED DIPRENORPHINE BINDING FOLLOWING ELECTRICALLY ELICITED FEEDING IN THE RAT
STEIN E A; CARR K D; SIMON E J
1989 ;15(1):896-896, Abstracts (Society for Neuroscience)
— id: 92230, year: 1989, vol: 15, page: 896, stat: Journal Article,

OPPOSITE EFFECTS OF ROSTRAL AND CAUDAL VENTRICULAR INFUSION OF NOR-BINALTORPHIMINE ON STIMULATION-INDUCED FEEDING
BAK T; CARR K D; SIMON E J; PORTOGHESE P S
1988 ;14(2):1107-1107, Abstracts (Society for Neuroscience)
— id: 92231, year: 1988, vol: 14, page: 1107, stat: Journal Article,

ANTIBODIES TO DYNORPHIN A 1-8 AND 1-17 ELEVATE THRESHOLD FOR BRAIN STIMULATION-INDUCED FEEDING IN RAT
CARR K D; BAK T H; SIMON E J
1988 ;14(2):1107-1107, Abstracts (Society for Neuroscience)
— id: 92232, year: 1988, vol: 14, page: 1107, stat: Journal Article,

Medial thalamic injection of opioid agonists: mu-agonist increases while kappa-agonist decreases stimulus thresholds for pain and reward
Carr KD; Bak TH
1988 Feb 16;441(1-2):173-184, Brain research
Selective agonists for mu- and kappa-opioid receptor types were infused, bilaterally, into the intralaminar central lateral nucleus of the rat. Subcataleptic doses of the mu-agonist, DAGO (0.25 and 1.0 microgram), elevated tailshock threshold for eliciting pain vocalization and motor responses. The hyperalgesic effect of U50,488 is not likely to be the result of antagonist action at a mu 2-isoreceptor; the general mu-antagonist, naloxone, and its less lipophilic quaternary analogue, both failed to produce a significant reduction in pain thresholds. Paralleling their effects on pain, DAGO and U50,488 elevated and reduced, respectively, lateral hypothalamic electrical stimulation threshold for positive reinforcement. These results suggest that medial thalamic opioid mechanisms are not exclusively involved in pain modulation but may generally regulate the responsiveness of the organism to motivating stimuli. Moreover, mu- and kappa-receptors may mediate opposite behavioral effects of opioid peptides
— id: 11182, year: 1988, vol: 441, page: 173, stat: Journal Article,

Regulation of electrically elicited feeding in the rat by CNS opioid peptides
Carr KD; Simon EJ
Regulatory roles of opioid peptides Weinheim : VCH Publishers, 1988,
— id: 3427, year: 1988, vol: , page: 378, stat: Chapter,

ANTIBODIES TO DYNORPHIN A 1-13 BUT NOT BETA ENDORPHIN INHIBIT ELECTRICALLY-ELICITED FEEDING IN THE RAT
CARR K D; BAK T H; GIOANNIN T L; SIMON E J
1987 ;13(2):877-877, Abstracts (Society for Neuroscience)
— id: 92233, year: 1987, vol: 13, page: 877, stat: Journal Article,

Lateral hypothalamic stimulation-produced analgesia: inferred refractory period of directly stimulated neurons and resistance to pimozide antagonism
Carr KD; Bak TH
1987 ;41(4):371-378, Physiology & behavior
Electrical stimulation in lateral hypothalamic sites (ESLH) supporting appetitive behavior and reward also diminishes pain and aversion responses that are organized high in the neuraxis. A paired-pulse stimulation technique was used, in two different behavioral paradigms, to infer the absolute refractory periods of LH neurons that mediate this apparent supraspinal analgesia. In both paradigms, recovery from refractoriness--reflected by increased analgesic action--was evident at intrapair intervals of 0.8 msec and greater. This finding suggests that the overlap, if any, between first stage neurons mediating analgesia and appetitive/reward behavior may be restricted to the 'heterogeneous slow population' distinguished by Gratton and Wise. The dopamine antagonist pimozide, at doses known to diminish ESLH-induced feeding and reward (0.25 and 0.5 mg/kg), failed to affect analgesia. Thus, the dopaminergic second stage neurons deemed critical to feeding and reward may not play an important role in analgesia. Finally, ESLH-induced ameliorative action as a case of 'aversion-gating' or a dimension of classical somatosensory analgesia is discussed
— id: 11415, year: 1987, vol: 41, page: 371, stat: Journal Article,

Antibodies to dynorphin A(1-13) but not beta-endorphin inhibit electrically elicited feeding in the rat
Carr KD; Bak TH; Gioannini TL; Simon EJ
1987 Oct 6;422(2):384-388, Brain research
Highly specific antibodies to dynorphin A(1-13), infused into the lateral ventricle, elevated brain stimulation threshold for eliciting feeding behavior. Antibodies to beta-endorphin had little or no effect. Temporal analysis of the anorectic action indicated a striking similarity to the effect of systemically administered naloxone. These findings suggest that central dynorphin is involved in the control of ingestive behavior and that the anorectic action of naloxone may result from antagonism of dynorphinergic transmission
— id: 11344, year: 1987, vol: 422, page: 384, stat: Journal Article,

[3H]-BUPRENORPHINE DISSOCIATION FROM OPIATE RECEPTORS INVIVO
Holland, MJC; Carr, KD; Simon, EJ
1987 Mar 1;46(3):868-868, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 31267, year: 1987, vol: 46, page: 868, stat: Journal Article,

Regulation of alpha and beta components of noradrenergic cyclic AMP response in cortical slices
Stone EA; McEwen BS; Herrera AS; Carr KD
1987 Sep 23;141(3):347-356, European journal of pharmacology
The cyclic AMP response to catecholamines in the rat cerebral cortex is mediated by both beta- and alpha-adrenoceptors. The beta-receptors cause a direct activation of adenylate cyclase whereas the alpha alpha-receptors play a modulatory role and act by potentiating the response to beta stimulation. The present study investigated whether the functions of these two types of cyclic AMP-linked receptors are regulated differently by various physiological factors known to affect adrenoceptor function. It was found that treatments that affect central noradrenergic neuronal function including repeated administration of desmethylimipramine or lesion of central noradrenergic pathways produced selective changes in the cAMP response to beta-receptor stimulation whereas treatments that affect adrenocortical function including ACTH of corticosterone administration and hypophysectomy or adrenalectomy produced selective changes in the potentiation response to alpha-receptor stimulation. The change in the alpha potentiation effect caused by corticosterone was found to be abolished in the presence of prazosin indicating that the hormone affects alpha 1-adrenoceptor function. The results support the hypothesis that the beta response in the cortex is under the control of the noradrenergic system while the alpha potentiation response is under the control of the adrenocortical system
— id: 11368, year: 1987, vol: 141, page: 347, stat: Journal Article,

OPPOSITE EFFECTS OF MEDIAL THALAMIC MU AND KAPPA OPIOID ACTIVITY ON MOTIVATIONAL-AFFECTIVE RESPONSES
CARR K D; SIMON E J
1986 ;12(2):939-939, Abstracts (Society for Neuroscience)
— id: 92235, year: 1986, vol: 12, page: 939, stat: Journal Article,

SYNTHESIS AND EVALUATION OF FLUORINATED DERIVATIVES OF FENTANYL AS CANDIDATES FOR OPIATE RECEPTOR STUDIES USING POSITRON EMISSION TOMOGRAPHY
HWANG, DR; FELIU, AL; WOLF, AP; MACGREGOR, RR; FOWLER, JS; ARNETT, CD; HOLLAND, MJ; CARR, K; SIMON, EJ
1986 MAR ;23(3):277-293, Journal of labelled compounds & radiopharmaceuticals
— id: 41607, year: 1986, vol: 23, page: 277, stat: Journal Article,

ROLE OF CENTRAL NORADRENERGIC AND PITUITARY ADRENAL SYSTEMS IN REGULATION OF BETA-ADRENOCEPTOR AND ALPHA-ADRENOCEPTOR FUNCTION IN RAT CENTRAL NERVOUS SYSTEM
STONE E A; MCEWEN B S; HERRERA A S; CARR K D
1986 ;12(2):1463-1463, Abstracts (Society for Neuroscience)
— id: 92234, year: 1986, vol: 12, page: 1463, stat: Journal Article,

SELECTIVE REGULATION OF BRAIN BETA-ADRENERGIC RECEPTORS BY THE NORADRENERGIC SYSTEM AND BRAIN ALPHA-ADRENERGIC RECEPTORS BY THE PITUITARY-ADRENAL SYSTEM
Stone, EA; Herrera, AS; Carr, KD; Mcewen, BS
1986 Mar 1;45(3):582-582, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 31083, year: 1986, vol: 45, page: 582, stat: Journal Article,

AVERSION-GATING SITES IN LATERAL HYPOTHALAMUS AN ANATOMIC AND PHARMACOLOGIC STUDY
CARR K D; UYSAL S
1985 ;11(2):1175-1175, Abstracts (Society for Neuroscience)
— id: 92236, year: 1985, vol: 11, page: 1175, stat: Journal Article,

Diphenhydramine potentiates narcotic but not endogenous opioid analgesia
Carr KD; Hiller JM; Simon EJ
1985 Feb;5(4-6):411-414, Neuropeptides
The analgesic effect of morphine in rats, as reflected in elevated thresholds for tail shock induced vocalizations, was markedly potentiated by the antihistamine, diphenhydramine. Intrinsic to the behavioral test paradigm employed are stressors which mobilize endogenous opioid activity as verified by the hyperalgesic effect of naloxone. Diphenhydramine failed to potentiate the analgesic effect of such endogenous opioid activity. The potentiating effect of antihistamines may therefore be mediated by mechanisms whose influence is restricted to systemically administered opiates
— id: 63644, year: 1985, vol: 5, page: 411, stat: Journal Article,

EVIDENCE OF A SUPRASPINAL OPIOID ANALGESIC MECHANISM ENGAGED BY LATERAL HYPOTHALAMIC ELECTRICAL-STIMULATION
CARR, KD; UYSAL, S
1985 ;335(1):55-62, Brain research
— id: 41224, year: 1985, vol: 335, page: 55, stat: Journal Article,

N-(3-Fluoropropyl)-N-normetazocine, a potentially useful opiate antagonist for opiate receptor studies with positron emission tomography (PET)
Feliu AL; Holland MJ; Carr KD; Fowler JS; Simon EJ
1985 Sep;49(3):323-336, Research communications in chemical pathology & pharmacology
A new fluorinated derivative of N-propylnormetazocine, N-(3-fluoropropyl)-N-normetazocine (1) was synthesized. 1 was similar to the unfluorinated analog 3 in its ability to compete with (3H)-naltrexone for binding sites in rat brain membranes and its potency in antagonizing morphine analgesia in rats. Competition of both compounds against (3H)-naltrexone was little affected by the presence of sodium chloride, a characteristic frequently exhibited by opiate antagonists. Morphine analgesia in rats was measured by suppression of locomotion and vocalization responses to footshock. The ability of 1 to antagonize morphine analgesia in rats was similar to that of 3. Neither 1 nor 3 showed any evidence of agonist activity in rats at doses as high as 1.0 mg/kg (the highest dose tested). These results suggest that 1, labeled with 18F, may be useful for in vivo studies of the opiate receptor using positron emission tomography (PET)
— id: 62115, year: 1985, vol: 49, page: 323, stat: Journal Article,

The physiology of opiate hedonic effects and the role of opioids in motivated behavior
Carr KD
1984 ;3(3):5-8, Advances in alcohol & substance abuse
— id: 46860, year: 1984, vol: 3, page: 5, stat: Journal Article,

Analgesic effects of ethylketocyclazocine and morphine in rat and toad
Carr KD; Aleman DO; Holland MJ; Simon EJ
1984 Aug 27;35(9):997-1003, Life sciences
We have previously found rat and toad (Bufo marinus) brain to contain inverse ratios of benzomorphan-preferring (kappa/sigma) and morphine-preferring (mu) opioid receptor types. The aim of the present study was to compare in vivo pharmacologic activity of a benzomorphan, ethylketocyclazocine (EKC) and morphine sulfate (MS) in rat and toad. Footshock intensity thresholds for eliciting locomotion were determined and dose-response curves for EKC and MS analgesia were obtained. Drugs were injected subcutaneously. In rats (high mu, low kappa in brain), both compounds produced analgesia and displayed similar sensitivity to naloxone antagonism. The analgesic effects of EKC and MS may, therefore, be mediated by a common receptor type (mu) in this pain test in rats. In toads (high kappa, low mu in brain), MS produced naloxone-reversible analgesia at doses 20-fold higher than were effective in rats. Toads did not display EKC analgesia at doses below those producing motor impairment. Moreover, 50-fold higher doses were required to produce such impairment in toads. Thirty minutes following subcutaneous injection of 3H-EKC, similar concentrations were found in rat and toad brain. Uptake into brain is probably not a factor in the behavioral resistance of toads to EKC
— id: 63650, year: 1984, vol: 35, page: 997, stat: Journal Article,

Potentiation of reward by hunger is opioid mediated
Carr KD; Simon EJ
1984 Apr 16;297(2):369-373, Brain research
In tests of frequency threshold for brain stimulation-induced feeding, naloxone (s.c.) did not affect the first in a brief series of threshold estimates but elevated subsequent estimates progressively. It was demonstrated that neither the time-course of drug action nor any cumulative disruptive effect of brain stimulation itself, accounts for the progressive elevation of threshold. Self-stimulation in 'feeding' electrodes was therefore studied, in combination with hunger manipulations, to inferentially evaluate naloxone's effect on feeding mechanisms. Results suggest naloxone's anoretic effect does not reflect heightened responsiveness of a satiety mechanism. Reversal by naloxone of the potentiating effect of hunger on self-stimulation, however, suggests the anoretic effect is due to blockade of an opioid process associated with hunger that otherwise enhances the reward value of food
— id: 63651, year: 1984, vol: 297, page: 369, stat: Journal Article,

Abuse of the elderly: screening and detection
Fulmer, T; Street, S; Carr, K
1984 ;10(3):131-40, Journal of emergency nursing
— id: 115103, year: 1984, vol: 10, page: 131, stat: Journal Article,

Effects of naloxone and its quarternary analogue on stimulation-induced feeding
Carr KD; Simon EJ
1983 Jan;22(1):127-130, Neuropharmacology
Feeding was induced in rats by electrical stimulation in the lateral hypothalamus. Naloxone (0.2 and 1.0 mg/kg) produced a dose-related elevation of the frequency threshold for stimulation-induced feeding while quarternary naloxone (2.0 and 10.0 mg/kg) had no effect. Since quarternary naloxone does not readily penetrate the blood-brain barrier, we conclude that the opiate receptors at which naloxone exerts its anorectic action are located in the brain rather than in potential peripheral tissues such as gastrointestinal tract, pancreas or adrenal medulla. The threshold-elevating effect of naloxone only became marked after rats had engaged in one or two 5-sec bouts of feeding. The effect continued to increase following each subsequent bout of feeding. Naloxone therefore appears to inhibit feeding by interacting with post-ingestive factors
— id: 63657, year: 1983, vol: 22, page: 127, stat: Journal Article,

The role of opioids in feeding and reward elicited by lateral hypothalamic electrical stimulation
Carr KD; Simon EJ
1983 ;33 Suppl 1:563-566, Life sciences
We have previously shown that feeding induced by electrical stimulation in the lateral hypothalamus of rats is inhibited by naloxone but not its quaternary analogue. In the present study, effects of morphine and loperamide -an opiate that does not pass the blood-brain barrier- were examined. Loperamide inhibited stimulation-induced feeding; reversal of this effect by quaternary naloxone confirmed the peripheral site of action. A low dose of morphine (1.25 mg/kg) facilitated feeding but higher doses were inhibitory. An inhibitory dose of morphine became facilitory, however, when preceded by quaternary naloxone. It therefore appears that central opioid activity promotes ingestive behavior while peripheral activity inhibits ingestion. To evaluate the function served by the central facilitory process, we exploited the relation that exists between feeding and self-stimulation elicited through a common electrode. It was found that potentiation of self-stimulation by food deprivation is blocked by naloxone. It is concluded that endogenous opioid activity may promote feeding by enhancing the reward value of food as a function of hunger
— id: 63658, year: 1983, vol: 33 Suppl 1, page: 563, stat: Journal Article,

Medial thalamic lesions reduce the aversion-gating action of lateral hypothalamic stimulation
Carr KD; Bonnet KA; Simon EJ
1982 Aug 26;246(2):342-346, Brain research
— id: 63666, year: 1982, vol: 246, page: 342, stat: Journal Article,

Mu and kappa opioid agonists elevate brain stimulation threshold for escape by inhibiting aversion
Carr KD; Bonnet KA; Simon EJ
1982 Aug 12;245(2):389-393, Brain research
Rats were trained to press a lever to escape electrical stimulation of the nucleus reticularis gigantocellularis and to obtain stimulation of the lateral hypothalamus. Morphine sulfate and ethylketocyclazocine (EKC) both elevated the intensity of stimulation required to sustain escape at doses which did not affect self-stimulation. Parallel dose-response lines were obtained for the two opioid agonists but the effect of EKC was more resistant to naloxone antagonism. These results suggest that both mu-and chi-sub-types of opiate receptor mediate the inhibition of supraspinally-elicited aversion
— id: 63667, year: 1982, vol: 245, page: 389, stat: Journal Article,

Lateral hypothalamic stimulation gates nucleus gigantocellularis-induced aversion via a reward-independent process
Carr KD; Coons EE
1982 Jan 28;232(2):293-316, Brain research
A monophasic pulse-pair stimulation technique was used behaviorally to infer neurophysiological interaction between 'reward' sites in the lateral hypothalamus (LH) and pain-implicated nucleus reticularis gigantocellularis (NGC). Rats lever-pressed for 3 s escapes from an otherwise continuous train of 0.1 ms NGC pulses delivered every 40 ms. When pulses to the LH were interdigitated with those to NGC, inter-response latencies were significantly longer. This occurred whether LH pulses were also interrupted by each lever-press (experiment 1) or not (experiment 2). Further, the same intensities of LH stimulation which inhibited escape supported high rates of lever-pressing for 3 s LH trains during inescapable NGC stimulation even though these LH trains were not of sufficient intensity to support 'rewarding' lever-pressing in the absence of NGC stimulation. This finding indicates that escape-inhibition in the first two experiments was not due to interfering motor effects of LH stimulation but most probably due to LH amelioration of NGC-induced aversion. Indeed, when aversion was ameliorated by morphine, lever-pressing for sub-reward-threshold LH stimulation during inescapable NGC stimulation decreased although classical self-stimulation did not. In the escape experiments, inhibition was greatest when each NGC pulse was preceded by an LH pulse at an interval of 0.1 or 10 ms. During inescapable NGC stimulation, rates of lever-pressing for LH trains were greatest when LH pulses preceded NGC pulses again at intervals of 0.1 or 10 ms. This congruence of the temporal bimodal profiles in the response functions of these two different behavioral experiments strongly suggests that the same integrative mechanism underlies both LH inhibition of NGC escape and lever-pressing for LH trains during inescapable stimulation of NGC. Since gastric loading did not alter lever-pressing for sub-reward-threshold LH trains during inescapable NGC stimulation but did inhibit classical self-stimulation, it was concluded that the inferred common integrative mechanism mediates a supraspinal gating of aversion which is independent of the LH self-stimulation reward process
— id: 46859, year: 1982, vol: 232, page: 293, stat: Journal Article,

Rats self-administer nonrewarding brain stimulation to ameliorate aversion
Carr KD; Coons EE
1982 Mar 19;215(4539):1516-1517, Science
Hypothalamic stimulation in rats both reduces escape from noxious hindbrain stimulation and sustains self-administration only when hindbrain stimulation is inescapable. Self-administration reflects an aversion-ameliorative action of brain stimulation and not a positive reinforcement process. The psychophysical testing used is offered as a model for establishing the analgesic properties of brain stimulation
— id: 46858, year: 1982, vol: 215, page: 1516, stat: Journal Article,