Eric A Stone, Ph.D.

Participation of brainstem monoaminergic nuclei in behavioral depression
Lin, Yan; Sarfraz, Yasmeen; Jensen, Ashley; Dunn, Adrian J; Stone, Eric A
2011 Dec;100(2):330-339, Pharmacology biochemistry & behavior
Several lines of research have now suggested the controversial hypothesis that the central noradrenergic system acts to exacerbate depression as opposed to having an antidepressant function. If correct, lesions of this system should increase resistance to depression, which has been partially but weakly supported by previous studies. The present study reexamined this question using two more recent methods to lesion noradrenergic neurons in mice: intraventricular (ivt) administration of either the noradrenergic neurotoxin, DSP4, or of a dopamine-beta-hydroxylase-saporin immunotoxin (DBH-SAP ITX) prepared for mice. Both agents given 2weeks prior were found to significantly increase resistance to depressive behavior in several tests including acute and repeated forced swims, tail suspension and endotoxin-induced anhedonia. Both agents also increased locomotor activity in the open field. Cell counts of brainstem monoaminergic neurons, however, showed that both methods produced only partial lesions of the locus coeruleus and also affected the dorsal raphe or ventral tegmental area. Both the cell damage and the antidepressant and hyperactive effects of ivt DSP4 were prevented by a prior i.p. injection of the NE uptake blocker, reboxetine. The results are seen to be consistent with recent pharmacological experiments showing that noradrenergic and serotonergic systems function to inhibit active behavior. Comparison with previous studies utilizing more complete and selective LC lesions suggest that mouse strain, lesion size or involvement of multiple neuronal systems are critical variables in the behavioral and affective effects of monoaminergic lesions and that antidepressant effects and hyperactivity may be more likely to occur if lesions are partial and/or involve multiple monoaminergic systems
— id: 139732, year: 2011, vol: 100, page: 330, stat: Journal Article,

Further evidence for an immediate antidepressant action of intracerebral drug administration in a model of chronic depression
Lin, Yan; Suckow, Raymond F; Sarfraz, Yasmeen; Stone, Eric A
2011 Jun;14(5):691-696, International journal of neuropsychopharmacology
This study was designed to replicate an earlier finding of a rapid acute therapeutic action of intracerebrally administered antidepressant in chronically depressed rodents. The effects of acute fourth ventricular (ivt.) injections were compared to those of acute peripheral (i.p.) injections of desipramine (DMI) in mice subjected to repeated open-space forced swim. In confirmation, it was found that a single ivt. injection of a low (3 nmol) but not high (30 nmol) dose immediately reversed the immobility and inactivity of the model whereas acute i.p. administration was without effect up to 30 mg/kg. The repeated forced swim stress was also found to significantly reduce the net accumulation of DMI in the brain but not liver after a single i.p. injection of a moderate dose (10 mg/kg). The results suggest that stress-induced alterations of regional drug uptake or metabolism in the CNS may contribute to the therapeutic lag for antidepressants and other compounds in disorders with high distress
— id: 131792, year: 2011, vol: 14, page: 691, stat: Journal Article,

Dipivalyl-6-fluoronorepinephrine (dp6fne), a Rapidly Acting Antidepressant and Sedation-free Anxiolytic
Stone, Eric A.; Lin, Yan; Sarfraz, Yasmeen; Quartermain, David
2011 MAY 1 ;69(9):128S-128S, Biological psychiatry
— id: 133327, year: 2011, vol: 69, page: 128S, stat: Journal Article,

Open-space forced swim model of depression for mice
Stone, Eric A; Lin, Yan
2011 Jan;Chapter 9:Unit9.36-Unit9.36, Current protocols in neuroscience
This protocol describes a simplified method for inducing a chronic depression-like state in mice that is based on the repeated open-space forced swim method originally developed for rats. The method consists of mice swimming daily in lukewarm water in rat tub cages, for 15 min/day for 4 days, and thereafter once per week. This procedure produces a progressive decrease in distance swum and a concomitant increase in immobility (floating) in approximately 70% of the mice, both of which persist unaltered for weeks. The model has predictive, face, and construct validity and has a number of advantages over previous methods in that it utilizes very mild stress, is short in duration, and is easily standardized. Moreover, since it utilizes a greater swimming area than the traditional (Porsolt) method it can be used to study interactions of depressive behavior with behavioral flexibility and perseveration. Curr. Protoc. Neurosci. 54:9.36.1-9.36.8. (c) 2011 by John Wiley & Sons, Inc
— id: 117358, year: 2011, vol: Chapter 9, page: Unit9.36, stat: Journal Article,

Antidepressant-like action of intracerebral 6-fluoronorepinephrine, a selective full alpha-adrenoceptor agonist
Stone, Eric A; Lin, Yan; Sarfraz, Yasmeen; Quartermain, David
2011 Apr;14(3):319-331, International journal of neuropsychopharmacology
The present study examined the ability of 6-fluoronorepinephrine (6FNE), a full selective alpha-adrenoceptor agonist, to produce antidepressant-like effects in mice. The drug, administered in the 4th ventricle, produced marked anti-immobility effects at mid-dose range in the acute forced swim, tail suspension and repeated open-space forced swim tests with minimal effect on open-field motor activity and also reversed anhedonia following lipopolysaccharide administration. Its antidepressant effects were equal to or greater than that of an established systemic antidepressant, desmethylimipramine, given subacutely. Experiments with alpha-adrenoceptor antagonists indicated that the drug acts primarily via the alpha2-receptor in contrast to endogenous catecholamines which appear to control depressive behaviour primarily via the alpha1-receptor. Antidepressant activity declined at higher doses signifying a possible pro-depressant effect of one of the alpha-adrenoceptor subtypes. Compared to the selective alpha2-agonist, dexmedetomidine, 6FNE showed equivalent antidepressant action in the tail suspension test but appeared to have a greater efficacy or speed of action in the repeated open-space forced swim test which produces a more sustained depression. Studies of regional brain Fos expression induced during the antidepressant tests showed that 6FNE tended to inhibit neural activity in two stress-responsive regions (locus coeruleus and paraventricular hypothalamus) but to enhance activity in two areas involved in motivated behaviour (nucleus accumbens shell and lateral septal nucleus) producing a neural pattern consistent with antidepressant action. It is concluded that 6FNE elicits a rapid and effective antidepressant and anti-stress response that may compare favourably with available antidepressants
— id: 130896, year: 2011, vol: 14, page: 319, stat: Journal Article,

The role of the central noradrenergic system in behavioral inhibition
Stone, Eric A; Lin, Yan; Sarfraz, Yasmeen; Quartermain, David
2011 Jun 24;67(1-2):193-208, Brain research. Brain research reviews
Although the central noradrenergic system has been shown to be involved in a number of behavioral and neurophysiological processes, the relation of these to its role in depressive illness has been difficult to define. The present review discusses the hypothesis that one of its chief functions that may be related to affective illness is the inhibition of behavioral activation, a prominent symptom of the disorder. This hypothesis is found to be consistent with most previous neuropsychopharmacological and immunohistochemical experiments on active behavior in rodents in a variety of experimental conditions using manipulation of neurotransmission at both locus coeruleus and forebrain adrenergic receptors. The findings support a mechanism in which high rates of noradrenergic neural activity suppress the neural activity of principal neurons in forebrain regions mediating active behavior. The suppression may be mediated through postsynaptic galaninergic and adrenergic receptors, and via the release of corticotrophin-releasing hormone. The hypothesis is consistent with clinical evidence for central noradrenergic system hyperactivity in depressives and with the view that this hyperactivity is a contributing etiological factor in the disorder. A similar mechanism may underlie the ability of the noradrenergic system to suppress seizure activity suggesting that inhibition of the spread of neural activation may be a unifying function
— id: 134305, year: 2011, vol: 67, page: 193, stat: Journal Article,

Marked behavioral activation from inhibitory stimulation of locus coeruleus alpha 1-adrenoceptors by a full agonist (vol 1291, pg 21, 2009)
Stone, EA; Lin, Y; Sarfraz, Y; Quartermain, D
2010 APR 22 ;1326(5):193-193, Brain research
— id: 109712, year: 2010, vol: 1326, page: 193, stat: Journal Article,

Partial Lesions of the Locus Coeruleus in Mice Reduce Depression and Modify the Effects of alpha-Adrenoceptor Stimulation and Blockade
Stone, EA; Lin, Y; Sarfraz, Y; Quartermain, D
2010 MAY 1 ;67(9):239S-239S, Biological psychiatry
— id: 111944, year: 2010, vol: 67, page: 239S, stat: Journal Article,

Regulation of Behavioral and Neural Activity by Alpha-1 Adrenergic Receptors of the Locus Coeruleus
Stone, EA; Lin, Y; Quartermain, D
2009 APR 15 ;65(8):109S-109S, Biological psychiatry
— id: 97977, year: 2009, vol: 65, page: 109S, stat: Journal Article,

Marked behavioral activation from inhibitory stimulation of locus coeruleus alpha1-adrenoceptors by a full agonist
Stone, Eric A; Lin, Yan; Sarfraz, Yasmeen; Quartermain, David
2009 Sep 29;1291:21-31, Brain research
alpha(1)-Adrenoceptors are concentrated in the locus coeruleus (LC) where they appear to regulate various active behaviors but have been difficult to stimulate effectively. The present study examined the behavioral, pharmacological and neural effects of possible stimulation of these receptors with 6-fluoronorepinephrine (6FNE), the only known selective alpha-agonist that has full efficacy at all brain alpha-receptors. Infusion of this compound in the mouse LC was found to produce extreme activation of diverse motivated behaviors of exploration, wheel-running and operant approach responding in different environments consistent with a global behavioral function of the dorsal noradrenergic system. Infusion of selective antagonists of alpha(1)- (terazosin) or alpha(2)- (atipamezole) receptors or of either the partial alpha(1)-agonist, phenylephrine, or full alpha(2)-agonist, dexmedetomidine, indicated that the behavioral effects of 6FNE were due largely due to activation of LC alpha(1)-receptors consistent with the known greater density of alpha(1)- than alpha(2)-adrenoreceptors in the mouse nucleus. Immunohistochemistry of fos in tyrosine hydroxylase-positive LC neurons following IV ventricular infusions indicated that 6FNE markedly depressed whereas terazosin strongly enhanced the apparent functional activity of the nucleus. The changes in fos expression following 6FNE and terazosin were significantly greater than those following dexmedetomidine and atipamezole. It is hypothesized that the alpha(1)-receptors of the mouse LC are strongly activated by 6FNE and serve to potently inhibit its tonic or stress-induced activity which in turn disinhibits prepotent motivated behaviors
— id: 101956, year: 2009, vol: 1291, page: 21, stat: Journal Article,

Possible dopaminergic stimulation of locus coeruleus alpha1-adrenoceptors involved in behavioral activation
Lin, Yan; Quartermain, David; Dunn, Adrian J; Weinshenker, David; Stone, Eric A
2008 Jul;62(7):516-523, Synapse
alpha(1)-Adrenoceptors of the locus coeruleus (LC) have been implicated in behavioral activation in novel surroundings, but the endogenous agonist that activates these receptors has not been established. In addition to the canonical activation of alpha(1)-receptors by norepinephrine (NE), there is evidence that dopamine (DA) may also activate certain brain alpha(1)-receptors. This study examined the contribution of DA to exploratory activity in a novel cage by determining the effect of infusion of various dopaminergic and adrenergic drugs into the mouse LC. It was found that the D2/D3 agonist, quinpirole, which selectively blocks the release of CNS DA, produced a dose-dependent and virtually complete abolition of exploration and all movement in the novel cage test. The quinpirole-induced inactivity was significantly attenuated by coinfusion of DA but not by the D1 agonist, SKF38390. Furthermore, the DA attenuation of quinpirole inactivity was blocked by coinfusion of the alpha(1)-adrenergic receptor antagonist, terazosin, but not by the D1 receptor antagonist, SCH23390. LC infusions of either quinpirole or terazosin also produced profound inactivity in DA-beta-hydroxylase knockout (Dbh -/-) mice that lack NE, indicating that their behavioral effects were not due to an alteration of the release or action of LC NE. Measurement of endogenous DA, NE, and 5HT and their metabolites in the LC during exposure to the novel cage indicated an increase in the turnover of DA and NE but not 5HT. These results indicate that DA is a candidate as an endogenous agonist for behaviorally activating LC alpha(1)-receptors and may play a role in the activation of this nucleus by novel surroundings. Synapse 62:516-523, 2008. (c) 2008 Wiley-Liss, Inc
— id: 78676, year: 2008, vol: 62, page: 516, stat: Journal Article,

Probable dopaminergic stimulation of alpha-1 adrenoceptors in locus coeruleus involved in behavioral activation
Stone, EA; Lin, Y; Quartermain, D
2008 APR 1 ;63(7):165S-165S, Biological psychiatry
— id: 78668, year: 2008, vol: 63, page: 165S, stat: Journal Article,

An anti-immobility effect of exogenous corticosterone in mice
Stone, Eric A; Lin, Yan
2008 Feb 2;580(1-2):135-142, European journal of pharmacology
Although traditionally considered to be etiological factors in depression, corticosteroids have been shown to exert an acute antidepressant action under some conditions. To investigate the mechanism of this effect, the present experiment sought to develop an animal model of it in mice using the repeated forced swim procedure. Corticosterone or desmethylimipramine was administered in the drinking water before, during or after repeated daily forced swims or a tail suspension test. Glucocorticoid and mineralocorticoid receptor involvement were assessed by coadministration of RU486 or spironolactone. Plasma corticosterone and fos expression in the paraventricular nucleus of the hypothalamus and piriform cortex were also measured in the treated animals. Corticosterone, given either before/during or after repeated swim, was found to produce a rapid reduction of immobility that was greater than that produced by desmethylimipramine given by the same route and dose and for the same duration. There was a nonsignificant tendency toward this effect in the tail suspension test. RU486 failed to block the effect but results with spironolactone were ambiguous. Plasma corticosterone was elevated in an inverted U-shaped fashion by the hormone treatment. Fos expression in response to the last swim was blunted in the paraventricular hypothalamus but enhanced in the piriform cortex. It is concluded that short-term treatment with corticosterone has a marked antidepressant effect in the mouse repeated forced swim test and merits further consideration as a short-term therapeutic agent in low doses. The hormone may act by suppression of neural activity in central stress circuits leading to a disinhibition of regions involved in active behavioral coping
— id: 75686, year: 2008, vol: 580, page: 135, stat: Journal Article,

A final common pathway for depression? Progress toward a general conceptual framework
Stone, Eric A; Lin, Yan; Quartermain, David
2008 ;32(3):508-524, Neuroscience & biobehavioral reviews
Functional neuroimaging studies of depressed patients have converged with functional brain mapping studies of depressed animals in showing that depression is accompanied by a hypoactivity of brain regions involved in positively motivated behavior together with a hyperactivity in regions involved in stress responses. Both sets of changes are reversed by diverse antidepressant treatments. It has been proposed that this neural pattern underlies the symptoms common to most forms of the depression, which are the loss of positively motivated behavior and increased stress. The paper discusses how this framework can organize diverse findings ranging from effects of monoamine neurotransmitters, cytokines, corticosteroids and neurotrophins on depression. The hypothesis leads to new insights concerning the relationship between the prolonged inactivity of the positive motivational network during a depressive episode and the loss of neurotrophic support, the potential antidepressant action of corticosteroid treatment, and to the key question of whether antidepressants act by inhibiting the activity of the stress network or by enhancing the activity of the positive motivational system
— id: 75687, year: 2008, vol: 32, page: 508, stat: Journal Article,

Evaluation of the repeated open-space swim model of depression in the mouse
Stone, Eric A; Lin, Yan; Quartermain, David
2008 Nov;91(1):190-195, Pharmacology biochemistry & behavior
The present study evaluated the extension of a new rat model of depression, repeated open-space swimming, which overcomes drawbacks of existing models, to mice. Mice were swum for 15 min daily in a large tank of tepid water for 4 days and thereafter at 4 day intervals for a period of 3 weeks. Some of the animals were provided with an active coping (escape) response. Variables measured included time floating, distance swum, immobility on a subsequent tail-suspension test, sucrose preference and brain cell proliferation (Ki67 immunohistochemistry) as well as responses to 2 antidepressant drugs, desmethylimipramine and fluoxetine, and 2 non-antidepressant drugs, haloperidol and diazepam. The repeated swims were found to increase time floating and tail-suspension immobility and to decrease distance swum, sucrose preference and brain cell proliferation. Both chronic antidepressant drugs as well as the active coping response attenuated the increased time floating while neither of the non-antidepressant drugs had this effect. The distance swum measure was found to be more variable. Chronic fluoxetine also reversed the increased tail-suspension immobility, reduced sucrose preference and reduced brain cell proliferation caused by the model. It is concluded that repeated open-space swim represents a useful new model of depression in the mouse
— id: 93348, year: 2008, vol: 91, page: 190, 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,

A final common pathway for depression: implications for therapy
Stone, Eric A
2007 Aug;11(8):1019-1032, Expert opinion on therapeutic targets
Depression in humans and animal models has been found to be accompanied by a hypoactivity of brain regions involved in positively motivated behavior together with a hyperactivity in regions involved in stress responses. Both sets of changes are reversed by diverse antidepressant treatments. It has been proposed that this neural pattern underlies the symptoms common to most forms of depression, which are the loss of positively motivated behavior and the increase in stress. The present paper discusses how this framework can organize diverse findings on the multiple factors associated with this disorder. The hypothesis suggests new therapeutic strategies involving treatment with low-dose corticosteroids to suppress the stress network or with antagonists of alpha(1A)- and agonists of alpha(1B)-adrenoceptors to disinhibit or activate the positive motivational network, respectively
— id: 75688, year: 2007, vol: 11, page: 1019, stat: Journal Article,

Reduced evoked fos expression in activity-related brain regions in animal models of behavioral depression
Stone, Eric A; Lehmann, Michael L; Lin, Yan; Quartermain, David
2007 Aug 15;31(6):1196-1207, Progress in neuro-psychopharmacology & biological psychiatry
A previous study showed that two mouse models of behavioral depression, immune system activation and depletion of brain monoamines, are accompanied by marked reductions in stimulated neural activity in brain regions involved in motivated behavior. The present study tested whether this effect is common to other depression models by examining the effects of repeated forced swimming, chronic subordination stress or acute intraventricular galanin injection - three additional models - on baseline or stimulated c-fos expression in several brain regions known to be involved in motor or motivational processes (secondary motor, M2, anterior piriform cortex, APIR, posterior cingulate gyrus, CG, nucleus accumbens, NAC). Each of the depression models was found to reduce the fos response stimulated by exposure to a novel cage or a swim stress in all four of these brain areas but not to affect the response of a stress-sensitive region (paraventricular hypothalamus, PVH) that was included for control purposes. Baseline fos expression in these structures was either unaffected or affected in an opposite direction to the stimulated response. Pretreatment with either desmethylimipramine (DMI) or tranylcypromine (tranyl) attenuated these changes. It is concluded that the pattern of a reduced neural function of CNS motor/motivational regions with an increased function of stress areas is common to 5 models of behavioral depression in the mouse and is a potential experimental analog of the neural activity changes occurring in the clinical condition
— id: 73821, year: 2007, vol: 31, page: 1196, stat: Journal Article,

Central alpha1-adrenergic system in behavioral activity and depression
Stone, Eric A; Quartermain, David; Lin, Yan; Lehmann, Michael L
2007 Apr 15;73(8):1063-1075, Biochemical pharmacology
Central alpha(1)-adrenoceptors are activated by norepinephrine (NE), epinephrine (EPI) and possibly dopamine (DA), and function in two fundamental and opposed types of behavior: (1) positively motivated exploratory and approach activities, and (2) stress reactions and behavioral inhibition. Brain microinjection studies have revealed that the positive-linked receptors are located in eight to nine brain regions spanning the neuraxis including the secondary motor cortex, piriform cortex, nucleus accumbens, preoptic area, lateral hypothalamic area, vermis cerebellum, locus coeruleus, dorsal raphe and possibly the C1 nucleus of the ventrolateral medulla, whereas the stress-linked receptors are present in at least three areas including the paraventricular nucleus of the hypothalamus, central nucleus of the amygdala and bed nucleus of the stria terminalis. Recent studies utilizing c-fos expression and mitogen-activated protein kinase activation have shown that various diverse models of depression in mice produce decreases in positive region-neural activity elicited by motivating stimuli along with increases in neural activity of stress areas. Both types of change are attenuated by various antidepressant agents. This has suggested that the balance of the two networks determines whether an animal displays depressive behavior. A central unresolved question concerns how the alpha(1)-receptors in the positive-activity and stress systems are differentially activated during the appropriate behavioral conditions and to what extent this is related to differences in endogenous ligands or receptor subtype distributions.
— id: 72727, year: 2007, vol: 73, page: 1063, stat: Journal Article,

Reduction of central neural response to motivating stimuli: A common effect of models of depression
Stone, EA; Lin, Y; Lehmann, ML; Quartermain, D
2006 DEC ;31(2):S110-S110, Neuropsychopharmacology
— id: 70913, year: 2006, vol: 31, page: S110, stat: Journal Article,

Depressive behavior in mice due to immune stimulation is accompanied by reduced neural activity in brain regions involved in positively motivated behavior
Stone, Eric A; Lehmann, Michael L; Lin, Yan; Quartermain, David
2006 Oct 15;60(8):803-811, Biological psychiatry
BACKGROUND: Immune stimulation inhibits positively motivated behavior and induces depressive illness. To help clarify the mechanism of these effects, neural activity in response to a positive stimulus was examined in brain regions associated with positively motivated activity defined on the basis of prior behavioral studies of central alpha1-adrenoceptor action. METHODS: Mice pretreated with either lipopolysaccharide or, for comparison, reserpine were exposed to a motivating stimulus (fresh cage) and subsequently assayed for fos expression and mitogen-activated protein kinase (MAPK) phosphorylation, two measures associated with alpha1-adrenoceptor-dependent neural activity, in several positive-activity-related (motor, piriform, cingulate cortex, nucleus accumbens, locus coeruleus) and stress-related brain regions (paraventricular hypothalamus, bed nucleus stria terminalis). RESULTS: Both lipopolysaccharide and reserpine pretreatment abolished fresh cage-induced fos expression and MAPK activation in the positive activity-related brain regions but enhanced these measures in the stress-related areas. CONCLUSIONS: The results support the hypothesis that immune activation reduces alpha1-adrenoceptor-related signaling and neural activity in brain regions associated with positive activity while it increases these functions in stress-associated areas. It is suggested that neural activities of these two types of brain regions are mutually antagonistic and that a reciprocal shift toward the stress regions is a factor in the loss of positively motivated behaviors in sickness behavior and depressive illness
— id: 69688, year: 2006, vol: 60, page: 803, stat: Journal Article,

Role of CNS alpha1-adrenoceptor activity in central fos responses to novelty
Stone, Eric A; Yan, Lin; Ahsan, Mohammed R; Lehmann, Michael L; Yeretsian, Joseph; Quartermain, David
2006 Apr;59(5):299-307, Synapse
The present study investigated, by use of fos immunohistochemistry, whether the functional activity of alpha(1)-adrenoceptors is elevated during heightened behavioral activity in brain regions shown earlier to contain motoric alpha(1)-receptors. In confirmation, marked c-fos responses that were blocked by an alpha(1)-antagonist (prazosin) were found in four of these brain regions (secondary motor, cingulate, piriform cortices, and nucleus accumbens) of animals exposed to a mildly novel environment (clean cage), which elicits a high degree of sustained exploratory activity. Experimental restriction of exploratory activity in the novel cage by a small enclosure did not reduce the fos responses in these areas, and in fact, enhanced gene expression when carried out in home-caged animals suggesting that the fos response may be more closely associated with the motivation to be active rather than activity itself. Experiments with locally administered alpha(1)-agonists and antagonists in the cortex by reverse dialysis showed that the above mentioned alpha(1)-dependent-fos responses were the result of activation of local alpha(1)-receptors in these brain regions. Unlike the aforementioned brain regions, the fos response of the locus coeruleus was not blocked by prazosin, and this nucleus also showed a marked fos increase to prazosin itself possibly as a compensatory response to the blockade of forebrain alpha(1)-receptors
— id: 64197, year: 2006, vol: 59, page: 299, stat: Journal Article,

Alpha(1)-adrenergic and alpha(2)-adrenergic balance in the dorsal pons and gross behavioral activity of mice in a novel environment
Stone, Eric A; Lin, Yan; Ahsan, Mohammad R; Quartermain, David
2005 Nov;183(1):127-132, Psychopharmacology
RATIONALE: Central alpha(1)- and alpha(2)-adrenoceptors in a number of different brain regions are known to have opposing actions on gross behavioral activity, with the former stimulating and the latter inhibiting activity. Therefore, blockade of alpha(1)-receptors may induce inactivity by leading to unopposed alpha(2) activity. OBJECTIVE: The aim of this study was to test if central blockade of alpha(2)-receptor function restores behavioral activity in alpha(1)-receptor-blocked mice. METHODS: Dose-response studies were undertaken on the effects of alpha(1)- and alpha(2)-agonists and antagonists microinjected into the dorsal pons on gross behavioral activity in a novel cage test. RESULTS: The behavioral inactivity resulting from blockade of alpha(1)-receptors in the pons with the antagonist, terazosin, was reversed by either a low dose of an alpha(2)-antagonist, atipamezole, or a low dose of an alpha(2)-agonist, dexmedetomidine, but was exacerbated by a high dose of the alpha(2)-agonist. CONCLUSION: The results support the hypothesis that blockade of alpha(1)-receptors in the dorsal pons of mice produces inactivity by causing unopposed activity of alpha(2)-receptors. This condition may be relevant to inactive states seen after stress or during depressive illness
— id: 69572, year: 2005, vol: 183, page: 127, stat: Journal Article,

Evidence of roles of central alpha1-adrenoceptors and epinephrine in orexin A-induced hyperactivity in mice
Stone, Eric A; Lin, Yan; Ahsan, Mohammad R; Quartermain, David
2005 Jun 24;381(3):325-328, Neuroscience letters
Previous studies have shown that central alpha1-adrenoceptor activity is necessary, acutely, for gross behavioral activity in response to novel surroundings and various psychostimulants. The present experiment tested whether it is also necessary for the hyperactivity produced by the peptide, orexin A, which is present in several central monoaminergic nuclei. Mice, pretreated intraventricularly with the alpha1-antagonist, terazosin, or the alpha2-antagonist, atipamezole, were given orexin A, intraventricularly (i.v.t.), and videotaped for gross movement and locomotion in the home cage between 30 and 60 min post-infusion. The alpha1-antagonist was found to produce a significant dose-dependent decrease of orexin A-induced activity, which was first seen at the 3 nmol dose and was near total at 30 nmol. The alpha2-antagonist, at 10 nmol, had no effect on the orexin A response. Pharmacological inhibition of the synthesis of epinephrine, a potential neurotransmitter at central motoric alpha1-adrenoceptors, with 2,3-dichloro-alpha-methylbenzylamine also significantly attenuated orexin A-induced hyperactivity. It is concluded that central alpha1-adrenoceptor activity, presumably caused by epinephrine release, is necessary for the gross behavioral activation produced by orexin A
— id: 56095, year: 2005, vol: 381, page: 325, stat: Journal Article,

Rate-dependent behavioral effects of stimulation of central motoric alpha(1)-adrenoceptors: hypothesized relation to depolarization blockade
Stone, Eric A; Quartermain, David
2005 Mar;178(2-3):109-114, Psychopharmacology
AIM: The purpose of this review is to clarify how central alpha(1)-adrenoceptors control behavioral activity under varying conditions of activity and stress. METHOD: The literature is reviewed regarding the behavioral actions of alpha(1)-agonists and antagonists, and alpha(2)-agonists and antagonists under conditions of high and low baseline activity and stress. RESULTS: It was found that alpha(1)-receptor stimulation of active behavior has a number of similarities to rate dependency including: (1) a dependence on low-active, low-stress conditions or on the prior depletion of endogenous brain catecholamines; (2) a nonmonotonic dose-response relationship with high doses producing a fall-off or actual depression of activity; (3) a failure to be blocked at high agonist doses by alpha(1)-antagonists; and (4) a facilitation by alpha(2)-adrenoceptor agonists which produce an opposing hyperpolarization. DISCUSSION: To explain these findings, it is proposed that high levels of stimulation of central alpha(1)-receptors produce, in host neurons, a depolarization block that impedes nerve impulse generation and inhibits active behavior. This effect is assumed to be precluded or mitigated by low-active, low-stress conditions, depletion of brain catecholamines, and by hyperpolarizing alpha(2)-agonists, and to be reversed at high agonist doses by alpha(1)-antagonists. CONCLUSION: Because brain alpha(1)-receptors are not only involved in motor activity but also in the mechanism of action of antidepressant and stimulant drugs, arousal, anxiety, stress and psychosis, a depolarization block from intense stimulation of these receptors could have broad psychopharmacological consequences and underlie rate dependency to a variety of stimulant drugs
— id: 56135, year: 2005, vol: 178, page: 109, stat: Journal Article,

The brain epinephrine- alpha -sub-1-adrenoceptor system in behavioral activation and depression
Stone, Eric A; Quartermain, David
2005 ;1(1):33-43 Jan, Current psychiatry reviews
Disabling behavioral inactivity is a prominent symptom of a number of psychiatric disorders, most notably, major depressive illness. The neurobiology of these inactive states is currently believed to involve alterations in central serotonergic, noradrenergic or dopaminergic neurotransmission as affected by various etiological and predisposing factors. Recent evidence suggests that there is another system that consists of a subset of brain alpha -sub-1-adrenoceptors stimulated primarily by brain epinephrine (EPI) that potentially modulates the above three monoamine systems and plays a critical role in behavioral activation and depression. The present review covers the evidence for this system and includes findings that brain alpha -sub-1-adrenoceptors are instrumental in behavioral activation, are located near the major monoamine cell groups or target areas, receive EPI as their neurotransmitter, are impaired or inhibited in depressed patients or after stress in animal models, and are restored by a number of antidepressants. This 'EPI- alpha -sub-1 system' may therefore represent a new target system for disabling inactivity. (journal abstract)
— id: 62407, year: 2005, vol: 1, page: 33, stat: Journal Article,

Gross mapping of alpha1-adrenoceptors that regulate behavioral activation in the mouse brain
Stone, Eric A; Lin, Yan; Ahsan, Rashedul; Quartermain, David
2004 Aug 9;152(2):167-175, Behavioural brain research
Brain alpha1-adrenoceptors that participate in behavioral activation were mapped in the mouse brain by determining where microinjection of the alpha1-antagonist, terazosin, inhibited behavioral activity in a novel cage test. A total of 5 out of 23 tested regions were shown to be involved including the dorsal pons/locus coeruleus region (DP/LC), the dorsal raphe/periaqueductal gray area (DR/PAG), the vermis cerebellum (CER), the nucleus accumbens (ACC) and the medial preoptic area (MPOA). Injection in the 4th ventricle was also effective perhaps by acting on several of these regions simultaneously. A partial inhibition was obtained from the motor cortex. Coinjection of the alpha1/2-agonist, 6-fluoronorepinephrine (6FNE) but not the alpha2-agonist, dexmedetomidine (DMT) reversed the behavioral inhibition in all regions. It is hypothesized that brain motoric alpha1-receptors elicit behavioral activation by coordinately exciting several monoaminergic, motor and motivational systems
— id: 46164, year: 2004, vol: 152, page: 167, stat: Journal Article,

Role of locus coeruleus alpha1-adrenoceptors in motor activity in rats
Stone, Eric A; Lin, Yan; Ahsan, Rashedul; Quartermain, David
2004 Dec 1;54(3):164-172, Synapse
The question of whether or not the locus coeruleus (LC) participates in the control of motor activity has been controversial due to difficulties in demonstrating permanent motor deficits after neurotoxic lesions of this nucleus or of the dorsal noradrenergic bundle (DNB). In the present experiments it was shown in rats that acute local blockade (with terazosin) or stimulation (with phenylephrine) of LC alpha(1)-adrenoceptors respectively blocked or stimulated exploratory behavior in a novel cage and the home cage. Moreover, previous lesion of the DNB by i.p. DSP4 abolished the behavioral changes to local LC alpha(1)-receptor manipulation but did not affect motor activity in the novel or home cage by itself. These findings are consistent with the hypothesis that the intact LC does contribute to motor activity control, exerted in part by its alpha(1)-receptors; however, the permanent loss of this nucleus is compensated for by remaining CNS motor structures
— id: 48076, year: 2004, vol: 54, page: 164, stat: Journal Article,

Localization of central alpha1 - adrenoceptors that control behavioral activity in monoaminergic neurons and related structures
Lin, Y.; Ahsan, R.; Yeretsian, J.; Quartermain, D.; Stone, E. A.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
It has been shown that a subgroup of alpha1-adrenoceptors are both essential for spontaneous and novelty-induced behavioral activity and play a key role in the hyperactivity produced by stimulant drugs. In order to define which brain areas these motoric alpha1-receptors operate in, we have conducted a series of studies over the past 2 years on the ability of microinjections of the soluble alpha1-antagonist, terazosin, in various brain regions to induce immobility in a novel cage test. A total of 23 brain areas including those implicated in motor activation, circadian rhythm regulation, or having unusually high densities of alpha1-receptors were examined in mice. A total of 4 regions were found to show 'positive' responses to terazosin: the dorsal pons in or near the locus coeruleus (LC), the dorsal raphe (DR), the nucleus accumbens (ACC) and the cerebellum. The IVth ventricle also yielded a strong immobility response probably due to combined action at the dorsal pons and cerebellum. Partial responses were obtained in the corpus striatum, anterior hypothalamus and medial preoptic region. No effect was found in the ventral tegmental area (VTA), substantia nigra, posterior hypothalamus, amygdala, BNST, prefrontal cortex or hippocampus. An increase in motor activity was found in the septum. The locations of these motoric alpha1-receptors in the dorsal pons, DR, ACC and possibly striatum suggests that they elicit behavioral activation by excitation of the 3 chief monoaminergic systems (NE, 5HT and DA)in the brain. In addition, the cerebellum is known to send efferents to the VTA, LC and DR. Other studies have suggested that motoric alpha1-adrenoceptors are innervated by brain epinephrine (EPI) and constitute a distinct neuronal system for coordinated behavioral activation
— id: 92472, year: 2003, vol: 2003, page: ?, stat: Journal Article,

Mutations induced by chemical mutagenesis affecting the mouse ERG and fundus
Siepka, S. H.; Lumayag, S.; Vitaterna, M.; Takahashi, J. S.; Mullins, R.; Heffron, E.; Sheffield, V.; Stone, E.; Kibbe, W. A.; Pinto, L. H.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
We use mutagenesis and screeening to create mouse models of human diseases and allow genetic dissection of the visual system. C57BL/6J mice were mutagenized with a chemical mutagen, ENU, and bred for 3 generations to generate animals homozygous for recessive mutations. At ca. 12 weeks of age the dark-adapted electroretinogram of each G3 mouse was measured and quantified and the fundus was photographed and anaylzed for abnormalities. The offspring of affected mice were bred to test for transmission of abnormal traits. In one pedigree 5 male and 2 female siblings with no detectable ERG were isolated. Their fundi showed narrowed retinal vessels and a pattern of pigmentation consistent with photoreceptor degeneration. The mutant animal showed complete degeneration of the photoreceptor layer of the retina and the presence of cysts in all retinal layers. These traits were inherited by their G4 offspring in manner consistent with a dominant mode of inheritance. In addition to this mutant 12 putative mutants were isolated with other ERG abnormalities and 13 putative mutatants were isolated with abnormalities of the fundus. These putative mutants are now being tested for genetic transmission. Thus, a mouse mutant model of autosomal dominant retinal degenerative disorders has been generated and several other mutants have probably already been generated. The genetic tools available for the mouse make it possible to identify the affected genes and determine the roles of their gene products. These mice are being available to the scientific community. Their detailed phenotypes, genetic mapping information, and information about how to obtain them can be found at the web sitehttp://www.genome.northwestern.edu
— id: 92474, year: 2003, vol: 2003, page: ?, stat: Journal Article,

A putative epinephrine ( EPI ) - innervated alpha1 - adrenoceptor CNS system may be a new target in depressive illness
Stone, E. A.; Lin, Y.; Ahsan, R.; Quartermain, D.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
A series of new findings on brain alpha1-adrenoceptors has confirmed and greatly extended the hypothesis that these receptors play a key role in depressive illness. First, in experiments using either the ivt. injection of the alpha1-antagonist, terazosin, and /or alpha1B-receptor deficient mice, it has been found that central alpha1 receptors are essential for spontaneous, novelty-and stimulant drug-induced behavioral activity. Second, these 'motoric' alpha1-receptors have also been shown to be present and to mediate neuronal excitation in 3 major monoamine-containing brain regions: the dorsal pons in or near the locus coeruleus (LC), the dorsal raphe (DR) and nucleus accumbens as well as in the cerebellum which sends efferents to the LC, DR and ventral tegmental area. Third, the endogenous neurotransmitter at these motoric alpha1 receptors now appears to be EPI, based on studies of the marked immobility effects of PNMT inhibitors and their reversal by central EPI infusion. Fourth, a long-lasting depletion of brain EPI and a desensitization of brain alpha1-receptors involved in the potentiation of cAMP responses and the motor activating effect of the stimulant, modafinil has been found in stress models of depression in animals. And fifth, depressive illness may be associated with a marked 70-75% depletion of CSF EPI, which is reversed by antidepressant treatment, as well as a subsensitivity of central postsynaptic alpha1-receptors involved in the plasma cortisol response to amphetamine and desmethylimipramine. Based on these findings we postulate the existence of an EPI-innervated-alpha1-adrenergic system that regulates behavioral activation by costimulation of NE-, 5HT-and DAergic processes and is impaired both pre-and postsynaptically by stress and depressive illness
— id: 92473, year: 2003, vol: 2003, page: ?, stat: Journal Article,

Role of epinephrine stimulation of CNS alpha1-adrenoceptors in motor activity in mice
Stone, Eric A; Grunewald, Gary L; Lin, Yan; Ahsan, Rashedul; Rosengarten, Helen; Kramer, H Kenneth; Quartermain, David
2003 Jul;49(1):67-76, Synapse
The role of brain epinephrine (EPI) in the regulation of motor activity and movement in mice was examined. Blockade of EPI synthesis with i.p. 2,3-dichloro-alpha-methylbenzylamine (DCMB) or LY134046 was found to produce marked behavioral inactivity which could be significantly reversed by intraventricular injection of EPI and by three other alpha(1)-adrenoceptor agonists, norepinephrine (NE), 6-fluoronorepinephrine (6FNE), and phenylephrine (PE), as well as by serotonin (5HT). EPI had the largest effect of these agonists and also was the only one that reversed nondrug-induced inactivity of mice in their home cages during the light phase. The effects of EPI were blocked by coinfusion of an alpha(1)-adrenoceptor antagonist (terazosin) but not of an alpha(2)-(atipamezole) or beta(1) (betaxolol)-blocker. The rank order of maximal behavioral responses to EPI, 6FNE, and PE in DCMB-treated mice was the same as the rank order of their maximal stimulation of hydrolysis of phosphatidylinositol at cloned alpha(1B)-adrenoceptors in cell culture. On the basis of the above findings and of the central distributions of adrenergic neurons and alpha(1)-adrenoceptors, the existence of a central EPI-innervated alpha(1)-adrenergic receptor system is postulated which serves to coexcite or enhance signaling in several monoaminergic brain regions involved in movement and motor activity
— id: 39239, year: 2003, vol: 49, page: 67, stat: Journal Article,

Immobility from administration of the alpha1-adrenergic antagonist, terazosin, in the IVth ventricle in rats
Stone, Eric A; Lin, Yan; Quartermain, David
2003 ;353(3):231-233, Neuroscience letters
Brain alpha1-adrenoceptors have been shown to be essential for motor activity and movement in mice using intraventricular injection of alpha1-antagonists. To facilitate subsequent neuroanatomical mapping of these receptors, the present study was undertaken to replicate these effects in the rat. Rats were administered the alpha1-antagonist, terazosin, in the absence and presence of the alpha1-agonist, phenylephrine, in the IVth ventricle and were tested for their motor activity responses to an environmental change. Terazosin was found to produce a dose-dependent, virtually complete cessation of behavioral activity that was reversed by coinfusion of phenylephrine. The results could not be explained by sedation. It is concluded that central alpha1-adrenoceptors are essential for behavioral activation in rats as in mice
— id: 46283, year: 2003, vol: 353, page: 231, stat: Journal Article,

Emerging evidence for a central epinephrine-innervated alpha 1-adrenergic system that regulates behavioral activation and is impaired in depression
Stone, Eric A; Lin, Yan; Rosengarten, Helen; Kramer, H Kenneth; Quartermain, David
2003 Aug;28(8):1387-1399, Neuropsychopharmacology
Currently, most basic and clinical research on depression is focused on either central serotonergic, noradrenergic, or dopaminergic neurotransmission as affected by various etiological and predisposing factors. Recent evidence suggests that there is another system that consists of a subset of brain alpha(1B)-adrenoceptors innervated primarily by brain epinephrine (EPI) that potentially modulates the above three monoamine systems in parallel and plays a critical role in depression. The present review covers the evidence for this system and includes findings that brain alpha(1)-adrenoceptors are instrumental in behavioral activation, are located near the major monoamine cell groups or target areas, receive EPI as their neurotransmitter, are impaired or inhibited in depressed patients or after stress in animal models, and are restored by a number of antidepressants. This 'EPI-alpha(1) system' may therefore represent a new target system for this disorder
— id: 39193, year: 2003, vol: 28, page: 1387, stat: Journal Article,

The NIH neurogenomics project: a genetics and genomics resource for neuroscientists
Vitaterna, M. H.; Siepka, S. M.; Shimomura, K.; Simpson, E.; Mohn, A.; Caron, M. G.; Kandel, E. R.; Kibbe, W. A.; Levine, J. E.; Takahashi, J. S.; Mullins, R.; Pinto, L. H.; Redei, E.; Sheffield, V.; Stone, E.; Turek, F. W.; Lotery, A. S.
2003 ;2003:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
As part of the National Institutes of Health (NIH) plan for mouse genomics and genetics resources (http://www.nih.gov/science/models/mouse/genomics/index.html) to create genetic tools for basic research, centers to produce mouse models for research have been established. One such center has been established at Northwestern University to use genome-wide chemical (N-ethyl-N-nitorosourea or ENU) mutagenesis combined with phenotypic screens to create and identify novel mutations affecting the nervous system and behavior of the mouse. A three-generation breeding scheme is used to produce both dominant and recessive mutations, and screens focus on the identification of mutations affecting five phenotypic domains: Learning and memory, Response to stress, Response to Psychostimulants, Circadian rhythmicity, and Vision. Heritability of the phenotype is confirmed, and mutations will be mapped to a modest resolution. Screens are ongoing, so that new mutations continue to be identified. Available mutants are listed at the Neurogenomics Project website at http://www.genome.northwestern.edu/neuro and at http://www.neuromice.org . These new mutants are created with the objective of widely distributing them to the research community. Such a phenotype-driven approach provides a powerful method for functional identification of new genes and pathways involved in neuroscience-relevant processes
— id: 92475, year: 2003, vol: 2003, page: ?, stat: Journal Article,

ANTAGONIST MAPPING OF THE MOUSE BRAIN FOR ALPHA 1 - ADRENOCEPTORS THAT REGULATE MOTOR ACTIVITY
Lin, Y.; Stone, E. A.; Ahsan, R.; Quartermain, D.
2002 ;2002:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
We have recently shown that brain alpha-1B-adrenoceptors are necessary for all spontaneous and novelty-induced motor activity and movement in the Swiss-Webster mouse (Neuropharmacology 40:254-261, 2001). The present study is part of a ongoing series of experiments to characterize the brain localization, operation and behavioral significance of these motoric receptors. Mice previously implanted with cannula guides in a wide range of brain structures were infused either uni-or bilaterally with the nonselective alpha-1 antagonist, terazosin at 2 nmoles/infusion in 350 nl saline or saline vehicle over 2.5 min and introduced immediately into a 'moderately' novel, freshly cleaned standard mouse cage where they were videotaped for 10 min. Motor activity was scored as either gross movements, head movements or time immobile. Terazosin produced the greatest suppression of activity when infused into the pons in or near the locus coeruleus and IV ventricle (approx 80% inhibition). A substantial but lesser inhibition (approx 60%) was found with infusion in the n. accumbens while substantia nigra and VTA infusions were largely ineffective. The striatum was sensitive to vehicle infusion and could not be assessed with terazosin. Unexpectedly, infusions in the hippocampus and septum facilitated gross movements. The results suggest that alpha 1 receptors that facilitate behavioral activation to novelty are located in the pons and parts of the basal ganglia, and that there appears to be a second population of these receptors in the septum and hippocampus that inhibits behavioral activation
— id: 92476, year: 2002, vol: 2002, page: ?, stat: Journal Article,

CENTRAL EPINEPHRINE ( EPI ) INJECTION REVERSES VIA ALPHA 1 - ADRENOCEPTOR THE BEHAVIORAL INACTIVITY CAUSED BY INHIBITION OF PNMT
Stone, E. A.; Grunewald, G. L.; Lin, Y.; Quartermain, D.
2002 ;2002:?-?, Society for Neuroscience Abstract Viewer & Itinerary Planner
Previous findings have suggested that brain EPI has a role in behavioral activity based on the finding that inhibition of PNMT reduces motor activity. The present study was undertaken to determine if intraventricular administration of EPI can restore active behavior in PNMT-inhibited mice, and, if so, which adrenergic receptor it activates to produce this effect. Mice previously implanted with intraventricular cannulas were administered either of the two PNMT inhibitors, dichloro-alpha-methylbenzylamine (DCMB), 60 mg/kg ip or LY 134046, 60 mg/kg ip, 30 min before receiving an intraventricular infusion of EPI (31.6 or 100 nmoles/mouse) with or without one of the following adrenoceptor antagonists: terazosin (alpha-1), betaxolol (beta-1) or atipamezole (alpha-2) each at 31.6 nmoles/mouse. Vehicle treated mice were administered either distilled water i.p. or normal saline ivt. Motor activity was measured by videotaping the mice placed individually in a 'moderately' novel clean cage for 90 min after the ivt injection.)EPI at both 31.6 and 100 nmoles produced a significant reversal of the inactivity produced by both of the above PNMT inhibitors. This effect of EPI was attenuated in animals coinjected with terazosin but not with either betaxolol or atipamezole. The latter agent, in fact, enhanced the reversal induced by EPI.)The results support the hypothesis that brain EPI plays a role in the regulation of active motor behavior and does so via activation of central alpha 1-adrenoceptors
— id: 92477, year: 2002, vol: 2002, page: ?, stat: Journal Article,

Role of brain alpha 1B-adrenoceptors in modafinil-induced behavioral activity
Stone, Eric A; Cotecchia, Susanna; Lin, Yan; Quartermain, David
2002 Dec 15;46(4):269-270, Synapse
These studies show that either central pharmacological blockade or genetic ablation of alpha(1B)-adrenoceptors markedly attenuates the behavioral activation caused by modafinil, implicating these receptors in the drug's action
— id: 34030, year: 2002, vol: 46, page: 269, stat: Journal Article,

Stress-induced subsensitivity to modafinil and its prevention by corticosteroids
Stone, Eric A; Lin, Yan; Suckow, Raymond F; Quartermain, David
2002 Nov;73(4):971-978, Pharmacology biochemistry & behavior
Brain alpha(1)-adrenoceptors are known to be necessary for motor activity in rodents and have been shown to be altered by stress and corticosteroids but only in biochemical experiments. To determine if the behaviorally coupled receptors are also affected by stress, the present study examined the effect of stress and corticosteroids treatment on the motor activity response to modafinil, a putative alpha(1)-adrenoceptor agonist, which is unique in that it elicits extremely high levels of activity via these receptors. Mice were subjected to various schedules of restraint stress for 1-6 days and were subsequently tested for either modafinil-induced or dopaminergically induced behavioral activity in the home cage using videotape recording. In experiments on corticosteroid treatment, mice received exogenous corticosterone or dexamethasone in the drinking water before and during the stress and were tested for modafinil-induced activity as above. It was found that the stress significantly reduced the response to the drug by the third daily session. Motor responses to dopaminergic agents including apomorphine, amphetamine, dihydrexidine and quinpirole were either not altered or were increased at this time. Treatment of animals with corticosterone or dexamethasone prior to and during stress prevented the behavioral subsensitivity to modafinil. Corticosterone pretreatment markedly suppressed the plasma corticosterone response to the stress. The present results provide further support for the hypothesis that stress produces a selective desensitization or inhibition of motor-related brain alpha(1)-adrenoceptors and that this effect can be prevented by corticosteroid treatment
— id: 34031, year: 2002, vol: 73, page: 971, stat: Journal Article,

Effect of local blockade of alpha 1-adrenoceptors in various brain regions on locomotor activity and movement in mice
Lin, Y.; Stone, E. A.
2001 ;27(1):769-769, Abstracts (Society for Neuroscience)
Neurotransmission at brain alpha 1B-adrenoceptors has been found to be necessary for motor activity and movement in the mouse, presumably reflecting adrenergic modulation of central dopaminergic activity (Neuropharmacol. 40:254, 2001). The brain region(s) involved in this action however has not yet been fully mapped although a previous study has suggested involvement of the nucleus accumbens (Neurosci. 99:55, 2000). In the present study this was investigated by examining the effect of bilateral microinjection of the nonselective alpha 1-adrenoceptor antagonist, terazosin, on motor activation and movement. Animals (8-10 week old male Swiss Webster mice) were implanted bilaterally with 26 gauge cannula guides in a variety of brain regions and after recovery tested with terazosin (2 nmoles/site) for 10 min in a novel cage. Preliminary results indicate that injection in the nucleus accumbens reduces locomotion and causes episodes of sudden freezing. No reductions in activity have been found from the amygdala, hippocampus, or prefrontal cortex but suggestive effects have been obtained in the ventral tegmental area and locus coeruleus. Studies of thalamic and other medullary regions are currently in progess
— id: 92479, year: 2001, vol: 27, page: 769, stat: Journal Article,

Pharmacological evidence for the role of central alpha 1B-adrenoceptors in the motor activity and spontaneous movement of mice
Stone EA; Lin Y; Itteera A; Quartermain D
2001 ;40(2):254-261, Neuropharmacology
Central alpha 1-noradrenergic neurotransmission has been shown to be an important complement of dopaminergic transmission in the control of motor activity but the identity of the responsible alpha 1 receptor subtype has not yet been identified. This was investigated in the present experiment by measuring the effects of intraventricular administration of a series of alpha 1 antagonists varying in affinities for the three known receptor subtypes--1a, 1b and 1d--on active behavior in mice in response to a cage change. It was found that the potency of the drugs to block both gross and small movements correlated highly with published affinities for the cloned 1b receptor but not for those of either the cloned 1a or 1d receptors. It is concluded that central alpha 1B receptors are critically involved in the mediation of the (nor)adrenergic influence on active behavior, a finding which has implications for basic and clinical research in both movement and mood disorders
— id: 26816, year: 2001, vol: 40, page: 254, stat: Journal Article,

Pharmacological blockade of brain alpha(1)-adrenoceptors as measured by ex vivo
Stone EA; Rosengarten H; Lin Y; Quartermain D
2001 May 25;420(2-3):97-102, European journal of pharmacology
The present studies examined the relationship between the blockade of central alpha(1)-adrenoceptors, as measured by ex vivo binding of [3H]prazosin in the cerebral cortex and the inhibition of behavioral activation to a mildly novel environment (cage change). It was found that intraventricular (i.v.t.) terazosin, a saline-soluble alpha(1)-adrenoceptor antagonist, dose dependently inhibited both ex vivo cortical binding and behavioral activation and that there was a highly significant positive correlation between the two with a slope near unity. Prazosin, a nonsaline soluble antagonist which had to be given intraperitoneally (i.p.), was much less potent at blocking both behavioral activity and cortical ex vivo binding, although it blocked ex vivo binding in the lung, indicating that it was effective peripherally but did not readily enter the brain. Despite this, however, the inhibition of cortical binding and behavioral activation that i.p. prazosin did produce were highly correlated with each other and had a slope near unity as with terazosin, whereas the more potent inhibition of lung binding was less well correlated with behavioral inhibition and had a slope significantly less than one. These results confirm our earlier studies, which have shown that alpha(1)-adrenoceptor activity is essential for gross and fine motor behavior in the mouse and that prazosin, which is used extensively in behavioral research, has difficulty entering the mouse brain
— id: 21187, year: 2001, vol: 420, page: 97, stat: Journal Article,

Modafinil has partial agonist activity at the alpha 1B-adrenoceptor in vitro and in vivo
Stone, E. A.; Rosengarten, H.; Kramer, H. K.
2001 ;27(2):1767-1767, Abstracts (Society for Neuroscience)
Modafinil is a behavioral stimulant and putative antidepressant whose mechanism of action is not yet fully understood. Several studies have suggested that it acts in part by stimulating brain alpha 1-adrenoceptors (ARs) (Brain Res. 591:319, 1992). We examined modafinil's action on alpha 1 receptors both in vitro measuring PI hydrolysis and MAPK phosphorylation in DDT1 MF-2 cells, which have endogenous alpha 1B-ARs, and in vivo by measuring both the MAPK response and the ability of a series of alpha 1 receptor antagonists to block the drug's behavioral activating effect. In vitro, modafinil (10-4M) was found to stimulate MAPK phosphorylation to 50% of that produced by a maximal concentration of a full alpha 1 agonist (epinephrine, 10-6M), and this action was blocked by the alpha 1 antagonist, terazosin. Modafinil had no effect on or slightly decreased basal levels of PI hydrolysis. In vivo, the drug stimulated MAPK phosphorylation also (25% increase) which again was blocked by intraventricular terazosin, and its behavioral activating effect was abolished by intraventricular administration of antagonists of the alpha 1B but not alpha 1A or 1D adrenoceptors. These results support the hypothesis that modafinil has partial agonist activity at alpha 1B-ARs and may produce its behavioral actions in part via this receptor
— id: 92478, year: 2001, vol: 27, page: 1767, stat: Journal Article,

Brain alpha 1B-adrenoceptor activity necessary for motor activity in the mouse
Stone, E. A.; Lin, Y.; Itteera, A.; Quartermain, D.
2000 ;26(1-2):?-?, Abstracts (Society for Neuroscience)
Central alpha 1-noradrenergic neurotransmission is known to synergize with dopaminergic transmission in the control of movement and active behavior however the responsible alpha 1 receptor subtype has not been identified. We previously reported a high correlation between the affinity of alpha 1 antagonists for the alpha 1B receptor and their ability to block exploration of a novel cage in mice after intraventricular injection (Abstr Soc Neurosci 25:244.5,1999). This study however was problematic in that the vehicle used for the lipophilic antagonists (water/dmso) affected the behavior by itself. We have therefore repeated the experiment using only hydrophilic or near hydrophilic antagonists in a saline vehicle. Mice, previously implanted with intraventricular cannulas, were infused various doses (0.1-300 nmoles) of one of six antagonists: terazosin, benoxathian, 5-methylurapidil, BMY7378, phentolamine and WB4101 in 2 ul saline shortly before being placed in a novel mouse cage in which they were videotaped for 30 min. Activity was measured as total forward movements (gross) and total head movements (small). A significant positive correlation was found between known affinities for the cloned alpha 1b receptor and ID50s for inhibition of both forward (r = 0.93, p < 0.01) and head movements (0.92, p = 0.01). No significant correlations were obtained for the alpha 1A and 1D receptors (0.3-0.4). The present results thus confirm our previous finding that alpha 1B adrenergic receptor actvity is necessary for motor activity and spontaneous movement to environmental stimulation in the mouse
— id: 92480, year: 2000, vol: 26, page: ?, stat: Journal Article,

Effects of stress, corticosterone and LPS on alpha 1-adrenergic mediated hyperactivity
Zhang, Y.; Itteera, A.; Quartermain, D.; Stone, E. A.
2000 ;26(1-2):?-?, Abstracts (Society for Neuroscience)
Stress, corticosterone and LPS have all been shown to be capable of desensitizing alpha 1-adrenoceptors. As brain alpha 1 receptors have recently been shown to be essential for motor activity and movement, and can be stimulated by the agonist-like compound, modafinil, it was of interest to determine the effects of these treatments on modafinil-induced hyperactivity. Mice were exposed to acute or repeated restraint stress (1 hr), acute or repeated corticosterone administration (50 mg/kg, sc) or acute LPS injection (50 ug/kg ip) and were injected with various doses of modafinil and videotaped for motor activity determination 6-24 hrs after the last treatment. Partial results indicate that acute stress and acute corticosterone produced some desensitization of the response whereas acute LPS markedly inhibited it dose-dependently. Studies of repeated stress and corticosterone are currently in progress. The results are suggestive that stress-related factors can desensitize brain alpha 1-adrenergic receptors that control movement and motor activity, and may induce depressive behavior in part via this action
— id: 92481, year: 2000, vol: 26, page: ?, stat: Journal Article,

Analysis of myocilin mutations in 1703 glaucoma patients from five different populations
Fingert, J H; Heon, E; Liebmann, J M; Yamamoto, T; Craig, J E; Rait, J; Kawase, K; Hoh, S T; Buys, Y M; Dickinson, J; Hockey, R R; Williams-Lyn, D; Trope, G; Kitazawa, Y; Ritch, R; Mackey, D A; Alward, W L; Sheffield, V C; Stone, E M
1999 May;8(5):899-905, Human molecular genetics
A glaucoma locus, GLC1A, was identified previously on chromosome 1q. A gene within this locus (encoding the protein myocilin) subsequently was shown to harbor mutations in 2-4% of primary open angle glaucoma patients. A total of 1703 patients was screened from five different populations representing three racial groups. There were 1284 patients from primarily Caucasian populations in Iowa (727), Australia (390) and Canada (167). A group of 312 African American patients was from New York City and 107 Asian patients from Japan. Overall, 61 different myocilin sequence variations were identified. Of the 61 variations, 21 were judged to be probable disease-causing mutations. The number of probands found to harbor such mutations in each population was: Iowa 31/727 (4.3%), African Americans from New York City 8/312 (2.6%), Japan 3/107 (2.8%), Canada 5/167 (3.0%), Australia 11/390 (2.8%) and overall 58/1703 (3. 4%). Overall, 16 (76%) of 21 mutations were found in only one population. The most common mutation observed, Gln368Stop, was found in 27/1703 (1.6%) glaucoma probands and was found at least once in all groups except the Japanese. Studies of genetic markers flanking the myocilin gene suggest that most cases of the Gln368Stop mutations are descended from a common founder. Although the specific mutations found in each of the five populations were different, the overall frequency of myocilin mutations was similar ( approximately 2-4%) in all populations, suggesting that the increased rate of glaucoma in African Americans is not due to a higher prevalence of myocilin mutations
— id: 148347, year: 1999, vol: 8, page: 899, stat: Journal Article,

Alpha-1-noradrenergic neurotransmission, corticosterone, and behavioral depression
Stone EA; Quartermain D
1999 Nov 1;46(9):1287-1300, Biological psychiatry
BACKGROUND: Impaired brain alpha-1 noradrenergic neurotransmission has been implicated in some of the symptoms of depressive illness but has been difficult to investigate experimentally because of the insensitivity of current animal models of depression. The present experiment addressed this problem by examining the effects of pharmacologic blockade and corticosteroid-induced desensitization of alpha-1 receptors on two newer, more sensitive models in mice: the inhibition of nest-leaving and the tail suspension tests (TST). METHODS: Male mice were administered either prazosin, betaxolol, atipamezole, corticosterone, or repeated restraint stress prior to measurement of either nest-leaving or TST. General behavioral function was assessed in horizontal wire, swim, and latency to escape footshock tests. RESULTS: Prazosin increased depressive behavior in the nest-leaving and TSTs, whereas corticosterone and restraint stress did so only in the more sensitive nest-leaving test. Betaxolol also reduced nest-leaving, suggestive of an alpha-1 beta-1 receptor synergy. The effects of these agents could not be attributed to hypotension, sedation, or general behavioral impairment. CONCLUSIONS: The fact that a reduction in alpha-1 noradrenergic neurotransmission increases depressive behavior, coupled with the fact that this change can result from elevated corticosteroid secretion, provides further support for a role of this factor in depressive illness. As not all alpha-1 functions are reduced in depression, it is likely that only a subgroup or specific locality of alpha-1 receptors are affected
— id: 6234, year: 1999, vol: 46, page: 1287, stat: Journal Article,

Brain alpha 1-adrenergic neurotransmission is necessary for behavioral activation to environmental change in mice
Stone EA; Zhang Y; Rosengarten H; Yeretsian J; Quartermain D
1999 ;94(4):1245-1252, Neuroscience
Terazosin, a water-soluble alpha 1 antagonist that can be administered in high doses intraventricularly was used to study the relationship between brain alpha 1 adrenoceptor neurotransmission and behavioral activation in the mouse. The antagonist was found to produce a dose-dependent, complete inhibition of motor activity and catalepsy which were reversed preferentially by coinfusion of an alpha 1 agonist (phenylephrine) compared to a D1 (SKF38393) or a D2 agonist, (quinpirole). Blockade of central beta-1 (betaxolol), alpha-2 (RX821002) or beta-2 (ICI 118551) adrenoceptors had smaller or non-significant effects. Terazosin's selectivity for alpha 1 receptors versus dopaminergic receptors was verified under the present conditions by showing that the intraventricularly administered antagonist protected striatal and cerebral cortical alpha 1 receptors but not striatal or cortical D1 receptors from in vivo alkylation by N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroxyquinoline. That its effect was due to blockade of brain rather than peripheral receptors was shown by the finding that intraperitoneal doses of terazosin three to 66 times greater than the maximal intraventricular dose produced less behavioral inhibition. Intraventricular terazosin also produced hypothermia and a reduced respiratory rate suggestive of a reduced sympathetic outflow. However, external heat did not affect the inactivity, and captopril, a hypotensive agent, did not mimic it. Terazosin did not impair performance on a horizontal wire test or the ability to make co-ordinated movements in a swim test suggesting that its activity-reducing effect was not due to sedation and may have a motivational or sensory gating component. It is concluded that central alpha 1-noradrenergic neurotransmission is required for behavioral activation to environmental change in the mouse and may operate on sensorimotor and motivational processes
— id: 10051, year: 1999, vol: 94, page: 1245, stat: Journal Article,

Religion and science
Stone, E
1999 JUN 11 ;284(5421):1773-1773, Science
— id: 54036, year: 1999, vol: 284, page: 1773, stat: Journal Article,

Evidence that central alpha 1B-adrenergic receptor function is necessary for behavioral activation in the mouse
Stone, E. A.; Quartermain, D.
1999 ;25(1-2):608-608, Abstracts (Society for Neuroscience)
— id: 92483, year: 1999, vol: 25, page: 608, stat: Journal Article,

Corticosterone-induced desensitization of brain alpha 1-adrenoceptors as a factor in behavioral depression
Zhang, Y.; Quartermain, D.; Stone, E. A.
1999 ;25(1-2):1582-1582, Abstracts (Society for Neuroscience)
— id: 92482, year: 1999, vol: 25, page: 1582, 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,

Role of the fos response in habituation to novelty: Preliminary findings
Manavalan, S.; Stone, E. A.; Zhang, Y.; Quartermain, D.
1998 ;24(1-2):688-688, Abstracts (Society for Neuroscience)
— id: 92486, year: 1998, vol: 24, page: 688, stat: Journal Article,

Selective blockade of brain alpha-1 adrenoceptors in mice produces immobility and catalepsy
Stone, E. A.; Zhang, Y.; Quartermain, D.
1998 ;24(1-2):455-455, Abstracts (Society for Neuroscience)
— id: 92485, year: 1998, vol: 24, page: 455, stat: Journal Article,

Role of alpha-1 adrenergic activity in resistance to stress
Zhang, Y.; Stone, E. A.; Canellas, F.; Quartermain, D.
1998 ;24(1-2):1193-1193, Abstracts (Society for Neuroscience)
— id: 92484, year: 1998, vol: 24, page: 1193, 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,

Effect of unilateral tympanotomy on auditory induced c-fos expression in cochlear nuclei
Hillman DE; Gordon CE; Troublefield Y; Stone E; Giacchi RJ; Chen S
1997 Feb 14;748(1-2):77-84, Brain research
The immediate early gene, c-fos, signals expression of target genes. Three natural occurring physiological entities: (1) learning, (2) plasticity, and (3) stress are proposed to use c-fos gene expression to signal molecular changes in neurons. The objective of this study was to determine whether c-fos expression is predominately activated by stress or by novel events associated with learning and plasticity. The approach was to quantitate the number of neurons in cochlear nuclei which express Fos protein following short-term novel sound stimuli together with either uni- or bilateral tympanotomy so as to differentiate novel sound stimuli from stress activation. The results show that routinely experienced sounds do not elicit c-fos expression in medullary cochlear nuclei, but novel sounds produced a 25-fold increase in the number of active cells. Following unilateral tympanotomy with novel sound stimulation, only a small number of cells were activated, ipsilaterally, (partially deafened side) while contralaterally, there was a 30-fold increase. After normalization of the data for control values, the data clearly indicate that novelty of sound stimuli induce c-fos gene expression. Furthermore, bilateral tympanotomy (bilateral partial deafening) with sound stimulation activated both sides by 20-fold, indicating that the c-fos response followed the sound stimulation. The data allow us to conclude that stress generates only a small contribution to c-fos gene expression while novel stimuli are potent signals, strongly implicating c-fos in novelty induced adaptation processes involved in learning and plasticity
— id: 8217, year: 1997, vol: 748, page: 77, stat: Journal Article,

Vulnerability to behavioral disturbance caused by stress in immature and mature male mice
Quartermain, D.; Zhang, Y.; Stone, E. A.
1997 ;23(1-2):1080-1080, Abstracts (Society for Neuroscience)
— id: 92488, year: 1997, vol: 23, page: 1080, stat: Journal Article,

Greater behavioral effects of stress in immature as compared to mature male mice
Stone EA; Quartermain D
1997 Dec 31;63(1):143-145, Physiology & behavior
The effect of sexual maturity on behavioral effects of stress was examined in male mice. Immature (4-week-old) or mature (8-week-old) animals were subjected to either social stress (exposure to an isolated adult male) or restraint stress for 5 days and examined for body weight, food intake, or plus-maze behavior. Social stress reduced food intake, body weight, and open-arm entries in 4-week-old but not 8-week-old mice. Restraint reduced body weight in 4-week-old but not 8-week-old mice. It is concluded that immature male mice show greater behavioral disturbances after stress than their mature counterparts. The findings are in agreement with much anecdotal evidence that children are more vulnerable to stress than adults
— id: 10052, year: 1997, vol: 63, page: 143, stat: Journal Article,

Activation of fos in mouse amygdala by local infusion of norepinephrine or atipamezole
Stone EA; Zhang Y; Hiller JM; Simon EJ; Hillman DE
1997 Dec 5;778(1):1-5, Brain research
Norepinephrine (NE) is known to activate a number of immediate-early genes (IEGs) in the brain which may be involved in prolonged changes in neuronal function. To investigate the function of these genes it would be useful to have a model system in which they are induced in specific populations of cells in specific brain regions without systemic drug administration which can affect multiple sites. In the present paper we have shown that local infusions of NE or of the alpha2-adrenoceptor antagonist, atipamezole, in the mouse amygdala produces localized expression of fos. The expression of fos was blocked by a cocktail of an alpha1-(prazosin) and beta1-adrenoceptor (betaxolol) blocker but not by a selective 5-HT1A blocker (WAY100135). Prazosin and betaxolol did not have a nonspecific reducing action on fos expression. It is concluded that localized expression of fos after NE infusion in the mouse amygdala represents a model system for further studies of the role of IEG expression in central noradrenergic function
— id: 7811, year: 1997, vol: 778, page: 1, stat: Journal Article,

The effect of catecholamine administration in the amygdala on stress-induced behavioral depression and fos levels in the mouse
Stone, E. A.; Zhang, Y.; Quartermain, D.
1997 ;23(1-2):1850-1850, Abstracts (Society for Neuroscience)
— id: 92487, year: 1997, vol: 23, page: 1850, stat: Journal Article,

Acute stress disrupts risk assessment behavior in mice
Quartermain D; Stone EA; Charbonneau G
1996 Apr-May;59(4-5):937-940, Physiology & behavior
The effects of stress on risk assessment behavior in mice were studied by examining latency to emerge from a safe compartment into a large, well-lit open field. In the first experiment different groups of mice were exposed for 1 h to tube restraint, fixed interval 2-min foot shock, or attack by an aggressive conspecific. Nonstressed controls were left undisturbed in the home cage. Thirty minutes following stress animals were placed in the safe compartment and latency to emerge was recorded. Results showed all of the stressed groups exhibited significantly faster emergence latencies than nonstressed controls. In the second experiment the duration of this effect was examined by testing different groups at varying intervals following tube restraint stress. Results showed that mice tested 0.5 and 1 h following stress exhibited short entry latencies and reduced head poke responses. Performance had returned to nonstress levels 3 h after stress. These data suggest that stress reduces caution by disrupting risk assessment behaviors
— id: 7238, year: 1996, vol: 59, page: 937, stat: Journal Article,

Delayed arousal from anesthesia: a further similarity between stress and beta-1 adrenoceptor blockade
Stone EA; Manavalan JS; Quartermain D
1996 Sep;55(1):131-133, Pharmacology biochemistry & behavior
The present studies investigated the role of beta adrenergic receptors in mediating arousal from anesthesia and the effects of stress on this process. In support of previous findings by others, it was found that blockade of beta-1 and beta-2 receptors by propranolol delayed arousal from halothane anesthesia and that this effect was attributable to blockade of beta-1 receptors because it was duplicated by betaxolol but not by ICI 118,551. Restraint stress also produced a delay in arousal from both halothane and hexobarbital anesthesia. This effect, which was observed at 0.5 but not 24 h after the stress, could not be explained by a stress-induced alteration in the metabolism of the anesthetic, as no difference in brain concentration of hexobarbital was found between stressed and control mice. The parallel effects of beta-1 blockade and stress further supports the hypothesis that stress produces an impairment in function at either the beta-1 receptor or some process coupled to this receptor
— id: 7050, year: 1996, vol: 55, page: 131, stat: Journal Article,

Blockade of effect of stress on risk assessment behavior in mice by a beta-1 adrenoceptor antagonist
Stone EA; Rhee J; Quartermain D
1996 Oct;55(2):215-217, Pharmacology biochemistry & behavior
Previous studies have shown that acute stress impairs risk assessment behavior in mice. The present study was undertaken to determine the role of beta adrenoceptors, which are known to be stimulated by stress, in this effect. Mice were treated with either a beta-1 antagonist, betaxolol, a beta-2 antagonist, ICI 118551, an alpha-1 antagonist, prazosin, or an alpha-2 antagonist, yohimbine, and 30 min later were subjected to a 1-h session of restraint stress. Thirty minutes after the stress the animals were tested for the entry latency, number of headpokes prior to entry, and the path of entry into a white open field from a small dark box. In agreement with previous findings, stress was found to markedly reduce risk assessment behaviors as reflected by a reduced entry latency, a reduced number of headpokes and a changed entry path from wall hugging to central entry. Betaxolol was found to prevent all of the above effects of stress dose dependently, whereas ICI 118551, prazosin, and yohimbine had no reversal effects. It is concluded that beta-1 receptor activation and possibly brain glycogen depletion is involved in the effects of stress on risk assessment behavior
— id: 10053, year: 1996, vol: 55, page: 215, stat: Journal Article,

The role of central noradrenergic mechanisms and fos responses to stress in stress-induced behavioral depression
Stone, E. A.; Zhang, Y.; Quartermain, D.
1996 ;22(1-3):463-463, Abstracts (Society for Neuroscience)
— id: 92489, year: 1996, vol: 22, page: 463, stat: Journal Article,

Association of brain c-fos response with behavioral depression after stress or high levels of stimulation: A possible inhibitory function for fos
Stone, EA; Zhang, Y; Quartermain, D
1996 MAR 8 ;10(3):4141-4141, FASEB journal
— id: 53045, year: 1996, vol: 10, page: 4141, stat: Journal Article,

The role of cerebral noradrenergic systems in the Fos response to interleukin-1
Swiergiel, AH; Dunn, AJ; Stone, EA
1996 OCT ;41(1):61-64, Brain research bulletin
Peripheral administration of interleukin-1 (IL-1) has been shown to activate induction of Fos in the brain, but the mechanism is not known. Because cerebral noradrenergic systems have been implicated in Fos induction, we studied the IL-1-induced appearance of Fos in mice pretreated with 6-hydroxydopamine (6-OHDA) which depleted cerebral norepinephrine (NE) by more than 90%, but did not significantly alter dopamine. Intraperitoneally injected IL-1 beta increased Fos in several brain regions, but most obviously in the hypothalamic paraventricular nucleus (PVN). Pretreatment with 6-OHDA substantially reduced the IL-1-induced Fos increase in the PVN which was no longer statistically significant. When the 6-OHDA treatment was preceded by administration of desmethylimipramine which prevents NE depletion, IL-1 treatment increased Fos in the PVN, suggesting that the effect of 6-OHDA was indeed related to the depletion of NE. These results suggest that the noradrenergic innervation of the PVN is involved in the IL-1-induced induction of Fos in the PVN. By contrast with previous experiments in rats, the IL-1-induced increase in plasma corticosterone was not significantly altered by the 6-OHDA pretreatment in mice
— id: 52808, year: 1996, vol: 41, page: 61, stat: Journal Article,

Stress-induced decrease in out of nest activity in the mouse: A model of stress-induced withdrawn behavior
Zhang, Y.; Stone, E. A.; Quartermain, D.
1996 ;22(1-3):461-461, Abstracts (Society for Neuroscience)
— id: 92490, year: 1996, vol: 22, page: 461, stat: Journal Article,

The role of cerebral norepinephrine in the fos response to interleukin-1
Dunn, A. J.; Swiergiel, A. H.; Stone, E. A.
1995 ;21(1-3):97-97, Abstracts (Society for Neuroscience)
— id: 92493, year: 1995, vol: 21, page: 97, stat: Journal Article,

Stress-induced inhibition of nocturnal foraging and ambulation in the mouse: A new potential animal model of depression
Manavalan, J. S.; Quartermain, D.; Stone, E. A.
1995 ;21(1-3):698-698, Abstracts (Society for Neuroscience)
— id: 92491, year: 1995, vol: 21, page: 698, stat: Journal Article,

Beta adrenoceptor blockade mimics effects of stress on motor activity in mice
Stone EA; Manavalan SJ; Zhang Y; Quartermain D
1995 Feb;12(1):65-71, Neuropsychopharmacology
Reduced central noradrenergic function has been implicated as a factor in reduced behavioral activity after stress. The present studies examined the role of reduced beta adrenergic neurotransmission in mediating this effect. This was done by testing the ability of beta receptor antagonists to mimic the behavioral actions of stress. Mice were subjected to stress or given various beta antagonists and tested for swimming behavior, locomotor activity, or grooming behavior. As previously reported, stress reduced swimming and locomotor activity and increased grooming. Both the nonselective antagonist, l-propranolol, and the beta-1 selective antagonist, betaxolol, produced the same effects as stress on all three measures. A beta-2 selective antagonist, ICI 118,551, was effective only on swimming, whereas a membrane stabilizing agent, d-propranolol, was effective only on grooming behavior. The peripherally active beta-1 antagonist, atenolol, was not effective on any measure. The nonspecific dopaminergic receptor blocker, fluphenazine, reduced locomotion but tended also to reduce grooming. The results indicate that blockade of beta-1 receptors in the CNS selectively mimics the action of stress on gross motor activity in mice and, along with previous data, suggest that stress leads to a relative deficiency in central beta-1 noradrenergic neurotransmission in these animals
— id: 6756, year: 1995, vol: 12, page: 65, stat: Journal Article,

Potentiation by propranolol of stress-induced changes in passive avoidance and open-field emergence tests in mice
Stone EA; Najimi M; Quartermain D
1995 Jun-Jul;51(2-3):297-300, Pharmacology biochemistry & behavior
Noradrenergic and serotonergic systems are known to be stimulated during various forms of stress. The present study examined the effect of the beta-adrenergic serotonin1A receptor blocker propranolol on the ability of stress to elicit behavioral inhibition in mice. Mice were given the drug before immobilization or tube-restraint stress, and then were tested for either passive avoidance performance or time to emerge into an open field. Propranolol markedly potentiated stress-induced increases in latency in both of these tests, suggesting that it exacerbated reactions to stress. These results agree with previous data indicating that under certain conditions, propranolol can potentiate the effects of stress in rodents. The results support the hypothesis that the response of the noradrenergic and/or serotonergic systems to stress may have anxiolytic or antistress effects
— id: 56852, year: 1995, vol: 51, page: 297, stat: Journal Article,

Adrenoceptor antagonists block c-fos response to stress in the mouse brain
Stone EA; Zhang Y
1995 Oct 2;694(1-2):279-286, Brain research
The present study examined the role of monoaminergic systems in mediating the c-fos response to stress in the mouse brain. Mice were pretreated with various monoamine receptor antagonists prior to immobilization stress and were assayed for c-fos immunohistochemically throughout the brain. It was found that the alpha-1 adrenergic antagonist, prazosin significantly reduced the response in 10/12 telencephalic, 2/6 diencephalic and 4/5 brainstem regions and that the beta-1 adrenergic antagonist, betaxolol reduced it in 6/12 telencephalic, 1/6 diencephalic and 015 brainstem regions. The effects of these drugs were not due to nonspecific depressions of neuronal activity as several brain regions with high fos responses were unaffected. Nor were they due to sedation as the drugs did not affect rotorod performance. Neither the brta-2 adrenergic blocker, ICI118,551, the D1/D2 receptor blocker, fluphenazine, the 5HT1A antagonist, WAY 100135, nor the 5HT2 antagonist, ketanserin, produced a clear pattern of effects on the response. It is concluded that of the monoaminergic systems, the noradrenergic is the one most involved in the central fos response to immobilization stress in the mouse brain and that the response is mediated by a mixture of alpha-1 and beta-1 receptors
— id: 12721, year: 1995, vol: 694, page: 279, 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,

ADRENERGIC-RECEPTORS MEDIATE BOTH THE BRAIN C-FOS RESPONSE AND A PROLONGED EMOTIONAL REACTION TO STRESS
STONE, EA; ZHANG, Y; QUARTERMAIN, D
1995 MAR 9 ;9(3):A408-A408, FASEB journal
— id: 87402, year: 1995, vol: 9, page: A408, stat: Journal Article,

Role of monoaminergic systems in the fos response to stress in the mouse and rat brain
Zhang, Y.; Stone, E. A.
1995 ;21(1-3):462-462, Abstracts (Society for Neuroscience)
— id: 92492, year: 1995, vol: 21, page: 462, stat: Journal Article,

Locus coeruleus lesions potentiate neurotoxic effects of MPTP in dopaminergic neurons of the substantia nigra
Bing G; Zhang Y; Watanabe Y; McEwen BS; Stone EA
1994 Dec 30;668(1-2):261-265, Brain research
The observation that Parkinson's disease (PD) is associated with locus coeruleus (LC) noradrenergic neuronal degeneration suggests that the LC noradrenergic system may be involved in the pathogenesis and natural progression of the destruction of the substantia nigra (SN) dopaminergic neurons in Parkinson's disease. The relationship of these two systems was examined by injection of subtoxic doses of MPTP into unilateral LC 6-hydroxydopamine (6-OHDA) lesioned mice. A significant loss of dopaminergic cells was only found in the SN on the side of the LC lesions. These results suggest that the LC may have protective effects on SN dopaminergic neurons
— id: 18505, year: 1994, vol: 668, page: 261, stat: Journal Article,

Immunohistochemical localization of mu-opioid receptors in rat brain using antibodies generated against a peptide sequence present in a purified mu-opioid binding protein
Hiller JM; Zhang Y; Bing G; Gioannini TL; Stone EA; Simon EJ
1994 Oct;62(3):829-841, Neuroscience
Light-microscope visualization in rat brain of a pattern of distribution of immunoreactivity, which included immunolabeled perikarya and beaded processes, was achieved using an immunoaffinity purified polyclonal antibody, Ab165, which recognizes the amino acid sequence, IRNLRQDRSKYY, found in the mu-opioid binding protein purified in our laboratory. Immunohistochemical staining with Ab165 was carried out by the avidin-biotin procedure. Antibody, preabsorbed with antigen, served as control. Extensive immunoreactivity was seen in the hippocampal formation, the amygdaloid complex, the striatal complex, cortical regions, select areas of the thalamus and hypothalamus and in laminae I and II of the dorsal horn in spinal cord. The distribution of immunoreactivity in the rat brain of antibody 165, which recognizes a purified mu-opioid binding protein, is concordant with the distribution of mu-opioid binding sites as determined by other laboratories in autoradiographic, electrophysiological and immunocytochemical studies. These findings have enabled us to distinguish areas possessing large fields of mu-opioid receptor containing cell bodies from areas possessing dense networks of immunolabeled neuronal processes or mixtures of both
— id: 56651, year: 1994, vol: 62, page: 829, stat: Journal Article,

Effect of propranolol on stress-induced changes in passive avoidance and open field emergence tests
Manavalan, J. S.; Najimi, M.; Stone, E. A.; Quartermain, D.
1994 ;20(1-2):1445-1445, Abstracts (Society for Neuroscience)
— id: 92495, year: 1994, vol: 20, page: 1445, stat: Journal Article,

Acute stress disrupts defensive behavior in mice
Quartermain, D.; Stone, E. A.; Charbeneau, G.
1994 ;20(1-2):1445-1445, Abstracts (Society for Neuroscience)
— id: 92494, year: 1994, vol: 20, page: 1445, stat: Journal Article,

Effect of yohimbine on nerve growth factor mRNA and protein levels in rat hippocampus
Stone EA; Manavalan JS; Basham DA; Bing G
1994 Feb 14;167(1-2):11-13, Neuroscience letters
Activation of noradrenergic receptors has been shown to increase expression of nerve growth factor (NGF) gene in brain cells in vitro. The present studies were undertaken to determine if this stimulation was effective in vivo as well. Rats were administered the norepinephrine-releasing drug, yohimbine (YOH), and had their hippocampi assayed for NGF mRNA and protein at various times after the injection. It was found that yohimbine caused a 3-fold increase of NGF mRNA levels at 24 h. Protein levels, however, were unaltered at this time. Thus norepinephrine release in vivo appears to be sufficient for increasing mRNA level but not for translation to protein
— id: 12996, year: 1994, vol: 167, page: 11, stat: Journal Article,

Beta-1 adrenoceptor blockade mimics the behavioral effects of acute stress in mice
Stone, E. A.; Quartermain, D.; Manavalan, J. S.; Zhang, Y.
1994 ;20(1-2):1444-1444, Abstracts (Society for Neuroscience)
— id: 92497, year: 1994, vol: 20, page: 1444, stat: Journal Article,

Postnatal neurogenesis in the developing retina of the Brazilian opossum
Stone, E.; Jensen, C.; Iqbal, J.; Elmquist, J.; Jacobson, C. D.; Sakaguchi, D. S.
1994 ;20(1-2):1322-1322, Abstracts (Society for Neuroscience)
— id: 92498, year: 1994, vol: 20, page: 1322, stat: Journal Article,

Induction and habituation of c-fos and zif/268 by acute and repeated stressors
Watanabe Y; Stone E; McEwen BS
1994 Jun 27;5(11):1321-1324, Neuroreport
Acute restraint and shaking stress each induced the mRNA for the immediate early gene (IEG), c-fos, within 1 h in locus coeruleus (LC), midbrain raphe nuclei and central gray. Both acute restraint stress and acute shaking stress activated c-fos and zif/268 mRNA in paraventricular nuclei within 1 h. Midbrain A9 and A10 dopaminergic neurons did not show any c-fos or zif/268 mRNA induction by either acute stressor. Repeated restraint stress (14d, 1h/d) produced habituation to acute restraint stress, but not to acute shaking stress, in PVN, raphe and central gray. In LC, repeated restraint stress caused some habituation to both acute stressors
— id: 18506, year: 1994, vol: 5, page: 1321, stat: Journal Article,

Effect of beta-1 adrenoceptor blockade on c-fos response to stress in mouse brain
Zhang, Y.; Stone, E. A.
1994 ;20(1-2):1445-1445, Abstracts (Society for Neuroscience)
— id: 92496, year: 1994, vol: 20, page: 1445, stat: Journal Article,

Hippocampal NGF mRNA following yohimbine (YOH) injection
Bing, G.; Manavalan, J. S.; Stone, E. A.
1993 ;19(1-3):256-256, Abstracts (Society for Neuroscience)
— id: 92500, year: 1993, vol: 19, page: 256, stat: Journal Article,

Immunohistochemical localization of mu opioid receptors in rat brain with antibodies against a peptide sequence derived from a purified opioid binding protein (OBP)
Hiller, J. M.; Bing, G.; Stone, E.; Gioannini, T. L.; Simon, E. J.
1993 ;19(1-3):74-74, Abstracts (Society for Neuroscience)
— id: 92502, year: 1993, vol: 19, page: 74, stat: Journal Article,

Effect of locus coeruleus lesion on c-fos expression in the cerebral cortex caused by yohimbine injection or stress
Stone EA; Zhang Y; John S; Filer D; Bing G
1993 Feb 19;603(2):181-185, Brain research
The injection of the alpha-2 adrenoceptor antagonist, yohimbine, has been shown to increase c-fos immunoreactivity in the rat cerebral cortex. To determine the extent to which this response is mediated by the central noradrenergic system, the present studies examined it in rats previously given unilateral 6-OHDA lesions of the locus coeruleus. The lesions were found to produce a significant attenuation of the response. A similar effect on the c-fos immunoreactive response to restraint stress was found. It is concluded that the noradrenergic system plays a necessary role in the above c-fos responses in the cortex to yohimbine and to stress. The c-fos protein therefore appears to be involved in the effects of noradrenergic neurotransmission in the CNS
— id: 8233, year: 1993, vol: 603, page: 181, stat: Journal Article,

The role of the noradrenergic system in central cfos responses
Stone, E. A.; Zhang, Y.; Bing, G.
1993 ;19(1-3):82-82, Abstracts (Society for Neuroscience)
— id: 92501, year: 1993, vol: 19, page: 82, stat: Journal Article,

INCREASE IN HIPPOCAMPAL NGF MESSENGER-RNA FOLLOWING YOHIMBINE (YOH) INJECTION
STONE, EA; BING, G
1993 FEB 19 ;7(3):A184-A184, FASEB journal
— id: 54345, year: 1993, vol: 7, page: A184, stat: Journal Article,

Stress-induced behavioral deficits: Behavioral and neuropharmacological factors
Zhang, Y.; Stone, E. A.
1993 ;19(1-3):1621-1621, Abstracts (Society for Neuroscience)
— id: 92499, year: 1993, vol: 19, page: 1621, stat: Journal Article,

Noradrenergic-induced expression of c-fos in rat cortex: neuronal localization
Bing G; Chen S; Zhang Y; Hillman D; Stone EA
1992 Jun 22;140(2):260-264, Neuroscience letters
beta Adrenoceptors in the rat forebrain have been shown to exist predominantly on astrocytes. Studies were undertaken to determine whether the cellular localization of c-fos expression caused by the activation of brain beta receptors would have a similar cellular localization. Double label light and electron microscopic immunohistochemical experiments with a glial (glial fibrillary acidic protein, GFAP) and neuronal marker (neurofilament protein, NFP) were undertaken in rats treated with the adrenergic drug, yohimbine. These studies revealed a predominantly neuronal localization of Fos protein in the cerebral cortex. The latter results indicate that neurons are the postsynaptic noradrenergic target cells in which this immediate early gene is expressed in response to the stimulation of beta adrenoceptors. The possible relation of these findings to the glial localization of these receptors is discussed
— id: 13557, year: 1992, vol: 140, page: 260, stat: Journal Article,

Immunohistochemical studies of noradrenergic-induced expression of c-fos in the rat CNS
Bing G; Stone EA; Zhang Y; Filer D
1992 Oct 2;592(1-2):57-62, Brain research
Previous studies have shown that stimulation of adrenergic receptors in the rat brain causes increased levels of mRNA of the immediate early gene, c-fos. The present studies were undertaken to determine if this stimulation also induces increased levels of c-fos immunoreactivity in the central nervous system (CNS). Rats were treated with the alpha-2 adrenoceptor blockers, yohimbine or atipamezole, or with restraint stress to activate central noradrenergic activity and were perfused 2 h later for immunohistochemical analysis of the cerebral cortex. Yohimbine, atipamezole and restraint stress each was found to cause increases in c-fos-like immunoreactivity (c-fos-li). Western blot analysis revealed increased c-fos protein in the cortex after yohimbine treatment. The c-fos-li response to yohimbine was blocked by prior administration of the beta receptor antagonist, dl-propranolol, and to a lesser degree by the alpha-1 antagonist, prazosin. It is concluded that adrenergic receptor stimulation in the cortex causes increased production of c-fos or fos related antigens and that this (these) immediate early gene product(s) may play a role in noradrenergic function in the CNS
— id: 8232, year: 1992, vol: 592, page: 57, stat: Journal Article,

Protective action of locus coeruleus noradrenergic system of substantia nigra (SN) of mice treated with MPTP
Bing, G.; Zhang, Y.; Stone, E. A.
1992 ;18(1-2):1375-1375, Abstracts (Society for Neuroscience)
— id: 92504, year: 1992, vol: 18, page: 1375, stat: Journal Article,

Effect of agents that increase brain norepinephrine (NE) release of brain extracellular cAMP levels
Johns, S. M.; Stone, E. A.
1992 ;18(1-2):458-458, Abstracts (Society for Neuroscience)
— id: 92506, year: 1992, vol: 18, page: 458, stat: Journal Article,

Cellular localization of responses to catecholamines in brain tissue
Stone EA; Bing G; John SM; Zhang Y; Filer D
1992 ;94:303-307, Progress in brain research
— id: 13792, year: 1992, vol: 94, page: 303, stat: Journal Article,

Stress-induced increase of extracellular levels of cyclic AMP in rat cortex
Stone EA; John SM
1992 Nov 27;597(1):144-147, Brain research
Previous studies have suggested that stress may increase levels of cyclic AMP (cAMP) in the brain but these findings have been controversial due to the use of stressful procedures to inactivate brain enzymes. The present experiment therefore used a non-stressful technique, microdialysis, to assay extracellular levels of cAMP in the rat cortex after stress. Experiments were conducted 2 days after implantation of probes in the frontal cortex. Significant increases were found after the mild stressors of restraint or intraperitoneal injection of saline suggesting that increased tissue levels of cAMP had occurred. These responses were potentiated by local infusion of the phosphodiesterase (PDE) inhibitor, rolipram. It is concluded that one or more adenylate cyclase-coupled receptors in the cortex is activated by mild stress and that this activation can be detected in vivo by microdialysis
— id: 13366, year: 1992, vol: 597, page: 144, stat: Journal Article,

Studies on the cellular localization of biochemical responses to catecholamines in the brain
Stone EA; John SM; Bing G; Zhang Y
1992 Sep-Oct;29(3-4):285-288, Brain research bulletin
Studies were undertaken to determine the cellular localization of the cyclic adenosine monophosphate (cAMP) response of various forebrain regions to beta-adrenoceptor stimulation. Using brain slices, it was found that the gliotoxin, fluorocitrate (FC), which blocks metabolism selectively in glial cells, virtually abolished the cAMP response to beta-receptor stimulation whereas the neurotoxin, kainic acid (KA), was without effect. FC was confirmed by electrophysiological recording to be selective for glial cells in the brain slices. Similar results were found for these agents on in vivo brain cAMP responses to beta-receptor stimulation using a new microdialysis technique to measure in vivo responses. It is concluded that the cAMP response to beta-adrenoceptor stimulation in various regions of the forebrain occurs predominantly in glia. To determine if this could be correlated with a second biochemical response to beta-receptor stimulation, preliminary studies were undertaken on the localization of the immediate early gene, c-fos, produced in the brain after in vivo stimulation of beta-receptors. It was found that unlike the cAMP responses the c-fos response to beta-receptor stimulation occurs predominantly in neurons. The possible relationship of these two responses is discussed
— id: 13470, year: 1992, vol: 29, page: 285, stat: Journal Article,

Locus coeruleus lesion reduces tyrosine hydroxylase immunoreactivity and mRNA levels in rat substantia nigra
Watanabe, Y.; Bing, G.; Zhang, Y.; McEwen, B. S.; Stone, E. A.
1992 ;18(1-2):1378-1378, Abstracts (Society for Neuroscience)
— id: 92503, year: 1992, vol: 18, page: 1378, stat: Journal Article,

Effect of locus coeruleus (LC) lesion on c-fos response to metrazol (PTZ) in rat brain
Zhang, Y.; Bing, G.; Filer, D.; Stone, E. A.
1992 ;18(1-2):1375-1375, Abstracts (Society for Neuroscience)
— id: 92505, year: 1992, vol: 18, page: 1375, stat: Journal Article,

IMMUNOHISTOCHEMICAL STUDIES OF NORADRENERGIC ACTIVATION OF C-FOS IN RAT CENTRAL NERVOUS SYSTEM
BING G; ZHANG Y; FILER D; JOHN S M; STONE E A
1991 ;17(1-2):83-83, Abstracts (Society for Neuroscience)
— id: 92509, year: 1991, vol: 17, page: 83, stat: Journal Article,

Noradrenergic activation of immediate early genes in rat cerebral cortex
Bing GY; Filer D; Miller JC; Stone EA
1991 Aug;11(1):43-46, Brain research. Molecular brain research
Previous studies have shown that stimulation of adrenergic receptors in the brain increases the expression of the immediate early gene (IEG), c-fos, in vivo (Mol. Brain Res., 6(1989) 39-45). The present study was undertaken to determine whether this also holds for other IEGs which have been shown to be activated in brain cell culture by adrenergic agonists. Both yohimbine injection and stressful stimulation, two treatments causing brain norepinephrine (NE) release, were found to cause a parallel, transient activation of at least 5 IEGs (c-fos, nur77, tis-7, zif-268 and tis-21) in the rat cortex. Genes that are not immediate early (beta-actin, NGF and HSP70) were found not to be affected in the interval used (6 h). The responses were mediated predominantly by beta-adrenoceptors with some contribution from alpha 1 receptors. The parallel activation of multiple genes by noradrenergic receptors may enable the coding of different biochemical responses to the activation of different receptors
— id: 8273, year: 1991, vol: 11, page: 43, stat: Journal Article,

MEASUREMENT OF ENDOGENOUS CENTRAL NORADRENERGIC NEUROTRANSMISSION FROM LEVELS OF CAMP EFFLUX IN-VIVO
STONE E A; JOHN S M
1991 ;17(1-2):84-84, Abstracts (Society for Neuroscience)
— id: 92508, year: 1991, vol: 17, page: 84, stat: Journal Article,

Further evidence for a glial localization of rat cortical beta-adrenoceptors: studies of in vivo cyclic AMP responses to catecholamines
Stone EA; John SM
1991 May 17;549(1):78-82, Brain research
The present experiments were designed to clarify the cellular localization of postsynaptic beta-receptors in the rat cortex by studying the cellular source and pharmacological characteristics of in vivo cAMP responses to catecholamines. The method used to study in vivo cAMP responses in the brain involved microdialysis both to deliver catecholamines to cerebral tissue and to sample cAMP released in response to local beta-receptor activation. It was found that selective blockade of the metabolism of glial cells by fluorocitrate infusion produced a virtually complete (90%) inhibition of the cortical cAMP response to norepinephrine (NE). Selective damage of neurons by kainic acid infusion had little effect on the response. Pharmacological experiments showed that the response was selectively antagonized by a beta 1-receptor blocker which also selectively antagonized the cAMP response to NE in brain slices known to be localized in glial cells. These results support the hypothesis that beta-adrenoceptors of the rat cortex are predominantly localized on glial cells and therefore strongly suggest that these cells are an important target of the locus coeruleus noradrenergic system
— id: 14019, year: 1991, vol: 549, page: 78, stat: Journal Article,

c-Fos response to administration of catecholamines into brain by microdialysis
Stone EA; Zhang Y; John SM; Bing G
1991 Nov 25;133(1):33-35, Neuroscience letters
The present studies investigated the use of microdialysis for the infusion of catecholamines into the brain in studies of immediate early gene (IEG) activation. c-Fos like immunoreactivity was examined histochemically in cortical tissue surrounding a dialysis probe implanted in the medial prefrontal cortex. No c-fos reactivity was observed at 48 h post implantation in control animals not probe-infused or infused 2 h earlier with Ringer's buffer. Marked reactivity was found in animals infused with a solution of norepinephrine (NE). The latter was blocked by coinfusion of the beta adrenoceptor antagonist, timolol. It is concluded that direct infusion of NE by dialysis can induce c-fos expression in cells of the cerebral cortex and that this effect is primarily via beta-adrenoceptors. Microdialysis therefore represents a useful technique in studies of IEG responses to brain catecholamines
— id: 13838, year: 1991, vol: 133, page: 33, stat: Journal Article,

EFFECTS OF REPEATED RESTRAINT STRESS IN RATS ON NEUROENDOCRINE AND MOLECULAR MARKERS OF THE BRAIN'S RESPONSE
WATANABE Y; ANGULO J; BING G; FILER D; STONE E A; MCEWEN B S
1991 ;17(1-2):1357-1357, Abstracts (Society for Neuroscience)
— id: 92507, year: 1991, vol: 17, page: 1357, stat: Journal Article,

BETA ADRENOCEPTOR-INDUCED EXPRESSION OF EARLY RESPONSE GENES IN THE RAT CEREBRAL CORTEX
BING G; STONE E A; MILLER J C; FRIEDHOFF A J; FILER D
1990 ;16(1):2-2, Abstracts (Society for Neuroscience)
— id: 92512, year: 1990, vol: 16, page: 2, stat: Journal Article,

BIOCHEMICAL STUDIES OF BETA-ADRENOCEPTOR FUNCTION IN-VIVO IN THE RAT CEREBRAL CORTEX
STONE E A; JOHN S M
1990 ;16(1):385-385, Abstracts (Society for Neuroscience)
— id: 92511, year: 1990, vol: 16, page: 385, stat: Journal Article,

In vivo measurement of extracellular cyclic AMP in the brain: use in studies of beta-adrenoceptor function in nonanesthetized rats
Stone EA; John SM
1990 Dec;55(6):1942-1949, Journal of neurochemistry
Microdialysis measurement of extracellular cyclic AMP (cAMP) in the cerebral cortex of conscious rats was evaluated as a method for assessing central beta-adrenoceptor function in vivo. Extracellular levels of the nucleotide were found to average 3 pmol/ml under baseline conditions. Local infusion of the beta-agonists norepinephrine (NE) and isoproterenol produced rapid (3 min) and marked (three- to sevenfold) dose-dependent increases in extracellular cAMP, which were potentiated by the phosphodiesterase inhibitor rolipram, and blocked by the beta-antagonist timolol. Responses to both catecholamines underwent rapid desensitization (6-9 min) and recovered within several hours. Time-course studies revealed that the baseline cAMP level underwent a gradual increase and then a decrease over the course of a single 8-h run, and peaked at 24 h postimplantation. Responses to NE were stable for the first 24 h after implantation, then increased at 48 and 120 h. The causes of the latter changes may include reactions to novelty, local inflammatory responses, and/or reactions of adjacent glial cells to implantation. Overall, the results indicate that the microdialysis-cAMP method can be extended to nonanesthetized animals and may be a useful tool for studying neurotransmission at central adenylate cyclase-coupled membrane receptors during various behavioral states
— id: 14261, year: 1990, vol: 55, page: 1942, stat: Journal Article,

Glial localization of adenylate-cyclase-coupled beta-adrenoceptors in rat forebrain slices
Stone EA; Sessler FM; Liu WM
1990 Oct 22;530(2):295-300, Brain research
Fluorocitrate (FC), a selective inhibitor of glial cell respiration, was used to estimate the extent to which glial cells contain adenylate cyclase-coupled beta-adrenoceptors in rat brain slices. The drug blocked 75-95% of the elevation of cyclic AMP caused by the beta-agonist, isoproterenol, in the 4 forebrain regions sampled (frontal and parietal cortex, caudate nucleus, olfactory tubercle). Intracellular recording of neurons in the treated slices confirmed that they were unaffected by FC. Treatment with the neurotoxin, kainic acid, eliminated all electrophysiological activity but did not affect the cAMP response. The results indicate that glial cells contain the preponderance of adenylate-cyclase-coupled beta-adrenoceptors in slices of the rat forebrain and may constitute an important target of the central noradrenergic system in vivo
— id: 14313, year: 1990, vol: 530, page: 295, stat: Journal Article,

INDUCTION OF C-FOS GENE EXPRESSION IN RAT CORTEX DURING STRESS
MILLER J C; STONE E A; FILER D; FRIEDHOFF A J
1989 ;15(1):799-799, Abstracts (Society for Neuroscience)
— id: 92513, year: 1989, vol: 15, page: 799, stat: Journal Article,

MEASUREMENT OF EXTRACELLULAR CYCLIC AMP IN THE BRAIN BY MICRODIALYSIS EXTENSION TO UNANESTHETIZED RATS
STONE E A; JOHN S M
1989 ;15(1):433-433, Abstracts (Society for Neuroscience)
— id: 92514, year: 1989, vol: 15, page: 433, stat: Journal Article,

Are glial cells targets of the central noradrenergic system? A review of the evidence
Stone EA; Ariano MA
1989 Oct-Dec;14(4):297-309, Brain research. Brain research reviews
It has been suggested by a number of investigators that glial cells as well as neurons are targets of the central noradrenergic system. This important hypothesis, however, has not been presented previously in a systematic and unified manner. The present review was therefore undertaken to accomplish this. The evidence supporting noradrenergic action on glia consists primarily of findings that beta-adrenoceptors, norepinephrine (NE)-stimulated cyclic AMP (cAMP) responses and glycogen are localized preferentially in glial cells and that beta-receptor density and glycogen hydrolysis are under the control of neuronally released NE. While there is some disagreement as to the extent to which beta-receptors are preferentially localized in glia, there is a consensus that most glycogen in the forebrain is localized in this cellular compartment. The presumed function of the noradrenergic action on glia appears to be the release of glucose for production of energy, the synthesis of neurotrophic factors such as nerve growth factor, and the release of substances which may affect local neurotransmission including taurine, cAMP and its metabolites. These glial responses may be intimately related to the electrophysiological actions of NE on neurons
— id: 10482, year: 1989, vol: 14, page: 297, stat: Journal Article,

Catecholamine-induced desensitization of brain beta adrenoceptors in vivo and reversal by corticosterone
Stone EA; Egawa M; Colbjornsen CM
1989 ;44(3):209-213, Life sciences
The function of beta adrenoceptors in the brain was studied with a new technique involving the microdialysis collection of extracellular cyclic AMP (cAMP). Prolonged infusion of isoproterenol (2 hr) was found to induce a marked desensitization of the beta receptor-cAMP response. Administration of corticosterone (10 mg/kg) 3 hrs prior to the infusion markedly attenuated the desensitization. The results indicate that the catecholamine-induced densensitization of brain beta adrenoceptors can be studied in vivo and that corticosterone is capable of reversing this effect in the brain as has been reported previously for peripheral tissues
— id: 10832, year: 1989, vol: 44, page: 209, stat: Journal Article,

Use of microdialysis to measure brain noradrenergic receptor function in vivo
Egawa M; Hoebel BG; Stone EA
1988 Aug 23;458(2):303-308, Brain research
The present studies were undertaken to explore the use of intracerebral microdialysis to measure brain adrenergic receptor activity in vivo using the efflux of cyclic adenosine monophosphate (cAMP) in the extracellular fluid as an index of receptor function. An initial study with brain slices showed that extracellular levels of cAMP were highly correlated with intracellular levels after noradrenergic receptor activation. Detectable levels of extracellular cAMP were obtained from microdialysis probes implanted in the frontal cortex. Stable levels (3.5 +/- 2.7 pmol/ml) were obtained between 1.5 and 7 h after implantation. Perfusion of probes with NE (10(-5) to 10(-3) M) led to dose-dependent increases in cAMP efflux. The response to NE was blocked by infusion of the beta-antagonist, timolol, indicating that it reflected beta-receptor activation. Similar responses were obtained at 2 and 24 h after implantation indicating that the responses were not affected by acute traumatic effects of implantation. The findings show that the microdialysis technique can be successfully applied to the in vivo study of central adrenoceptor function. This suggests that the in vivo measurement of second messengers by microdialysis will provide a valuable new neurochemical and neuropharmacological technique
— id: 10987, year: 1988, vol: 458, page: 303, stat: Journal Article,

MEASUREMENT OF EXTRACELLULAR CYCLIC AMP IN BRAIN BY MICRODIALYSIS A METHOD TO STUDY BRAIN RECEPTOR FUNCTION IN-VIVO
STONE E A; EGAWA M
1988 ;14(2):925-925, Abstracts (Society for Neuroscience)
— id: 92515, year: 1988, vol: 14, page: 925, stat: Journal Article,

Novel effect of chronic corticosterone treatment on escape behavior in rats
Stone EA; Egawa M; McEwen BS
1988 Jul;50(1):120-125, Behavioral & neural biology
Chronic administration of corticosterone in rats (4-35 mg/kg/day) produces a marked dose-dependent increase in the frequency of escape behavior observed when animals are held by the tail on a flat surface. The effect is fully developed after 3 days treatment. It is not the result of an increase in spontaneous motor activity since the hormone tends to reduce the latter behavior. Adrenalectomy decreases the escape behavior and tends to do so to a greater degree in rats subjected to chronic stress (restraint) than in nonstressed controls. The results suggest that endogenous corticosterone serves to maintain the above escape behavior during chronic stress
— id: 11034, year: 1988, vol: 50, page: 120, stat: Journal Article,

REDUCTION IN 2-DEOXY-D-GLUCOSE ANALGESIA FOLLOWING ACUTE, BUT NOT CHRONIC ANTIDEPRESSANT TREATMENT
Bodnar, RJ; Romero, MT; Kest, B; Stone, EA
1987 Dec;91(2):207-208, Psychopharmacology
— id: 31341, year: 1987, vol: 91, page: 207, stat: Journal Article,

CHRONIC CORTICOSTERONE ADMINISTRATION INCREASES ESCAPE BEHAVIOR IN RATS
EGAWA M; STONE E A; MCWEN B M
1987 ;13(1):58-58, Abstracts (Society for Neuroscience)
— id: 92518, year: 1987, vol: 13, page: 58, stat: Journal Article,

STRESS-INDUCED ALTERATIONS IN CORTICAL SPIRODECANONE RECEPTORS
FRIEDHOFF A J; ROSENGARTEN H R; STONE E A; EGAWA M
1987 ;13(1):200-200, Abstracts (Society for Neuroscience)
— id: 92517, year: 1987, vol: 13, page: 200, stat: Journal Article,

ROLE OF CORTICOSTERONE IN STRESS-INDUCED DESENSITIZATION OF CORTICAL ALPHA-1 RECEPTORS
STONE E A; MCEWEN B M; HERRERA A S
1987 ;13(2):897-897, Abstracts (Society for Neuroscience)
— id: 92516, year: 1987, vol: 13, page: 897, stat: Journal Article,

Central cyclic-AMP-linked noradrenergic receptors: new findings on properties as related to the actions of stress
Stone EA
1987 Winter;11(4):391-398, Neuroscience & biobehavioral reviews
Central noradrenergic receptors that control cyclic AMP formation in the brain may be involved in the process of adaptation to stress and in the clinical actions of antidepressant drugs. The present paper reviews recent findings on the properties and susceptibility to stress of these receptors. Two types of adrenergic receptors are known to mediate the central cAMP response, beta and alpha receptors. It has been found that chronic stress causes a selective desensitization of the alpha receptors (alpha-1 subtype) producing a partial reduction of the overall cAMP response to catecholamines. This desensitization occurs in the cerebral cortex, hypothalamus and possibly other areas of the forebrain. The physiological factor responsible for the effect appears to be an elevated corticosterone secretion. The behavioral function of the stress-induced desensitization may be to reduce behavioral inhibition and facilitate the recovery of behavioral function during adaptation to stress
— id: 11429, year: 1987, vol: 11, page: 391, 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,

INCREASE IN D-2 RECEPTOR DENSITY IN RAT BRAIN AFTER REPEATED STRESS
FRIEDHOFF A J; ROSENGARTEN H; STONE E A
1986 ;12(1):192-192, Abstracts (Society for Neuroscience)
— id: 92519, year: 1986, vol: 12, page: 192, 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,

Effect of repeated restraint stress, desmethylimipramine or adrenocorticotropin on the alpha and beta adrenergic components of the cyclic AMP response to norepinephrine in rat brain slices
Stone, E A; Platt, J E; Herrera, A S; Kirk, K L
1986 Jun;237(3):702-707, Journal of pharmacology & experimental therapeutics
The cyclic AMP response to catecholamines in rat cortical slices is mediated by a beta adrenergic receptor which is coupled to adenylate cyclase and an alpha adrenergic receptor which potentiates the response to beta receptor stimulation. The present studies examined the effects of repeated restraint stress, adrenocorticotropin or desmethylimipramine administration on the beta and alpha adrenergic components of this response. Restraint was found to produce a small nonsignificant decrease of the beta receptor response accompanied by a significant reduction of the alpha receptor-induced potentiation of the beta response. Desmethylimipramine was found to lower the cyclic AMP response to beta receptor stimulation but not to alter the alpha-induced potentiation of the beta response. Adrenocorticotropin, like restraint stress, was found to reduce only the alpha-induced potentiation of the beta response. Experiments with adenosine and histamine showed that restraint stress lowered the alpha-induced potentiation of cyclic AMP responses to these neurohormones also. It is concluded that restraint stress acts primarily to reduce the response to stimulation of central alpha adrenergic receptors whereas desmethylimipramine acts primarily to reduce the response to stimulation of beta adrenergic receptors. Adrenocorticotropin has the same effect as restraint stress suggesting that pituitary adrenal hormones mediate the stress effect
— id: 114742, year: 1986, vol: 237, page: 702, stat: Journal Article,

ALPHA-ADRENERGIC MODULATION OF CYCLIC-AMP FORMATION IN RAT CNS - HIGHEST LEVEL IN OLFACTORY-BULB
STONE, EA; HERRERA, AS
1986 OCT 8 ;384(2):401-403, Brain research
— id: 41344, year: 1986, vol: 384, page: 401, 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,

POTENTIATION OF COLD-WATER SWIM ANALGESIA BY ACUTE, BUT NOT CHRONIC DESIPRAMINE ADMINISTRATION
BODNAR, RJ; MANN, PE; STONE, EA
1985 ;23(5):749-752, Pharmacology biochemistry & behavior
— id: 41139, year: 1985, vol: 23, page: 749, stat: Journal Article,

COMPARISON OF THE ACTIONS OF REPEATED STRESS AND REPEATED ANTIDEPRESSANT TREATMENT ON RAT BRAIN NORADRENERGIC CYCLIC AMP FORMATION IN BRAIN SLICES
STONE E A; PLATT J E; HERRERA A S
1985 ;11(2):1271-1271, Abstracts (Society for Neuroscience)
— id: 92520, year: 1985, vol: 11, page: 1271, stat: Journal Article,

Reduction of the cyclic adenosine 3',5'-monophosphate response to catecholamines in rat brain slices after repeated restraint stress
Stone, E A; Slucky, A V; Platt, J E; Trullas, R
1985 May;233(2):382-388, Journal of pharmacology & experimental therapeutics
Restraint stress reduces the cyclic AMP (cAMP) response to norepinephrine (NE) in slices of the rat cerebral cortex and hypothalamus. This effect is found after repeated but not single exposure to stress and persists for at least 24 hr poststress. The magnitude of the reduction is dose-dependent in that greater decreases are found after higher frequencies and longer durations of restraint as well as after more disturbance during the stress. Analysis of the NE-cAMP dose-response curve indicates that the stress reduces the maximum cAMP response to NE but does not increase the EC50 value of NE. The cAMP response to isoproterenol is only slightly affected by the stress. No effect is observed on specific [3H]dihydroalprenolol binding in either brain region at 24 hr poststress. These results suggest that repeated restraint stress produces a selective persistent reduction of the function of brain non-beta adrenergic receptors. This effect may be mediated by an increased release of adrenocorticotropic hormone as chronic infusion of the latter hormone mimics the action of stress on cAMP responses to catecholamines. An increased release of brain NE may also be involved as repeated administration of the NE-reuptake inhibiting antidepressant, desmethylimipamine, reduces the function of non-beta as well as beta adrenergic receptors as evidenced by reductions of both the NE- and isoproterenol-cAMP responses
— id: 114743, year: 1985, vol: 233, page: 382, stat: Journal Article,

SUBSENSITIVITY TO NOREPINEPHRINE IN RAT BRAIN AFTER REPEATED STRESS CHARACTERIZATION AND COMPARISON WITH EFFECTS OF STRESS HORMONES AND ANTIDEPRESSANTS
STONE E A; SLUCKY A V; PLATT J E; TRULLAS R
1984 ;10(1):262-262, Abstracts (Society for Neuroscience)
— id: 92521, year: 1984, vol: 10, page: 262, stat: Journal Article,

Reduction of the cAMP response to norepinephrine in rat cerebral cortex following repeated restraint stress
Stone, E A; Platt, J E; Trullas, R; Slucky, A V
1984 ;82(4):403-405, Psychopharmacology
The present studies examined the effect of restraint stress on the sensitivity of the catecholamine-cAMP generating system in the rat cerebral cortex. Restraint was found to cause a persistent reduction in the magnitude of the cAMP response to catecholamines. This effect occurred after repeated but not acute stress and was more marked with twice-daily as compared to once-daily treatment. The reduction in response was more marked with norepinephrine than with isoproterenol, indicating a selective action of stress on the non-beta component of the noradrenergic response. The findings suggest that subsensitivity of the cAMP response to norepinephrine is a general response to chronic stressful stimuli and may be related to the action of certain antidepressant agents
— id: 114747, year: 1984, vol: 82, page: 403, stat: Journal Article,

The effect of acute and chronic administration of desmethylimipramine on responses to stress in rats
Stone, E A; Trullas, R; Platt, J E
1984 ;8(4-6):587-592, Progress in neuro-psychopharmacology & biological psychiatry
Rats were given single or repeated injection of desmethylimipramine (DMI) and subjected to a single session of restraint or footshock stress. The degree of anorexia and plasma corticosterone elevation in response to the stress was measured. Repeated but not single injection of DMI was found to reduce the anorectic response to restraint and footshock but not to affect the corticosterone response to restraint. It is concluded that repeated DMI treatment has differential effects on responses to acute stress
— id: 114746, year: 1984, vol: 8, page: 587, stat: Journal Article,

Adaptation to stress and brain noradrenergic receptors
Stone EA
1983 Winter;7(4):503-509, Neuroscience & biobehavioral reviews
The present paper reviews the effects of stress on noradrenergic receptor function in the brain. Most forms of stress thus far examined have been found to reduce either the magnitude of the cAMP response to stimulation by catecholamines (CAs) and/or the density of beta adrenergic receptors in the brain. These effects (a) generally occur in the cerebral cortex, (b) are more marked after chronic than acute stress, (c) may be the result of excessive release of norepinephrine (NE), ACTH or serotonin (5-HT) and (d) may occur in neurons glia or both. The function of these receptor alterations is not known but is presumed to be related in some manner to adaptation to chronic stress. A review of similar changes occurring in peripheral organs after repeated stress or CA injections reveals that subsensitivity of beta adrenergic receptors can be associated with either decreases or increases in CA-stimulated organ output. The latter findings caution against concluding that there is a decreased postsynaptic noradrenergic function after adaptation to chronic stress. Instead they suggest that it may be more appropriate to view stress-induced receptor subsensitivity as part of a more complex pattern of adaptive changes which includes alterations in the size, number, efficiency and output of CA effector cells
— id: 63240, year: 1983, vol: 7, page: 503, stat: Journal Article,

Rapid adaptation of the stimulatory effect of CO2 on brain norepinephrine metabolism
Stone EA
1983 Dec;324(4):313-315, Naunyn-Schmiedeberg's archives of pharamacology
The present study examined the effects of exposure of rats to elevated environmental levels of CO2 on norepinephrine metabolism in the hypothalamus and other regions of the brain. In confirmation of previous findings by others CO2 at 10 or 15% was found to elevate both dopa accumulation after dopa decarboxylase inhibition and norepinephrine utilization after tyrosine hydroxylase inhibition. These effects however were found to be transient occurring only during the first 30 min of 2.5 h exposure. In this regard CO2 differs from another form of stress, restraint which produces a sustained 2.5 h increase of dopa accumulation and NE accumulation. Restraint was also more effective than CO2 in depleting endogenous stores of hypothalamic NE. The factor responsible for the adaptation of the catecholamine response to CO2 was not identified although it was shown not to be hypothermia and it was reversed by a 2 h CO2-free recovery period
— id: 63274, year: 1983, vol: 324, page: 313, stat: Journal Article,

Reduction in cortical beta adrenergic receptor density after chronic intermittent food deprivation
Stone EA
1983 Sep 19;40(1):33-37, Neuroscience letters
The effect of chronic intermittent food deprivation on beta adrenergic receptor binding in the rat brain was studied. Rats subjected to six 48 h fasts given over a period of 3 weeks demonstrated a reduction in the density of beta adrenergic receptors in the cerebral cortex but not in the hypothalamus or lower brainstem. This receptor alteration did not occur after one 48 h fast. This effect of chronic food deprivation is shared by several other forms of repeated stress, suggesting that it is a general mechanism of adaptation
— id: 63182, year: 1983, vol: 40, page: 33, stat: Journal Article,

Adaptation to stress: tyrosine hydroxylase activity and catecholamine release
Stone EA; McCarty R
1983 Spring;7(1):29-34, Neuroscience & biobehavioral reviews
The effects of adaptation to stress and of genetic differences on levels of in vitro tyrosine hydroxylase (TH) activity and in vivo catecholamine (CA) release are reviewed. It is shown that adaptation of animals to a wide variety of stressors including immobilization, electroconvulsive shock, footshock, hemorrhage, exercise and cold exposure results in a reduced CA response in the plasma, brainstem and heart to subsequent exposure to the same stress. Adaptation to many of the latter stressors also produces increased in vitro levels of TH activity. A similar inverse relation between in vitro TH activity and in vivo CA release is described for two inbred rat strains which differ in emotionality (Brown-Norway and Wistar Kyoto). The inverse relationship between TH activity and CA release may reflect different processes of biochemical adaptation utilized either for acclimation to stress, for preparation for emergency reactions or for changes in the metabolic costs of transmitter release. The similarity between environmental and genetic effects on these variables suggests that the above changes have a common adaptive function
— id: 63238, year: 1983, vol: 7, page: 29, stat: Journal Article,

INPUT ON OUTPUT
STONE, EA
1983 ;6(4):561-569, Behavioral & brain sciences
— id: 40865, year: 1983, vol: 6, page: 561, stat: Journal Article,

PROBLEMS WITH CURRENT CATECHOLAMINE HYPOTHESES OF ANTIDEPRESSANT AGENTS - SPECULATIONS LEADING TO A NEW HYPOTHESIS
STONE, EA
1983 ;6(4):535-547, Behavioral & brain sciences
— id: 40863, year: 1983, vol: 6, page: 535, stat: Journal Article,

Chronic restraint stress elicits a positive antidepressant response on the forced swim test
Platt, J E; Stone, E A
1982 Aug 27;82(3-4):179-181, European journal of pharmacology
The present study investigated behavioral parallels between adaptation to stress and antidepressant treatment using the forced swim test. Restraint stress given repeatedly for 11 days significantly reduced immobility on this test. A single application of stress had no effect. The reduction in immobility produced by repeated restraint was quantitatively similar to that produced by repeated administration of desmethylimipramine. These results confirm previous findings of similarities in the behavioral and neurochemical response to chronic stress and chronic antidepressant treatment
— id: 114748, year: 1982, vol: 82, page: 179, stat: Journal Article,

Brain adrenergic receptors and resistance to stress
Stone EA; Platt JE
1982 Apr 15;237(2):405-414, Brain research
The relationship between brain beta-adrenergic receptors and adaptation to stress was studied in rats subjected to repeated restraint stress. The stress was found to produce a reduction in the density of these receptors in the hypothalamus, cerebral cortex and brain stem. This change first appeared after 4-7 days and persisted for the duration of the two-week stress. Adaptation, as judged by resistance to the anorexic and gastric lesion-inducing effects of the stress, occurred progressively over the full two-week period. The loss of beta-receptors was found to correlate positively with the degree of adaptation. The relationship was strongest for the hypothalamus but was also apparent in the cortex and brain stem. These findings support the hypothesis that a reduction in the number of brain adrenergic receptors is one of the biochemical factors underlying adaptation to stress
— id: 63172, year: 1982, vol: 237, page: 405, stat: Journal Article,

NORADRENERGIC FUNCTION DURING STRESS AND DEPRESSION - AN ALTERNATIVE VIEW
Stone, EA
1982 ;5(1):122-122, Behavioral & brain sciences
— id: 30311, year: 1982, vol: 5, page: 122, stat: Journal Article,

MECHANISM OF STRESS-INDUCED SUBSENSITIVITY TO NOREPINEPHRINE
Stone, EA
1981 ;14(5):719-723, Pharmacology biochemistry & behavior
— id: 30213, year: 1981, vol: 14, page: 719, stat: Journal Article,

[DIHYDROALPRENOLOL-H-3 BINDING IN THE RAT BRAIN-STEM
Stone, EA; Uprichard, DC
1981 ;75(2-3):159-161, European journal of pharmacology
— id: 30235, year: 1981, vol: 75, page: 159, stat: Journal Article,

REDUCTION BY STRESS OF NOREPINEPHRINE-STIMULATED ACCUMULATION OF CYCLIC-AMP IN RAT CEREBRAL-CORTEX
Stone, EA
1979 ;32(4):1335-1337, Journal of neurochemistry
— id: 30027, year: 1979, vol: 32, page: 1335, stat: Journal Article,

SUBSENSITIVITY TO NOREPINEPHRINE AS A LINK BETWEEN ADAPTATION TO STRESS AND ANTI-DEPRESSANT THERAPY - HYPOTHESIS
Stone, EA
1979 ;4(3):241-255, Research communications in psychology, psychiatry & behavior
— id: 29977, year: 1979, vol: 4, page: 241, stat: Journal Article,

EFFECT OF STRESS AND OF PHENYLETHANOLAMINE-N-METHYLTRANSFERASE INHIBITION ON CENTRAL NOREPINEPHRINE AND EPINEPHRINE LEVELS
SAUTER, AM; STONE, EA; BABA, Y; GOLDSTEIN, M
1978 ;144(2):415-419, Brain research
— id: 98685, year: 1978, vol: 144, page: 415, stat: Journal Article,

EFFECT OF STRESS ON NOREPINEPHRINE-STIMULATED CYCLIC-AMP FORMATION IN BRAIN-SLICES
STONE, EA
1978 ;8(5):583-591, Pharmacology biochemistry & behavior
— id: 40045, year: 1978, vol: 8, page: 583, stat: Journal Article,

IMPROVED POLYETHYLENE INTRACEREBROVENTRICULAR CANNULAS FOR RATS
Stone, EA
1978 ;20(5):657-659, Physiology & behavior
— id: 29933, year: 1978, vol: 20, page: 657, stat: Journal Article,

POSSIBLE GROOMING DEFICIT IN STRESSED RATS
STONE, EA
1978 ;3(2):109-115, Research communications in psychology, psychiatry & behavior
— id: 40039, year: 1978, vol: 3, page: 109, stat: Journal Article,

BRAIN AND ADRENAL TYROSINE-HYDROXYLASE ACTIVITY AFTER CHRONIC FOOTSHOCK STRESS
Stone, EA; Freedman, LS; Morgano, LE
1978 ;9(4):551-553, Pharmacology biochemistry & behavior
— id: 29866, year: 1978, vol: 9, page: 551, stat: Journal Article,

CENTRAL NORADRENERGIC ACTIVITY AND FORMATION OF GLYCOL SULFATE METABOLITES OF BRAIN NOREPINEPHRINE
Stone, EA
1976 ;19(10):1491-1498, Life sciences
— id: 28694, year: 1976, vol: 19, page: 1491, stat: Journal Article,

SURVIVAL AND DEVELOPMENT OF MATERNALLY DEPRIVED RATS - ROLE OF BODY-TEMPERATURE
Stone, EA; Bonnet, KA; Hofer, MA
1976 ;38(4):242-249, Psychosomatic medicine
— id: 28699, year: 1976, vol: 38, page: 242, stat: Journal Article,

EFFECT OF STRESS ON SULFATED GLYCOL METABOLITES OF BRAIN NOREPINEPHRINE
Stone, EA
1975 ;16(11):1725-1729, Life sciences
— id: 28487, year: 1975, vol: 16, page: 1725, stat: Journal Article,

SEPARATION OF CONJUGATED GLYCOL METABOLITES OF [H-3] NOREPINEPHRINE IN RAT-BRAIN
Stone, EA; Mendlinger, S
1974 ;62(2):592-597, Analytical biochemistry
— id: 28591, year: 1974, vol: 62, page: 592, stat: Journal Article,

EFFECT OF INTRAVENTRICULAR AMINES ON MOTOR ACTIVITY IN HYPOTHERMIC RATS
Stone, EA; Mendling[...], S
1974 ;7(3):549-556, Research communications in chemical pathology & pharmacology
— id: 28343, year: 1974, vol: 7, page: 549, stat: Journal Article,

Adrenergic activity in rat hypothalamus following extreme muscular exertion
Stone, E A
1973 Jan;224(1):165-169, American journal of physiology
— id: 134959, year: 1973, vol: 224, page: 165, stat: Journal Article,

ACCUMULATION AND METABOLISM OF NOREPINEPHRINE IN RAT HYPOTHALAMUS AFTER EXHAUSTIVE STRESS
STONE, EA
1973 ;21(3):589-601, Journal of neurochemistry
— id: 39778, year: 1973, vol: 21, page: 589, stat: Journal Article,