Jonathan D Brodie, M.D., Ph.D.

(1S, 3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic Acid (CPP-115), a Potent gamma-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Cocaine Addiction
Pan, Yue; Gerasimov, Madina R; Kvist, Trine; Wellendorph, Petrine; Madsen, Karsten K; Pera, Elena; Lee, Hyunbeom; Schousboe, Arne; Chebib, Mary; Brauner-Osborne, Hans; Craft, Cheryl M; Brodie, Jonathan D; Schiffer, Wynne K; Dewey, Stephen L; Miller, Steven R; Silverman, Richard B
2012 Jan 12;55(1):357-366, Journal of medicinal chemistry
Vigabatrin, a GABA aminotransferase (GABA-AT) inactivator, is used to treat infantile spasms and refractory complex partial seizures and is in clinical trials to treat addiction. We evaluated a novel GABA-AT inactivator (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115, compound 1) and observed that it does not exhibit other GABAergic or off-target activities and is rapidly and completely orally absorbed and eliminated. By use of in vivo microdialysis techniques in freely moving rats and microPET imaging techniques, 1 produced similar inhibition of cocaine-induced increases in extracellular dopamine and in synaptic dopamine in the nucleus accumbens at (1)/(300) to (1)/(600) the dose of vigabatrin. It also blocks expression of cocaine-induced conditioned place preference at a dose (1)/(300) that of vigabatrin. Electroretinographic (ERG) responses in rats treated with 1, at doses 20-40 times higher than those needed to treat addiction in rats, exhibited reductions in ERG responses, which were less than the reductions observed in rats treated with vigabatrin at the same dose needed to treat addiction in rats. In conclusion, 1 can be administered at significantly lower doses than vigabatrin, which suggests a potential new treatment for addiction with a significantly reduced risk of visual field defects
— id: 150262, year: 2012, vol: 55, page: 357, stat: Journal Article,

Integrating molecular imaging and behavioral neuroscience: Seeing animal models in a new light
Schiffer W.; Carrion J.; Eidelberg D.; Brodie J.D.
2010 ;12:S664-S664, Molecular Imaging & Biology
We will describe the development and validation of a new paradigm in which PET and a host of receptor specific radiotracers can be used to capture dynamic molecular events in behaving animals. Key to our paradigm, radiotracer uptake occurs while animals move freely in a range of test environments, followed by anesthesia and scan. Using 11C-raclopride (¹¹C-rac) as a prototypical probe whose displacement reflects changing dopamine, we validated this paradigm with drug challenges designed to directly perturb 11C-rac (loading doses of cold rac) or indirectly change 11C-rac by changing dopamine (METH to increase and AMPT to decrease dopamine). Systematic variations in uptake duration, type and presence of anesthetic, route of 11C-rac administration and image acquisition methods were used to optimize the protocol. For these validations, paired scans were performed where uptake occurred in the awake state, followed by anesthesia and scanning. While still in the gantry, a second scan gave full time activity data from the same animal. Comparing these data allowed us to validate derivations of binding potential used to quantitate awake uptake. All awake studies were videoed and analyzed with behavioral phenotyping software. With this information, individual behaviors were directly related changes in 11C-rac binding. Behavioral challenges revealed striking parallels analagous to human PET studies. First, stress decreased 11C-rac binding, an effect that significantly correlated with behavior and was similar in magnitude to that following METH. Second, cue exposure in cocaine-addicted animals significantly decreased 11C-rac, and this decrease correlated with individual measures of craving using the CPP model. The magnitude was similar to the decrease in 11C-rac from an acute dose of cocaine. Microdialysis data revealed that cue exposure produces lower but sustained increases in dopamine, while cocaine produces large, rapid increases that quickly return to baseline. Comparable decreases in 11C-rac in behavioral and drug challenge studies have recently been raised in clinical PET studies. Perhaps the most important message, individual changes in 11C-rac are associated with individual differences in behavior in each model. Animals with little genetic variation and no difference in rearing will, for example, respond uniquely to stress and this response closely reflects 11C-rac. This mimics the inherent variability commonly observed in clinical PET which, in animals, can be obscured by examining group responses in single-focus behavioral or biological experiments. (Figure presented)
— id: 119244, year: 2010, vol: 12, page: S664, stat: Journal Article,

Randomized, Double-Blind, Placebo-Controlled Trial of Vigabatrin for the Treatment of Cocaine Dependence in Mexican Parolees
Brodie, Jonathan D; Case, Brady G; Figueroa, Emilia; Dewey, Stephen L; Robinson, James A; Wanderling, Joseph A; Laska, Eugene M
2009 Nov;166(11):1269-1277, American journal of psychiatry
Objective Cocaine dependence is associated with severe medical, psychiatric, and social morbidity, but no pharmacotherapy is approved for its treatment in the United States. The atypical antiepileptic vigabatrin (gamma-vinyl gamma-aminobutyric acid [GABA]) has shown promise in animal studies and open-label trials. The purpose of the present study was to assess the efficacy of vigabatrin for short-term cocaine abstinence in cocaine-dependent individuals. Method Participants were treatment seeking parolees who were actively using cocaine and had a history of cocaine dependence. Subjects were randomly assigned to a fixed titration of vigabatrin (N=50) or placebo (N=53) in a 9-week double-blind trial and 4-week follow-up assessment. Cocaine use was determined by directly observed urine toxicology testing twice weekly. The primary endpoint was full abstinence for the last 3 weeks of the trial. Results Full end-of-trial abstinence was achieved in 14 vigabatrin-treated subjects (28.0%) versus four subjects in the placebo arm (7.5%). Twelve subjects in the vigabatrin group and two subjects in the placebo group maintained abstinence through the follow-up period. The retention rate was 62.0% in the vigabatrin arm versus 41.5% in the placebo arm. Among subjects who reported prestudy alcohol use, vigabatrin, relative to placebo, was associated with superior self-reported full end-of-trial abstinence from alcohol (43.5% versus 6.3%). There were no differences between the two groups in drug craving, depressed mood, anxiety, or Clinical Global Impression scores, and no group differences in adverse effects emerged. Conclusions This first randomized, double-blind, placebo-controlled trial supports the safety and efficacy of short-term vigabatrin treatment of cocaine dependence
— id: 101865, year: 2009, vol: 166, page: 1269, stat: Journal Article,

Racemic gamma vinyl-GABA (R,S-GVG) blocks methamphetamine-triggered reinstatement of conditioned place preference
DeMarco, Amy; Dalal, Reema M; Pai, Jessica; Aquilina, Stefanie D; Mullapudi, Uma; Hammel, Crystie; Kothari, Shiva K; Kahanda, Milan; Liebling, Courtney N B; Patel, Vinal; Schiffer, Wynne K; Brodie, Jonathan D; Dewey, Stephen L
2009 Feb;63(2):87-94, Synapse
Preventing relapse poses a significant challenge to the successful management of methamphetamine (METH) dependence. Although no effective medication currently exists for its treatment, racemic gamma vinyl-GABA (R,S-GVG, vigabatrin) shows enormous potential as it blocks both the neurochemical and behavioral effects of a variety of drugs, including METH, heroin, morphine, ethanol, nicotine, and cocaine. Using the reinstatement of a conditioned place preference (CPP) as an animal model of relapse, the present study specifically investigated the ability of an acute dose of R,S-GVG to block METH-triggered reinstatement of a METH-induced CPP. Animals acquired a METH CPP following a 20-day-period of conditioning, in which they received 10 pairings of alternating METH and saline injections. During conditioning, rats were assigned to one of four METH dosage groups: 1.0, 2.5, 5.0, or 10.0 mg/kg (i.p., n = 8/group). Animals in all dosage groups demonstrated a robust and consistent CPP. This CPP was subsequently extinguished in each dosage group with repeated saline administration. Upon extinction, all groups reinstated following an acute METH challenge. On the following day, an acute dose of R,S-GVG (300 mg/kg, i.p.) was administered 2.5 h prior to an identical METH challenge. R,S-GVG blocked METH-triggered reinstatement in all four groups. Given that drug re-exposure may potentiate relapse to drug-seeking behavior, the ability of R,S-GVG to block METH-triggered reinstatement offers further support for its use in the successful management of METH dependence
— id: 95221, year: 2009, vol: 63, page: 87, stat: Journal Article,

Cue-induced dopamine release predicts cocaine preference: positron emission tomography studies in freely moving rodents
Schiffer, Wynne K; Liebling, Courtney N B; Reiszel, Corinne; Hooker, Jacob M; Brodie, Jonathan D; Dewey, Stephen L
2009 May 13;29(19):6176-6185, Journal of neuroscience
Positron emission tomography studies in drug-addicted patients have shown that exposure to drug-related cues increases striatal dopamine, which displaces binding of the D(2) ligand, [(11)C]-raclopride. However, it is not known if animals will also show cue-induced displacement of [(11)C]-raclopride binding. In this study, we use [(11)C]-raclopride imaging in awake rodents to capture cue-induced changes in dopamine release associated with the conditioned place preference model of drug craving. Ten animals were conditioned to receive cocaine in a contextually distinct environment from where they received saline. Following conditioning, each animal was tested for preference and then received two separate [(11)C]-raclopride scans. For each scan, animals were confined to the cocaine and/or the saline-paired environment for the first 25 min of uptake, after which they were anesthetized and scanned. [(11)C]-raclopride uptake in the saline-paired environment served as a within-animal control for uptake in the cocaine-paired environment. Cocaine produced a significant place preference (p = 0.004) and exposure to the cocaine-paired environment decreased [(11)C]-raclopride binding relative to the saline-paired environment in both the dorsal (20%; p < 0.002) and ventral striatum (22%; p < 0.05). The change in [(11)C]-raclopride binding correlated with preference in the ventral striatum (R(2) = -0.87; p = 0.003). In this region, animals who showed little or no preference exhibited little or no change in [(11)C]-raclopride binding in the cocaine-paired environment. This noninvasive procedure of monitoring neurochemical events in freely moving, behaving animals advances preclinical molecular imaging by interrogating the degree to which animal models reflect the human condition on multiple dimensions, both biological and behavioral
— id: 109179, year: 2009, vol: 29, page: 6176, stat: Journal Article,

Subchronic racemic gamma vinyl-GABA produces weight loss in Sprague Dawley and Zucker fatty rats
DeMarco, Amy; Dalal, Reema M; Kahanda, Milan; Mullapudi, Uma; Pai, Jessica; Hammel, Crystie; Liebling, Courtney N B; Patel, Vinal; Brodie, Jonathan D; Schiffer, Wynne K; Dewey, Stephen L; Aquilina, Stefanie D
2008 Nov;62(11):870-872, Synapse
Given the growing obesity epidemic, pressure to develop an effective pharmacologic treatment is mounting. Following the completion of a randomized, double-blind, placebo controlled trial as well as two small open label trials, gamma vinyl-GABA (GVG) has been shown to be safe and effective for treating cocaine and/or methamphetamine dependence. In an extension of these findings, the present study examined whether GVG could produce weight loss in adolescent as well as genetically obese animals. Specifically, adolescent Sprague Dawley and adolescent and adult Zucker fatty rats received GVG at various doses (75-300 mg/kg, i.p., racemic) for treatment periods lasting no longer than 14 consecutive days. GVG produced significant weight loss in a dose dependent fashion in all groups. These effects were marked, as average decreases of 12-20% of original body weight were observed. These findings suggest that GVG may be useful as a treatment for obesity. Further, that these results occurred in genetically obese animals offers the possibility that GVG may even help manage severe obesity resulting from binge-eating, a disorder involving food consumption in a pattern similar to the compulsive drug-seeking behavior observed in cocaine and methamphetamine dependent subjects
— id: 95222, year: 2008, vol: 62, page: 870, stat: Journal Article,

Gamma-vinyl GABA inhibits cocaine-triggered reinstatement of drug-seeking behavior in rats by a non-dopaminergic mechanism
Peng, Xiao-Qing; Li, Xia; Gilbert, Jeremy G; Pak, Arlene C; Ashby, Charles R Jr; Brodie, Jonathan D; Dewey, Stephen L; Gardner, Eliot L; Xi, Zheng-Xiong
2008 Oct 1;97(3):216-225, Drug & alcohol dependence
Relapse to drug use is a core feature of addiction. Previous studies demonstrate that gamma-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, attenuates the acute rewarding effects of cocaine and other addictive drugs. We here report that systemic administration of GVG (25-300mg/kg) dose-dependently inhibits cocaine- or sucrose-induced reinstatement of reward-seeking behavior in rats. In vivo microdialysis data indicated that the same doses of GVG dose-dependently elevate extracellular GABA levels in the nucleus accumbens (NAc). However, GVG, when administered systemically or locally into the NAc, failed to inhibit either basal or cocaine-priming enhanced NAc dopamine in either naive rats or cocaine extinction rats. These data suggest that: (1) GVG significantly inhibits cocaine- or sucrose-triggered reinstatement of reward-seeking behavior; and (2) a GABAergic-, but not dopaminergic-, dependent mechanism may underlie the antagonism by GVG of cocaine-triggered reinstatement of drug-seeking behavior, at least with respect to GVG's action on the NAc
— id: 76198, year: 2008, vol: 97, page: 216, stat: Journal Article,

The brain and behavior: limitations in the legal use of functional magnetic resonance imaging
Tancredi, Laurence R; Brodie, Jonathan D
2007 ;33(2-3):271-294, American Journal of Law & Medicine
— id: 75386, year: 2007, vol: 33, page: 271, stat: Journal Article,

Correlation of PET and qEEG in normal subjects
Alper, Kenneth R; John, E Roy; Brodie, Jonathan; Gunther, Wilfred; Daruwala, Raoul; Prichep, Leslie S
2006 Apr 30;146(3):271-282, Psychiatry research
Positron emission tomography (PET) and quantitative electroencephalography (qEEG) were obtained in 15 normal male subjects with eyes closed at rest. Correlations between qEEG variables and regional metabolism were examined as an approach to investigating the metabolic and neuroanatomical basis of the generation of the EEG. Analogous to the neurometric approach to qEEG, a normative 2-fluoro-deoxyglucose voxel data base was developed for the PET image. The PET image was transformed to an idealized cylindrical set of coordinates to allow registration with the Talairach stereotactic atlas. PET regions of interest for the thalamus, the left and right temporal lobes, the medial frontal cortex and the dorsolateral prefrontal cortex were defined using Talairach coordinates and correlated to the QEEG. Salient findings included a negative correlation of thalamic metabolism to alpha power and a positive correlation of medial frontal cortical metabolism to delta EEG power. The significance of these findings is discussed with reference to the existing literature on the physiology of the generation of the EEG
— id: 67000, year: 2006, vol: 146, page: 271, stat: Journal Article,

Metabolic correlates of toluene abuse: decline and recovery of function in adolescent animals
Dewey, Stephen L; Ferrieri, Rich; Alexoff, David L; Schiffer, Wynne K; Lee, Dianne E; Brodie, Jonathan D
2006 Jun;186(2):159-167, Psychopharmacology
RATIONALE: Children and adolescents will readily abuse household products that contain solvents such as toluene. It is likely that reinforcing exposures to toluene alter brain glucose metabolism. OBJECTIVE: Using an animal model of drug reinforcement, we sought to identify a metabolic signature of toluene abuse in the adolescent rodent brain. Small animal PET (microPET), in combination with the glucose analog radiotracer, (18)FDG, were used to evaluate the metabolic consequences of inhaled toluene. METHODS: The exposure protocol paralleled our previously established method for assessing the conditioned reinforcing effects of toluene (5,000 ppm) using the conditioned place preference (CPP) paradigm. Animals were scanned at baseline and 2 h after the last exposure. Follow-up (18)FDG scans occurred 1 day, 3 weeks, and 2 months later. Results: After six pairings, 38% of the animals preferred the toluene paired chamber and 25% were averse. The immediate metabolic effect in toluene-exposed animals was a 20% decline in whole brain (18)FDG uptake. Twenty-four hours following the last exposure, the whole brain decline was 40%, and 2 months later, the decline was 30% of pretoluene levels. A region-by-region analysis demonstrated significant additional decreases in the pons, cerebellum, striatum, midbrain, temporal cortex, and hippocampus. Two months after toluene cessation, regions of complete metabolic recovery were the thalamus and cerebellum; however, the temporal cortex did not recover. CONCLUSIONS: Brain uptake of (18)FDG appears to be a useful tool for examining the metabolic impact of toluene abuse, which include a profound decline followed by region-specific recovery after cessation
— id: 67949, year: 2006, vol: 186, page: 159, stat: Journal Article,

Short-term Treatment of Cocaine and/or Methamphetamine Abuse With Vigabatrin: Ocular Safety Pilot Results
Fechtner, Robert D; Khouri, Albert S; Figueroa, Emilia; Ramirez, Marina; Federico, Martha; Dewey, Stephen L; Brodie, Jonathan D
2006 Sep;124(9):1257-1262, Archives of ophthalmology
OBJECTIVE: To evaluate the ocular safety of short-term use of vigabatrin to treat cocaine and/or methamphetamine addiction. METHODS: Individuals who were actively using cocaine and/or methamphetamine were eligible for enrollment. Enrolled subjects were scheduled for comprehensive eye examinations at the beginning and end of the study. Visual field testing was performed at baseline and 1 week, 4 weeks, 8 weeks, and 1 month or more after discontinuing vigabatrin. Twenty-eight subjects received at least 1 dose of vigabatrin; however, only 20 subjects continued beyond the initial escalating vigabatrin dose phase to the treatment phase. Of these 20 subjects, 18 completed the study with full follow-up. Visual fields were evaluated subjectively by 2 glaucoma specialists and analyzed objectively for group and individual changes in quadrant mean sensitivity. The objective analysis was also repeated for superior field quadrants after excluding the uppermost peripheral points to minimize the eyelid effect. The main outcome measures were change of visual field, visual acuity, and ocular adverse effects. RESULTS: Vigabatrin seemed to help treat cocaine and/or methamphetamine addiction. Of 18 subjects, 16 had negative test results for cocaine and methamphetamine use during the last 6 weeks of the trial. No ocular adverse events were detected. The subjective evaluation did not reveal visual field constriction in any of the 18 evaluable participants. Objective group and individual analyses for quadrant mean sensitivity did not show any change from baseline in any quadrant. No changes in visual acuity were noted. CONCLUSIONS: In this short-term pilot study, vigabatrin seemed to help treat cocaine and/or methamphetamine abuse. There was no evidence of ocular or visual field adverse effects
— id: 67948, year: 2006, vol: 124, page: 1257, stat: Journal Article,

Safety and efficacy of gamma-vinyl GABA (GVG) for the treatment of methamphetamine and/or cocaine addiction
Brodie, Jonathan D; Figueroa, Emilia; Laska, Eugene M; Dewey, Stephen L
2005 Feb;55(2):122-125, Synapse
This study examined the safety and efficacy of gamma vinyl-GABA (GVG, vigabatrin) for the treatment of methamphetamine and/or cocaine addiction. A total of 30 subjects, who met DSM-IV criteria for methamphetamine and/or cocaine dependence, were enrolled in an open label 9-week safety study. The protocol was specifically designed to include extensive visual field monitoring as well as outcome measures of therapeutic efficacy. Patients were screened twice weekly for the presence of urinary cocaine, methamphetamine, heroin, alcohol, and marijuana. In total, 18/30 subjects completed the study and 16/18 tested negative for methamphetamine and cocaine during the last 6 weeks of the trial. GVG did not produce any visual field defects or alterations in visual acuity. Furthermore, it did not produce changes in vital signs even with continued use of methamphetamine and cocaine. Thus, under conditions that appear to be appropriate for the successful treatment of methamphetamine and/or cocaine addiction, GVG is safe. Synapse 55:122-125, 2005. (c) 2004 Wiley-Liss, Inc
— id: 46891, year: 2005, vol: 55, page: 122, stat: Journal Article,

Imaging addiction with PET: is insight in sight?
Schiffer, Wynne K; Lee, Dianne E; Brodie, Jonathan D; Dewey, Stephen L
2005 Apr 15;10(8):547-562, Drug discovery today
Neurochemical imaging studies can identify molecular targets of abused drugs and link them to the underlying pathology associated with behaviors such as drug dependence, addiction and withdrawal. positron emission tomography (PET) is opening new avenues for the investigation of the neurochemical disturbances underlying drug abuse and addiction and the in vivo mechanisms by which medications might ameliorate these conditions. PET can identify vulnerable human populations, treatment strategies and monitor treatment efficacy. Thus, with this tool and the knowledge it provides, the potential for developing novel drugs and treatment strategies for drug addiction is now close at hand
— id: 67950, year: 2005, vol: 10, page: 547, stat: Journal Article,

Treating cocaine addiction: from preclinical to clinical trial experience with gamma-vinyl GABA
Brodie, Jonathan D; Figueroa, Emilia; Dewey, Stephen L
2003 Dec 1;50(3):261-265, Synapse
— id: 39052, year: 2003, vol: 50, page: 261, stat: Journal Article,

Limitations of brain imaging in forensic psychiatry
Reeves, Donald; Mills, Mark J; Billick, Stephen B; Brodie, Jonathan D
2003 ;31(1):89-96, Journal of the American Academy of Psychiatry & the Law
— id: 45033, year: 2003, vol: 31, page: 89, stat: Journal Article,

Gamma-vinyl GABA, an irreversible inhibitor of GABA transaminase, alters the acquisition and expression of cocaine-induced sensitization in male rats
Gardner, Eliot L; Schiffer, Wynne K; Horan, Bryan A; Highfield, David; Dewey, Stephen L; Brodie, Jonathan D; Ashby, Charles R Jr
2002 Dec 15;46(4):240-250, Synapse
We examined the effect of (+/-)-gamma-vinyl GABA (GVG, Vigabatrin), an irreversible inhibitor of the enzyme GABA transaminase, on the acquisition and expression of cocaine-induced sensitization in albino male Sprague-Dawley rats. Animals received a single injection of 1 ml/kg i.p. of 0.9% saline or 15 mg/kg i.p. of (-)-cocaine and locomotor activity was assessed using automated locomotor cages and stereotyped behaviors were scored using a 4-point rating scale (Day 1). Subsequently, animals were given 15 mg/kg i.p. of cocaine every 48 h in their home cage for 1 week (Days 3, 5, and 7) and then given no treatment for 1 week. A challenge injection of 15 mg/kg i.p. of cocaine, but not vehicle, produced a significant increase in locomotor activity and stereotyped behaviors on Day 15 compared to animals that received cocaine on Day 1. Administration of 75 mg/kg i.p. of GVG 2.5 h before the cocaine injections did not significantly alter the acquisition of cocaine-induced locomotor sensitization. However, 150 mg/kg i.p. of GVG significantly attenuated the acquisition of cocaine-induced locomotor sensitization. Administration of 150 mg/kg i.p. of GVG 2.5 h before the cocaine challenge injection on Day 15 significantly attenuated the expression of cocaine-induced locomotor sensitization. Acquisition and expression of cocaine-induced sensitization of stereotypy was also significantly attenuated by 150 mg/kg i.p. of GVG. Since sensitization may be one of the factors involved in relapse to drug use, the present results, in combination with previous findings that GVG blocks the rewarding and incentive motivating effects of cocaine, suggest that GVG might prove useful in the treatment of cocaine addiction
— id: 67951, year: 2002, vol: 46, page: 240, stat: Journal Article,

GABAergic blockade of cocaine-associated cue-induced increases in nucleus accumbens dopamine
Gerasimov MR; Schiffer WK; Gardner EL; Marsteller DA; Lennon IC; Taylor SJ; Brodie JD; Ashby CR; Dewey SL
2001 Mar 2;414(2-3):205-209, European journal of pharmacology
Environments previously associated with drug use can become one of the most common factors triggering relapse to drug-seeking behavior. To better understand the neurochemical mechanisms potentially mediating these cues, we measured nucleus accumbens dopamine levels in animals exposed to environmental cues previously paired with cocaine administration. In animals exposed to a cocaine-paired environment nucleus accumbens dopamine increased by 25%. When administered 2.5 h prior to presentation of the environmental trigger, racemic vigabatrin (an irreversible inhibitor of gamma-aminobutyric acid (GABA)-transaminase) abolished this cue-induced increase. Conversely, R-(-)-vigabatrin, the inactive enantiomer, had no effect. Combined with our earlier findings, these studies support the potential therapeutic benefit of this enzyme-based GABAergic strategy to modulate brain dopamine and the subsequent treatment of drug addiction
— id: 18575, year: 2001, vol: 414, page: 205, stat: Journal Article,

The selective sigma(1) receptor agonist, 1-(3,4-dimethoxyphenethyl)-4-(phenylpropyl)piperazine (SA4503), blocks the acquisition of the conditioned place preference response to (-)-nicotine in rats
Horan, B; Gardner, E L; Dewey, S L; Brodie, J D; Ashby, C R Jr
2001 Aug 24;426(1-2):R1-R2, European journal of pharmacology
We examined the effect of the sigma(1) receptor agonist, 1-(3,4-dimethoxyphenethyl)-4-(phenylpropyl)piperazine (SA4503), on the acquisition of the conditioned place preference response to subcutaneously administered (-)-nicotine in rats. (-)-Nicotine, but not SA4503 or vehicle, produced a significant conditioned place preference response. Pretreatment of animals with either 1 or 3 mg/kg of SA4503 significantly attenuated the conditioned place preference response to (-)-nicotine
— id: 76268, year: 2001, vol: 426, page: R1, stat: Journal Article,

Gamma-vinyl GABA (GVG) blocks expression of the conditioned place preference response to heroin in rats
Paul, M; Dewey, S L; Gardner, E L; Brodie, J D; Ashby, C R Jr
2001 Sep 1;41(3):219-220, Synapse
We examined the effect of gamma-vinyl GABA (GVG) on the expression of the conditioned place preference response to intraperitoneally (i.p.) administered heroin in rats. Heroin, but not vehicle, produced a significant conditioned place preference response. Pretreatment of animals with 300 mg/kg of GVG significantly attenuated the expression of the heroin-induced conditioned place preference response. These results are the first to suggest that systemic GVG may provide an effective alternative to methadone maintenance in the treatment of heroin addiction, since it is without abuse potential and can be used for treatment outside an institutional setting
— id: 76221, year: 2001, vol: 41, page: 219, stat: Journal Article,

Gamma vinyl-GABA differentially modulates NMDA antagonist-induced increases in mesocortical versus mesolimbic DA transmission
Schiffer, W K; Gerasimov, M; Hofmann, L; Marsteller, D; Ashby, C R; Brodie, J D; Alexoff, D L; Dewey, S L
2001 Nov;25(5):704-712, Neuropsychopharmacology
To explore the role of endogenous GABA in NMDA antagonist induced dopamine (DA) release, we used in vivo microdialysis to study the effects of pretreatment with gamma-vinyl GABA (GVG) on phencyclidine (PCP)-induced DA release in terminal regions of midbrain DA neurons. GVG, an irreversible inhibitor of the GABA catabolizing enzyme GABA-AT, significantly reduced the DA response to PCP (7.0 mg/kg) in freely moving animals. Preferential increases in PCP-induced DA release in the PFC (four-fold those of NAcc) were dose-dependently inhibited by acute pretreatment with GVG at doses of 150 (51% inhibition), 300 (68% inhibition), and 500 (82% inhibition) mg/kg, whereas NAcc PCP-induced DA activity was unresponsive to 150 mg/kg and only partially inhibited by 300 and 500 mg/kg. Subchronic treatment with GVG did not enhance the inhibitory capacity of the GABAergic system. While GVG evidently modulates PCP-induced increases in mesocorticolimbic DA transmission, the character of this modulation is regionally specific, with cortical NMDA-antagonist induced increases appearing more sensitive to inhibition by endogenous GABA than subcortical areas
— id: 76217, year: 2001, vol: 25, page: 704, stat: Journal Article,

Manipulations in mechanical ventilation influence the transport constant (K-1) of the reversible radiotracer C-11-cocaine
Schiffer, WK; Carter, P; Alexoff, DL; Fowler, JS; Logan, J; Shea, C; Gerasimov, M; Brodie, J; Dewey, S
2001 MAY ;42(5):213P-213P, Journal of nuclear medicine
— id: 55050, year: 2001, vol: 42, page: 213P, stat: Journal Article,

MK-801 increases dopamine transporter (DAT) availability: A positron emission tomography (PET) investigation in non-human primates
Schiffer, WK; Gerasimov, MR; Fowler, JS; Volkow, ND; Gifford, A; Ashby, CR; Brodie, JD; Dewey, SL
2001 MAY ;42(5):16P-16P, Journal of nuclear medicine
— id: 55049, year: 2001, vol: 42, page: 16P, stat: Journal Article,

Positron emission tomography (PET) investigations of synaptic dopamine (DA) release and re-uptake in phencyclidine (PCP) treated primates
Schiffer, WK; Gerasimov, MR; Fowler, JS; Volkow, ND; Logan, J; Alexoff, DL; Shea, C; Brodie, JD; Dewey, SL
2001 MAY ;42(5):15P-15P, Journal of nuclear medicine
— id: 55048, year: 2001, vol: 42, page: 15P, stat: Journal Article,

gamma-aminobutyric acid mimetic drugs differentially inhibit the dopaminergic response to cocaine
Gerasimov MR; Schiffer WK; Brodie JD; Lennon IC; Taylor SJ; Dewey SL
2000 Apr 28;395(2):129-135, European journal of pharmacology
Dopaminergic activity in the mesocorticolimbic system is associated with reinforcing properties of psychostimulant drugs. We previously demonstrated that increased gamma-aminobutyric acid (GABA)-ergic activity produced by gamma-vinyl GABA [D,L-4-amino-hex-5-enoic acid (Vigabatrin(R))], an irreversible inhibitor of GABA-transaminase, attenuated cocaine, nicotine, heroin, alcohol, and methamphetamine-induced increases in extracellular nucleus accumbens dopamine as well as behaviors associated with these biochemical changes. In the present study, using in vivo microdialysis techniques, we compared three different strategies to increase GABAergic activity in order to modulate cocaine-induced increase in extracellular dopamine. Our data demonstrate that the anticonvulsant 1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5, 6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (NNC-711), a GABA uptake inhibitor, dose and time dependently diminished increases in extracellular dopamine following acute cocaine challenge. Furthermore, we demonstrated that cyclized analogue of vigabatrin, a competitive reversible GABA-transaminase inhibitor, is a more potent inhibitor of cocaine-induced dopamine increase than vigabatrin. Our data suggest that in addition to irreversible inhibition of GABA transaminase, inhibition of GABA uptake represent another potentially effective, indirect strategy for the treatment of cocaine abuse
— id: 18576, year: 2000, vol: 395, page: 129, stat: Journal Article,

Stereoselective inhibition of dopaminergic activity by gamma vinyl-GABA following a nicotine or cocaine challenge: a PET/microdialysis study
Schiffer WK; Gerasimov MR; Bermel RA; Brodie JD; Dewey SL
2000 Feb 18;66(13):PL169-PL173, Life sciences
Elevation of endogenous GABA by the racemic mixture of gamma vinyl-GABA (GVG, Vigabatrin) decreases extracellular nucleus accumbens (NAc) dopamine (DA) levels and diminishes the response to many drugs of abuse known to elevate DA in the mesocorticolimbic system. We investigated the effects of the individual enantiomers (S(+)-GVG, R(-)-GVG) on cocaine-induced NAc DA in rodents as well as the effects of nicotine-induced increases in primates. In a series of microdialysis experiments in freely moving animals, S(+)-GVG (150 mg/kg), R(-)-GVG (150 mg/kg) or racemic (R, S) GVG (300 mg/kg) was administered 2.5 hours prior to cocaine (20 mg/kg) administration. When compared with cocaine alone, the R(-) enantiomer did not significantly inhibit cocaine induced NAc DA release. S(+)-GVG, at half the dose of the racemic mixture (150 mg/kg), inhibited cocaine-induced DA elevation by 40%, while the racemic mixture (300 mg/kg) inhibited cocaine-induced DA release by 31%. In addition, our PET studies in primates demonstrated that S(+)-GVG completely inhibits nicotine-induced increases in the corpus striatum, again at half the dose of the racemic mixture. The R(-) enantiomer was ineffective. Although the S(+) enantiomer has been well established as the active compound in the treatment of epilepsy, the efficacy of this enantiomer with regard to mesolimbic DA inhibition generates a complex series of clinical and neurochemical issues. Further investigations will determine the locus of action and physiologic properties of each enantiomer
— id: 11786, year: 2000, vol: 66, page: PL169, stat: Journal Article,

Implication of the GABA(B) receptor in gamma vinyl-GABA's inhibition of cocaine-induced increases in nucleus accumbens dopamine
Ashby CR; Rohatgi R; Ngosuwan J; Borda T; Gerasimov MR; Morgan AE; Kushner S; Brodie JD; Dewey SL
1999 Feb;31(2):151-153, Synapse
Previously, we demonstrated that gamma vinyl-GABA (GVG, Vigabatrin) dose-dependently inhibits cocaine-induced increases in dopamine (DA) concentrations in both the rodent and primate brain. Furthermore, it abolishes cocaine self-administration and conditioned place preference, while having no effect on locomotor activity or drug delivery to the brain. In an effort to better understand the mechanisms underlying this inhibition, we examined the effect of the selective GABA(B) receptor antagonist SCH 50911 on the GVG-induced decrease in cocaine's elevation of extracellular DA concentrations in the nucleus accumbens (NACC). Cocaine administration alone (20 mg/kg i.p.) produced a 480% increase in extracellular NACC DA levels. GVG (300 mg/kg i.p.) significantly reduced this increase by 25% (P<0.01). In sharp contrast, extracellular DA levels increased to 550% after the sequential administration of SCH 50911 (3 mg/kg i.p.), GVG, and cocaine. This increase is significantly different than GVG and cocaine (P<0.05) but similar to cocaine alone. These results demonstrate that the GABA(B) antagonist SCH 50911 was able to completely abolish GVG's inhibition of cocaine-induced increases in DA in the NACC and implicates the GABA(B) receptor in the mechanism underlying this inhibition
— id: 18578, year: 1999, vol: 31, page: 151, stat: Journal Article,

A pharmacologic strategy for the treatment of nicotine addiction
Dewey SL; Brodie JD; Gerasimov M; Horan B; Gardner EL; Ashby CR Jr
1999 Jan;31(1):76-86, Synapse
Like many psychostimulant drugs, nicotine elevates extracellular and synaptic dopamine (DA) concentrations in the nucleus accumbens (NAc). This elevation has been linked to its reinforcing properties. Dopaminergic transmission within the NAc is modulated by gamma-aminobutyric acid (GABA). Therefore, we examined the utility of gamma vinyl-GABA (GVG, Vigabatrin) for inhibiting nicotine's biochemical effects on NAc DA as well as its effects on behaviors associated with these biochemical changes. Given 2.5 hours prior to nicotine, GVG (75 mg/kg) had no effect on nicotine-induced increases in extracellular NAc DA. However, at 90 mg/kg, GVG significantly inhibited nicotine-induced increases by approximately 50% while at 100 or 150 mg/kg, GVG completely abolished nicotine-induced increases in both naive and chronically nicotine-treated animals. When given 12 or 24 hours prior to nicotine administration at a dose of 100 mg/kg, GVG-induced inhibition was diminished or abolished, respectively. In addition, at a dose of 18.75 mg/kg GVG abolished the expression of nicotine-induced conditioned place preference (CPP) while a dose of 75 mg/kg abolished the acquisition phase of CPP. Finally, using positron emission tomography (PET) and 11C-raclopride in primates, GVG (100 mg/kg) abolished nicotine-induced increases in synaptic DA while having no effect on the rate of metabolism of the radiotracer or its regional distribution. Together, these data suggest that GVG may be useful for the treatment of nicotine addiction and further support the strategy of targeting the GABAergic system with a suicide inhibitor of GABA-transaminase for the treatment of drug addiction
— id: 57135, year: 1999, vol: 31, page: 76, stat: Journal Article,

Gamma-vinyl GABA inhibits methamphetamine, heroin, or ethanol-induced increases in nucleus accumbens dopamine
Gerasimov MR; Ashby CR; Gardner EL; Mills MJ; Brodie JD; Dewey SL
1999 Oct;34(1):11-19, Synapse
We examined the acute effect of the irreversible GABA-transaminase inhibitor, gamma-vinyl GABA (GVG, Sabril((R)), Vigabatrin((R))) on increases in nucleus accumbens (NAc) dopamine (DA) following acute administration of methamphetamine, heroin, or ethanol. Methamphetamine (2.5 mg/kg) produced a dose-dependent increase (2, 700%) in NAc DA. GVG preadministration (300 or 600 mg/kg), however, inhibited this response by approximately 39 and 61%, respectively. The lower dose of methamphetamine (1.25 mg/kg), increased DA by 1, 700%. This response was inhibited to a similar extent (44%) regardless of the GVG dose preadministered (300 or 600 mg/kg). In addition, heroin-induced increases in NAc DA (0.5 mg/kg, 170%) were inhibited or completely abolished by GVG (150 or 300 mg/kg, 65 and 100%, respectively). Finally, at half the dose necessary for heroin, GVG (150 mg/kg) also completely abolished ethanol-induced increases in NAc DA following a 0.25 g/kg challenge dose (140%). Taken with our previous findings using nicotine or cocaine as the challenge drug, these results indicate that GVG attenuates increases in NAc DA by a mechanism common to many drugs of abuse. However, it appears unlikely that an acute dose of GVG can completely inhibit increases in NAc DA following challenges with a drug whose mechanism of action is mediated primarily through the DA reuptake site
— id: 18577, year: 1999, vol: 34, page: 11, stat: Journal Article,

Task-specific deactivation patterns in functional magnetic resonance imaging
Hutchinson M; Schiffer W; Joseffer S; Liu A; Schlosser R; Dikshit S; Goldberg E; Brodie JD
1999 Dec;17(10):1427-1436, Magnetic resonance imaging
In general, image analysis of cognitive experiments using functional magnetic resonance imaging techniques has emphasized those regions of the brain where increases in signal intensity, with regard to the reference state, are associated with activation. Nevertheless, a number of recent papers have shown that there are areas of deactivation as well. In this study, we have used a univariate analysis and echo-planar functional magnetic resonance imaging to address the relationship of the reference state to the deactivations. We employed two dichotomous covert tasks, orthographic lexical retrieval and pure visual retrieval, to contrast with the reference state (baseline) of silent counting. Our analysis yielded extensive, task-specific landscapes of regional incremental and decremental responses. We have specifically demonstrated that the decremental responses are not due to activation in the reference state. We have also demonstrated that they are not an artifact of a specific part of the image analysis, and propose that they represent a physiological, task specific signal that should be considered an integral component of neural networks representing brain function
— id: 11891, year: 1999, vol: 17, page: 1427, stat: Journal Article,

Correlation of qEEG with PET in schizophrenia
Alper K; Gunther W; Prichep LS; John ER; Brodie J
1998 ;38(1):50-56, Neuropsychobiology
PET relative metabolism was correlated with quantitative EEG in 9 schizophrenic patients. The PET metabolic regions of interest were the frontal lobes, thalamus and basal ganglia, and right and left temporal lobes. Significant positive correlations were seen for the frontal lobes and delta EEG power, and alpha power with subcortical metabolism. The physiologic plausibility of those correlations is discussed with reference to the possible effect of neuroleptic medication
— id: 7481, year: 1998, vol: 38, page: 50, stat: Journal Article,

Effect of a haloperidol challenge on regional brain metabolism in neuroleptic-responsive and nonresponsive schizophrenic patients
Bartlett EJ; Brodie JD; Simkowitz P; Schlosser R; Dewey SL; Lindenmayer JP; Rusinek H; Wolkin A; Cancro R; Schiffer W
1998 Mar;155(3):337-343, American journal of psychiatry
OBJECTIVE: The CNS metabolic response to a neuroleptic challenge in treatment-responsive and nonresponsive schizophrenic patients was measured in order to examine the relation between treatment outcome and the capacity to alter neurochemical function in response to acute receptor blockade. METHOD: Positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG) were used to measure regional cerebral metabolism in seven schizophrenic patients judged to have been responsive to drug treatment previously and seven nonresponsive schizophrenic patients after a drug-free period of at least 3 weeks (baseline) and again 12 hours after administration of 5.0 mg of haloperidol. RESULTS: The haloperidol challenge caused widespread decreases in absolute metabolism in the nonresponsive patients but not the responsive patients. These group differences reflect the findings on the second (challenge) scans, since metabolic values at baseline were not statistically different in the two groups. The pattern of decreased metabolic activity in the nonresponders after the haloperidol challenge is similar to that previously observed in normal subjects. CONCLUSIONS: The metabolic response to drug challenge separates treatment responders from nonresponders and normal subjects. The results suggest that subtyping of schizophrenia (and other psychiatric disorders) can be achieved by measuring the physiologic response to a pharmacologic challenge in vivo with chemical brain-imaging techniques
— id: 7497, year: 1998, vol: 155, page: 337, stat: Journal Article,

A novel strategy for the treatment of cocaine addiction
Dewey SL; Morgan AE; Ashby CR Jr; Horan B; Kushner SA; Logan J; Volkow ND; Fowler JS; Gardner EL; Brodie JD
1998 Oct;30(2):119-129, Synapse
Cocaine's addictive liability has been linked to its pharmacologic actions on mesotelencephalic dopamine (DA) reinforcement/reward pathways in the central nervous system (CNS). Dopaminergic transmission within these pathways is modulated by gamma-aminobutyric acid (GABA). With this knowledge, we examined the utility of gamma vinylGABA (GVG), a selective and irreversible inhibitor of GABA-transaminase (GABA-T) known to potentiate GABAergic inhibition, to alter cocaine's biochemical effects as well as its effects on behaviors associated with these biochemical changes. GVG significantly attenuated cocaine-induced increases in neostriatal synaptic DA in the non-human primate (baboon) brain as assessed by positron emission tomography (PET) and abolished both the expression and acquisition of cocaine-induced conditioned place preference (CPP). It had no effect on CPP for a food reward, the delivery of cocaine to the brain or locomotor activity. These findings suggest the possible therapeutic utility in cocaine addiction of a pharmacologic strategy targeted at the GABAergic neurotransmitter system, a system distinct from but functionally linked to the DA mesotelencephalic reward/reinforcement system. However, rather than targeting the GABA receptor complex with a direct GABA agonist, this novel approach with GVG takes advantage of the prolonged effects of an irreversible enzyme inhibitor that raises endogenous GABA levels without the addictive liability associated with GABA agonists acting directly at the receptor itself. Human trials with GVG are currently being developed to directly examine the utility of this novel strategy for the treatment of cocaine addiction
— id: 57134, year: 1998, vol: 30, page: 119, stat: Journal Article,

A new gabaergic strategy for treating cocaine addiction
Dewey, SL; Morgan, AE; Ashby, CR; Logan, J; Kushner, SA; Kornetsky, C; Volkow, ND; Fowler, JS; Brodie, JD
1998 MAY ;39(5):388-69, Journal of nuclear medicine
— id: 98344, year: 1998, vol: 39, page: 388, stat: Journal Article,

Long-term stability of neurotransmitter activity investigated with 11C-raclopride PET
Schlosser R; Brodie JD; Dewey SL; Alexoff D; Wang GJ; Fowler JS; Volkow N; Logan J; Wolf AP
1998 Jan;28(1):66-70, Synapse
There is evidence for the shift of regulatory setpoints of functionally linked neurotransmitter systems as a basis of psychiatric disorders. 11C-raclopride PET, which has been shown to be sensitive to changes in endogenous dopamine and has a high short-term test-retest reliability, can be used to investigate different regulatory states of the dopaminergic system with respect to psychiatric diseases and pharmacological influences. Prior to these studies, the reliability of the method over time has to be established. The current study was performed in order to evaluate the long-term stability of the striatal dopaminergic system. Eight normal healthy subjects (mean age: 48.1 years; range: 24-75) were studied twice with 11C-raclopride PET two times under resting conditions with a mean time interval between the scans of 11.3 months (range: 1-19). The ratio of basal ganglia (BG) to cerebellar (CB) distribution volumes (DVs) revealed a mean absolute change of 6.94 (range: 0.0-12.87%) between study A and B. BG DVs mean absolute change was 6.30% (range: 0.55-30.46%), CB DVs mean absolute change was 8.65% (range: 3.51-16.33%). The mean change of the BG/CB ratio was -0.33% (range: 12.87-12.34%). BG DVs mean change was 4.55% (range: 4.2-30.46%), CB DVs mean change was 5.10% (range: -10.71-16.33%). The intraindividual differences between the two scans in our study were not significantly different as compared to the 24 hour interval test-retest data, which have been published earlier (repeated measures ANOVA with df = 11; F = 0.49; P = 0.50) [Volkow et al. (1993) J. Nucl. Med., 34:609-613]. The intraclass correlation of the DV ratio index was r = 0.81. The binding potential in the baseline scans and repeated scans showed a non-significant correlation with age (r = -0.58, P = 0.13). Interindividually, the DV ratio index revealed a mean of 3.18 (range = 2.55-3.68, SD = 0.42 in study A and of 3.16 (range 2.37-3.57, SD = 0.41) in study B. The intrasubject stability of the 11C-raclopride binding over a long-term period in normal human subjects suggests the feasibility of study designs investigating the long-term changes of the dopaminergic responsivity after pharmacological challenges. The baseline stability will also serve as a necessary reference for further dose-response studies and investigations of subchronical pharmacological interventions
— id: 7781, year: 1998, vol: 28, page: 66, stat: Journal Article,

Functional magnetic resonance imaging of human brain activity in a verbal fluency task
Schlosser R; Hutchinson M; Joseffer S; Rusinek H; Saarimaki A; Stevenson J; Dewey SL; Brodie JD
1998 Apr;64(4):492-498, Journal of neurology neurosurgery & psychiatry
OBJECTIVES: Functional MRI (fMRI) holds the promise of non-invasive mapping of human brain function in both health and disease. Yet its sensitivity and reliability for mapping higher cognitive function are still being determined. Using verbal fluency as a task, the objective was to ascertain the consistency of fMRI on a conventional scanner for determining the anatomic substrate of language between subjects and between sexes. Comparison was made with previous PET studies. METHODS: Using a 1.5 Tesla magnet and an echoplanar pulse sequence, whole brain fMRI was obtained from 12 normal right handed subjects (6 males and 6 females) as they performed a verbal fluency task. RESULTS: A broadly consistent pattern of response was seen across subjects. Areas showing activation changes included the left prefrontal cortex and right cerebellum, in agreement with previous PET 15O-H2O studies. In addition, significantly decreased responses were seen in the posterior cingulate and over an extensive area of mesial and dorsolateral parietal and superior temporal cortices. The male cohort showed a slight asymmetry of parietal deactivation, with more involvement on the right, whereas the female cohort showed a small region of activation in the right orbitofrontal cortex. There were individual task related regional changes in all 12 subjects with the area showing the most significant change being the left prefrontal cortex in all cases. CONCLUSIONS: Magnetic resonance scanners of conventional field strength can provide functional brain mapping data with a sensitivity at least that of PET. Activation was seen in left prefrontal and right cerebellar regions, as with PET. However, decremental responses were seen over a much larger area of the posterior cortex than had been anticipated by prior studies. The ability to see a response in each subject individually suggests that fMRI may be useful in the preinterventional mapping of pathological states, and offers a non-invasive alternative to the Wada test for assessment of hemispheric dominance. There were no gross differences in the pattern of activation between male and female subjects
— id: 57250, year: 1998, vol: 64, page: 492, stat: Journal Article,

Glutamate modulation of dopamine measured in vivo with positron emission tomography (PET) and 11C-raclopride in normal human subjects
Smith GS; Schloesser R; Brodie JD; Dewey SL; Logan J; Vitkun SA; Simkowitz P; Hurley A; Cooper T; Volkow ND; Cancro R
1998 Jan;18(1):18-25, Neuropsychopharmacology
Subanesthetic doses of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist ketamine exacerbate psychosis in schizophrenic patients, and ketamine has significant abuse liability. These observations indicate that a secondary effect of ketamine may be to increase dopamine concentrations. The present study was undertaken using positron emission tomography (PET) and the dopamine (D2) radiotracer 11C-raclopride to determine whether ketamine would decrease D2 receptor availability, indicative of an increase in dopamine concentrations. Two scans were performed in seven male control subjects before and after administration of ketamine (0.5 mg/kg, i.v. infused over 20 min). Ketamine significantly increased cortisol levels and decreased dopamine receptor availability in the striatum (specific binding), but not in the cerebellum (nonspecific binding). In addition, the cerebellar binding subtracted from the striatal binding (to account for changes in nonspecific binding) was significantly decreased after ketamine administration. These results provide in vivo evidence for the ability of ketamine to increase striatal dopamine concentrations, consistent with the role of the NMDA receptor in modulating dopamine function
— id: 12191, year: 1998, vol: 18, page: 18, stat: Journal Article,

GABAergic attenuation of cocaine-induced dopamine release and locomotor activity
Dewey, S L; Chaurasia, C S; Chen, C E; Volkow, N D; Clarkson, F A; Porter, S P; Straughter-Moore, R M; Alexoff, D L; Tedeschi, D; Russo, N B; Fowler, J S; Brodie, J D
1997 Apr;25(4):393-398, Synapse
GABA modulates dopamine concentrations in the nucleus accumbens and corpus striatum. Using in vivo microdialysis techniques we examined this modulatory role and the extent to which three different GABAergic drugs can attenuate cocaine's ability to increase extracellular dopamine concentrations and gross locomotor activity. Ethanol, lorazepam (Ativan), and gamma-vinyl GABA (GVG) significantly and dose-dependently attenuated cocaine-induced dopamine release in the corpus striatum of freely moving animals. Unlike ethanol or lorazepam, however, GVG is not a sedative hypnotic in the doses used, and hence the strategy of selectively increasing GABAergic activity by suicide inhibition of the catabolic enzyme, GABA-transaminase, offers the unique advantage of attenuating cocaine-induced dopamine release without the apparent side effects typically associated with sedative hypnotics
— id: 76225, year: 1997, vol: 25, page: 393, stat: Journal Article,

Serotonergic modulation of dopamine measured with [11C]raclopride and PET in normal human subjects
Smith GS; Dewey SL; Brodie JD; Logan J; Vitkun SA; Simkowitz P; Schloesser R; Alexoff DA; Hurley A; Cooper T; Volkow ND
1997 Apr;154(4):490-496, American journal of psychiatry
OBJECTIVE: This study was undertaken to measure serotonergic modulation of dopamine in vivo by using positron emission tomography (PET), a radiotracer for the striatal dopamine D2 receptor ([11C]raclopride), and a pharmacologic challenge of the serotonin system (d,l-fenfluramine). METHOD: Two PET studies using [11C]raclopride were performed in 11 normal male subjects before administration of the serotonin-releasing agent and reuptake inhibitor fenfluramine (60 mg p.o.) and 3 hours afterward. A graphical analysis method was used with the [11C]raclopride data to derive the distribution volume of D2 receptors. Plasma levels of fenfluramine, norfenfluramine, homovanillic acid (HVA), cortisol, and prolactin were determined. RESULTS: Levels of fenfluramine and prolactin were elevated 2 hours after fenfluramine administration and remained significantly elevated during the second scan, while levels of HVA and cortisol were not altered significantly during the time of scanning. A significant decrease in the specific binding (striatum) and the nonspecific binding subtracted from the specific binding (striatum minus cerebellum) of [11C]raclopride was observed. The rate of metabolism of [11C]raclopride and the nonspecific binding (cerebellum) were not significantly altered by the fenfluramine intervention. CONCLUSIONS: The observed decrease in [11C]raclopride binding is consistent with an increase in dopamine concentrations and with the ability of serotonin to stimulate dopamine activity. The ability to measure serotonergic modulation of dopamine in vivo may have implications for the study of etiologic and therapeutic mechanisms in schizophrenia, major depressive disorder, obsessive-compulsive disorder, and substance abuse
— id: 12349, year: 1997, vol: 154, page: 490, stat: Journal Article,

Time-dependent effects of a haloperidol challenge on energy metabolism in the normal human brain
Bartlett EJ; Brodie JD; Simkowitz P; Dewey SL; Rusinek H; Volkow ND; Wolf AP; Smith G; Wolkin A; Cancro R
1996 Mar 29;60(2-3):91-99, Psychiatry research
Positron emission tomography and the fluorodeoxyglucose method were used to measure regional brain metabolism before and 2 h after haloperidol (5 mg, i.m.) in 11 young normal men. These data were compared with measures obtained from nine previously studied normal men who had received no drug intervention. Although a previously published study had demonstrated significantly decreased metabolism in whole brain, neocortex, limbic cortex, thalamus, and caudate nucleus 12 h after a 5-mg dose of haloperidol, the present 2-h study did not show significant metabolic changes despite the fact that significant extrapyramidal effects occurred. Taken together, these studies demonstrate differences in the temporal organization of behavioral and metabolic responses to haloperidol challenge
— id: 12632, year: 1996, vol: 60, page: 91, stat: Journal Article,

Imaging for the clinical psychiatrist: facts, fantasies, and other musings
Brodie JD
1996 Feb;153(2):145-149, American journal of psychiatry
— id: 6892, year: 1996, vol: 153, page: 145, stat: Journal Article,

Two psychiatrists and their points of view imagery in psychiatry: Fact and reverie
Brodie, JD
1996 JUL-AUG ;5(289):114-116, La recherche
— id: 52867, year: 1996, vol: 5, page: 114, stat: Journal Article,

Opioid receptor imaging and displacement studies with [6-O-[11C] methyl]buprenorphine in baboon brain
Galynker, I; Schlyer, D J; Dewey, S L; Fowler, J S; Logan, J; Gatley, S J; MacGregor, R R; Ferrieri, R A; Holland, M J; Brodie, J; Simon, E; Wolf, A P
1996 Apr;23(3):325-331, Nuclear medicine & biology
Buprenorphine (BPN) is a mixed opiate agonist-antagonist used as an analgesic and in the treatment of opiate addiction. We have used [6-O-[11C]methyl]buprenorphine ([11C]BPN) to measure the regional distribution in baboon brain, the test-retest stability of repeated studies in the same animal, the displacement of the labeled drug by naloxone in vivo, and the tissue distribution in mice. The regional distribution of radioactivity in baboon brain determined with PET was striatum > thalamus > cingulate gyrus > frontal cortex > parietal cortex > occipital cortex > cerebellum. This distribution corresponded to opiate receptor density and to previously published data (37). The tracer uptake in adult female baboons showed no significant variation in serial scans in the same baboon with no intervention in the same scanning session. HPLC analysis of baboon plasma showed the presence of labeled metabolites with 92% +/- 2.2% and 43% +/- 14.4% of the intact tracer remaining at 5 and 30 min, respectively. Naloxone, an opiate receptor antagonist, administered 30-40 min after tracer injection at a dose of 1.0 mg/kg i.v., reduced [11C]BPN binding in thalamus, striatum, cingulate gyrus, and frontal cortex to values 0.25 to 0.60 of that with no intervention. There were minimal (< 15%) effects on cerebellum. Naloxone treatment significantly reduced the slope of the Patlak plot in receptor-containing regions. These results demonstrate that [11C]BPN can be displaced by naloxone in vivo, and they affirm the feasibility of using this tracer and displacement methodology for short-term kinetics studies with PET. Mouse tissue distribution data were used to estimate the radiation dosimetry to humans. The critical organ was the small intestine, with a radiation dose estimate to humans of 117 nrad/mCi
— id: 76239, year: 1996, vol: 23, page: 325, stat: Journal Article,

The study of neurotransmitter interactions using positron emission tomography and functional coupling
Schloesser R; Simkowitz P; Bartlett EJ; Wolkin A; Smith GS; Dewey SL; Brodie JD
1996 Oct;19(5):371-389, Clinical neuropharmacology
Functional brain imaging with positron emission tomography (PET) has opened up new avenues for the investigation of possible functional disturbances related to psychiatric disease as well as pharmacodynamic assessment of drug treatment in vivo. Different strategies to study pharmacologic effects on the brain have been developed in recent years. The basic methods are to measure (a) blood flow or glucose metabolism, (b) parameters of specific receptor binding, or (c) neurotransmitter metabolism. Each of these can be performed either in a resting state or after perturbation with a pharmacologic challenge. Our group has developed a general strategy for investigating pharmacologic effects on brain function: (a) determining indirect drug-induced metabolic changes with fluorodeoxyglucose PET and (b) characterizing functional interactions of neurotransmitter systems by assaying drug-induced displacement of specific receptor ligands. These study designs reflect a paradigm shift where functional coupling of brain regions and interaction of different neurotransmitter systems are seen as the basis for a multitransmitter hypothesis of schizophrenia. In this view, any disturbance in the self-regulatory process is reflected in the loss of functional interaction between systems. An overview of recent studies and their possible clinical importance will be presented
— id: 12529, year: 1996, vol: 19, page: 371, stat: Journal Article,

Blunted change in cerebral glucose utilization after haloperidol treatment in schizophrenic patients with prominent negative symptoms
Wolkin A; Sanfilipo M; Duncan E; Angrist B; Wolf AP; Cooper TB; Brodie JD; Laska E; Rotrosen JP
1996 Mar;153(3):346-354, American journal of psychiatry
OBJECTIVE: The purpose of this report was to determine 1) the effects of chronic haloperidol treatment on cerebral metabolism in schizophrenic patients, 2) the relation between negative symptoms and haloperidol-induced regional changes in cerebral glucose utilization, and 3) the relation between metabolic change and clinical antipsychotic effect. METHOD: Cerebral glucose utilization, as determined by position emission tomography (PET), was studied in 18 male schizophrenic subjects before and after chronic treatment with haloperidol at a standardized plasma level. RESULTS: Overall, haloperidol caused a widespread decrease in absolute cerebral glucose metabolism. The cerebral metabolic response to haloperidol was blunted in patients with high pretreatment negative symptom scores. CONCLUSIONS: Taken together with the results from a previously reported PET study of the effects of an acute amphetamine challenge (in which 14 of the current subjects participated), these data suggest that the negative symptom complex is associated with diminished cerebral response to change in dopaminergic activity. This deficit cannot be solely accounted for by structural differences
— id: 7060, year: 1996, vol: 153, page: 346, stat: Journal Article,

SEROTONERGIC MODULATION OF STRIATAL DOPAMINE MEASURED WITH POSITRON EMISSION TOMOGRAPHY (PET) AND IN-VIVO MICRODIALYSIS
DEWEY, SL; SMITH, GS; LOGAN, J; ALEXOFF, D; DING, YS; KING, P; PAPPAS, N; BRODIE, JD; ASHBY, CR
1995 JAN ;15(1):821-829, Journal of neuroscience
Positron emission tomography and in vivo microdialysis were used to study serotonin's role in modulating striatal dopamine. Serial PET studies were performed in adult female baboons at baseline and following drug treatment, using the dopamine (D-2) selective radiotracer, C-11-raclopride. The serotonergic system was manipulated by administration of the selective 5-HT reuptake inhibitor, citalopram, or by serotonergic (5-HT2) receptor blockade (using altanserin, a 5-HT2 antagonist). C-11-Raclopride time-activity data from striatum and cerebellum were combined with plasma arterial input functions and analyzed by calculating a distribution volume as described previously (Logan et al., 1990). Additionally, in vivo microdialysis studies were performed in awake freely moving rats using similar pharmacologic challenges plus SR 46349B, a new highly selective 5-HT2 receptor antagonist. Altanserin and SR 46349B increased extracellular striatal dopamine concentrations (35% and 910%, respectively) while altanserin decreased striatal C-11-raclopride binding (37%). Citalopram, however, decreased extracellular striatal dopamine concentrations (50%) and increased C-11-raclopride binding (33%). These data demonstrate that 5-HT-selective drugs produce changes in striatal dopamine that can be measured noninvasively with PET. Furthermore, the PET data obtained from anesthetized baboons is consistent with in vivo microdialysis data obtained from awake and freely moving rats. Finally, these studies have implications for understanding the therapeutic efficacy of atypical neuroleptics and their utility for treating schizophrenia and affective disorders
— id: 87461, year: 1995, vol: 15, page: 821, stat: Journal Article,

HUMAN SPECT STUDIES OF AMPHETAMINE-INDUCED CHANGE IN DOPAMINE ACTIVITY
SIMKOWITZ, P; BRODIE, JD; SMITH, GS; LANDSMAN, D; KRAMER, EL; SANGER, J; NOZ, M; BARTLETT, E; DEWEY, S; FRIEDHOFF, AJ
1995 MAY 1 ;37(9):598-598, Biological psychiatry
— id: 87282, year: 1995, vol: 37, page: 598, stat: Journal Article,

Haloperidol blocks the uptake of [18F]N-methylspiroperidol by extrastriatal dopamine receptors in schizophrenic patients
Yousef, K A; Volkow, N D; Schlyer, D J; Fowler, J S; Wolf, A P; Wang, G J; Smith, M R; Brodie, J D; Warner, D
1995 Jan;19(1):14-17, Synapse
We had previously demonstrated extrastriatal uptake of [18F]N-methylspiroperidol (18F-NMS) in the human brain. This study evaluates the effect of haloperidol on 18F-NMS binding in extrastriatal brain regions. Six schizophrenic patients on haloperidol underwent two PET scans with 18F-NMS at 12 h and at 6 days after haloperidol withdrawal. There was a significant increase in 18F-NMS uptake in striatal, thalamic, and temporal regions but not in frontal, occipital, or cerebellar regions, following drug withdrawal. Haloperidol's ability to block the uptake of 18F-NMS is an indication of the specificity of the radioligand's binding in these regions and supports the postmortem data demonstrating the presence of dopamine D2 receptors in the thalamus and temporal cortex of the human brain
— id: 107917, year: 1995, vol: 19, page: 14, stat: Journal Article,

Effects of haloperidol challenge on regional cerebral glucose utilization in normal human subjects
Bartlett EJ; Brodie JD; Simkowitz P; Dewey SL; Rusinek H; Wolf AP; Fowler JS; Volkow ND; Smith G; Wolkin A
1994 May;151(5):681-686, American journal of psychiatry
OBJECTIVE: Positron emission tomography and the fluorodeoxyglucose (FDG) method were used to determine the brain's metabolic response to neuroleptic challenge in a normal, disease-free state. METHOD: FDG measurements were obtained before and 12 hours after administration of 5 mg of haloperidol to 12 young normal men. These values were compared with test-retest FDG measures obtained from nine normal male control subjects who received no drug intervention. RESULTS: After haloperidol administration, the haloperidol subjects showed significantly lower glucose utilization in the neocortex, limbic cortex, thalamus, and caudate nucleus but not in the putamen or cerebellum. After adjustment for global effects, significant reductions were still evident in the frontal, occipital, and anterior cingulate cortex, whereas the putamen and cerebellum showed significant increases. CONCLUSIONS: This study, measuring the brain's metabolic response to acute receptor blockade, is a first step in the development of an assay of CNS pharmacological activity. By determining the response to neuroleptic challenge in a normal state, the study establishes a comparison group for determining response to challenge in various psychiatric conditions
— id: 6319, year: 1994, vol: 151, page: 681, stat: Journal Article,

Diminished cerebral metabolic response to motor stimulation in schizophrenics: a PET study
Guenther, W; Brodie, J D; Bartlett, E J; Dewey, S L; Henn, F A; Volkow, N D; Alper, K; Wolkin, A; Cancro, R; Wolf, A P
1994 ;244(3):115-125, European archives of psychiatry & clinical neuroscience
Positron emission tomography (PET) and the deoxyglucose method were used to measure cerebral metabolism in 14 normals and 13 schizophrenics at rest and during performance of simple and complex finger-movement sequences. The normals, but not the schizophrenics, showed significant metabolic activation in mesial frontal and contralateral sensorimotor and premotor regions during the complex movement. The relative metabolism of schizophrenics was significantly lower than normal in frontal regions and higher than normal in thalamus and basal ganglia under all scanning conditions. The results suggest that schizophrenics may have a brain dysfunction which limits their capacity to produce a focal metabolic response to stimulation in several functionally distinct brain regions
— id: 76242, year: 1994, vol: 244, page: 115, stat: Journal Article,

THE SEROTONIN-DOPAMINE INTERACTION MEASURED WITH POSITRON EMISSION TOMOGRAPHY (PET) AND C-11 RACLOPRIDE IN NORMAL HUMAN-SUBJECTS
SMITH, GS; DEWEY, SL; LOGAN, J; BRODIE, JD; VITKUN, S; SIMKOWITZ, P; ALEXOFF, D; FOWLER, JS; VOLKOW, ND; WOLF, AP
1994 MAY ;35(5):P85-P85, Journal of nuclear medicine
— id: 52448, year: 1994, vol: 35, page: P85, stat: Journal Article,

Intersubject variability of brain glucose metabolic measurements in young normal males
Wang, G J; Volkow, N D; Wolf, A P; Brodie, J D; Hitzemann, R J
1994 Sep;35(9):1457-1466, Journal of nuclear medicine
This study evaluates intersubject variability on regional glucose metabolic values in a group of 50 healthy right-handed males between 20 and 40 yr of age. METHODS: Brain glucose metabolism was measured using PET and 2-deoxy-2[18F]fluoro-D-glucose under resting conditions and was separately assessed for subjects in their twenties (n = 34) and those in their thirties (n = 16). RESULTS: Regional brain metabolic values showed significant intersubject variability with coefficients of variation (CV) that ranged between 11.1% to 15.2% (twenties) and 7.2% to 12.6% (thirties). Relative measures (regional/global) were less variable than absolute measures and the CV ranged between 4.1% to 8.3% (twenties) and 3.9% to 10% (thirties). Whereas global brain metabolic rate for subjects in their twenties was not significantly different from that of subjects in their thirties, the metabolic rate in left frontal regions was significantly lower in the older subjects. CONCLUSION: The correlations between age and absolute and relative metabolism in the left frontal region were r = 0.438, p < 0.002 and r = 0.447, p < 0.001, respectively. This study shows significant intersubject variability for regional brain metabolic values in normal controls and documents age-related decreases in frontal metabolism that occur even in relatively young adults
— id: 144598, year: 1994, vol: 35, page: 1457, stat: Journal Article,

Acute d-amphetamine challenge in schizophrenia: effects on cerebral glucose utilization and clinical symptomatology
Wolkin A; Sanfilipo M; Angrist B; Duncan E; Wieland S; Wolf AP; Brodie JD; Cooper TB; Laska E; Rotrosen JP
1994 Sep 1;36(5):317-325, Biological psychiatry
The effects of d-amphetamine (0.5 mg/kg orally) on regional cerebral glucose utilization were measured with positron emission tomography (PET) in 17 schizophrenics (along with a placebo-control group of an additional six schizophrenic patients). The acute d-amphetamine challenge tended to decrease glucose utilization throughout much of the brain, with a regional effect that was statistically significant in the left temporal cortex. There was no apparent relationship between the effects of amphetamine-induced changes in regional cerebral metabolism and psychotic symptom exacerbation. An exploratory analysis suggested that features characteristic of Crow's type II syndrome were significant predictors of cerebral hyporesponsivity to stimulant challenge, however
— id: 8462, year: 1994, vol: 36, page: 317, stat: Journal Article,

Striatal binding of the PET ligand 11C-raclopride is altered by drugs that modify synaptic dopamine levels
Dewey SL; Smith GS; Logan J; Brodie JD; Fowler JS; Wolf AP
1993 Apr;13(4):350-356, Synapse
Bilateral decreases in striatal 11C-raclopride binding were observed in adult female baboons with high resolution PET following administration of drugs that act centrally on dopaminergic neurons. At baseline and following administration of d-amphetamine (a dopamine-releasing drug), GBR-12909 (a potent dopamine reuptake inhibitor), or tetrabenazine (a biogenic amine depleting drug) PET scans of 11C-raclopride binding were obtained in a CTI 931 positron tomograph. In all studies, the ratio of the distribution volumes for the striatum to the cerebellum for 11C-raclopride binding decreased significantly by an average of 16.2% for d-amphetamine, 22.1% for GBR-12909, and 28.3% for tetrabenazine while there were no significant changes observed in the cerebellum or in the rate of systemic metabolism of the radiotracer. These decreases exceed the test/retest variability of striatal 11C-raclopride binding measured in the same animals under identical experimental conditions (Dewey et al., 1992b). Together these studies demonstrate that PET measurements of striatal 11C-raclopride binding can be used to indirectly and non-invasively monitor changes in synaptic dopamine concentrations that result from a variety of neurophysiologic mechanisms
— id: 63165, year: 1993, vol: 13, page: 350, stat: Journal Article,

Modulation of central cholinergic activity by GABA and serotonin: PET studies with 11C-benztropine in primates
Dewey, S L; Smith, G S; Logan, J; Brodie, J D
1993 Jun;8(4):371-376, Neuropsychopharmacology
The pharmacologic treatment of many neuropsychiatric disorders (Alzheimer's disease, schizophrenia, depressive illness) has been targeted at the central hypothesis that defects in a single neurotransmitter system underlie the pathophysiology of the disease state. With the recognition that such treatments have not been efficacious consistently, recent drug development has been directed at altering other functionally linked neurotransmitters involved in these diseases. Using positron emission tomography, we have noninvasively investigated the effects of two noncholinergic drugs on the release of acetylcholine. By examining the effects of gamma-vinyl gamma-aminobutyric acid (GABA) (a GABA transaminase inhibitor) or altanserin (a serotonergic antagonist) on the regional binding of 11C-benztropine in the primate brain (Papio anubis), we demonstrated that drugs acting upon either GABAergic or serotonergic neurons produce profound regional changes in acetylcholine release. These findings indicate that the mechanisms of action and the subsequent therapeutic efficacy of these centrally acting drugs may be linked to their multitransmitter effects. This application of positron emission tomography represents an extremely promising experimental approach that can be directed towards elucidating abnormalities in neurotransmitter modulation relevant to disease progression and pharmacologic treatment
— id: 76267, year: 1993, vol: 8, page: 371, stat: Journal Article,

Effects of central cholinergic blockade on striatal dopamine release measured with positron emission tomography in normal human subjects
Dewey, S L; Smith, G S; Logan, J; Brodie, J D; Simkowitz, P; MacGregor, R R; Fowler, J S; Volkow, N D; Wolf, A P
1993 Dec 15;90(24):11816-11820, Proceedings of the National Academy of Sciences of the United States of America
Previously we demonstrated that positron emission tomography (PET) can be used to measure changes in the concentrations of synaptic dopamine and acetylcholine. Whether induced directly or indirectly through interactions with other neurotransmitters, these studies support the use of PET for investigating the functional responsiveness of a specific neurotransmitter to a pharmacologic challenge. In an extension of these findings to the human brain, PET studies designed to measure the responsiveness of striatal dopamine release to central cholinergic blockade were conducted in normal male volunteers using high-resolution PET and [11C]raclopride, a D2-dopamine receptor antagonist. [11C]Raclopride scans were performed prior to and 30 min after systemic administration of the potent muscarinic cholinergic antagonist, scopolamine (0.007 mg/kg). After scopolamine administration, [11C]raclopride binding decreased in the striatum (specific binding) but not in the cerebellum (nonspecific binding) resulting in a significant decrease, exceeding the test/retest variability of this ligand (5%), in the ratio of the distribution volumes of the striatum to the cerebellum (17%). Furthermore, scopolamine administration did not alter the systemic rate of [11C]raclopride metabolism or the metabolite-corrected plasma input function. These results are consistent not only with the known inhibitory influence that acetylcholine exerts on striatal dopamine release but also with our initial 18F-labeled N-methylspiroperidol and benztropine studies. Thus these data support the use of PET for measuring the functional responsiveness of an endogenous neurotransmitter to an indirect pharmacologic challenge in the living human brain
— id: 76243, year: 1993, vol: 90, page: 11816, stat: Journal Article,

THE DOPAMINERGIC-CHOLINERGIC INTERACTION MEASURED WITH POSITRON EMISSION TOMOGRAPHY (PET) AND 11C-RACLOPRIDE IN NORMAL HUMAN-SUBJECTS
DEWEY, SL; SMITH, GS; LOGAN, J; SIMKOWITZ, P; BRODIE, JD; FOWLER, JS; VOLKOW, ND; WOLF, AP
1993 MAY ;34(5):P67-P67, Journal of nuclear medicine
— id: 54153, year: 1993, vol: 34, page: P67, stat: Journal Article,

3-DIMENSIONAL PET-PET BRAIN IMAGE REGISTRATION AND ENHANCEMENT OF THE SIGNAL-NOISE RATIO IN FUNCTIONAL PATTERNS - ANALYSIS OF FUNCTIONAL PATTERN ENHANCEMENT DURING A MOTOR TASK
LEVY, AV; BERTOLLO, D; DHAWAN, A; ARATA, L; BARTLETT, E; RUSINEK, H; VOLKOW, N; BRODIE, JD
1993 MAY ;34(5):P40-P40, Journal of nuclear medicine
— id: 73279, year: 1993, vol: 34, page: P40, stat: Journal Article,

ACUTE CEREBRAL METABOLIC RESPONSE TO HALOPERIDOL - BIOCHEMICAL AND BEHAVIORAL CORRELATIONS
SIMKOWITZ, P; BARTLETT, EJ; BRODIE, JD; CONVIT, A; WOLKIN, A; FRIEDHOFF, AJ; DEWEY, SL; WOLF, AP
1993 MAR 15 ;33(6A):A68-A68, Biological psychiatry
— id: 54173, year: 1993, vol: 33, page: A68, stat: Journal Article,

TEST-RETEST VARIABILITY OF TC-99M-HMPAO SPECT BRAIN PERFUSION STUDIES IN NORMAL HUMAN-SUBJECTS
SMITH, GS; MARTINO, J; KRAMER, EL; NOZ, M; SANGER, JJ; HEISIGER, E; JAFFAR, J; BRODIE, JD
1993 MAY ;34(5):P63-P64, Journal of nuclear medicine
— id: 54152, year: 1993, vol: 34, page: P63, stat: Journal Article,

GABAergic inhibition of endogenous dopamine release measured in vivo with 11C-raclopride and positron emission tomography
Dewey, S L; Smith, G S; Logan, J; Brodie, J D; Yu, D W; Ferrieri, R A; King, P T; MacGregor, R R; Martin, T P; Wolf, A P
1992 Oct;12(10):3773-3780, Journal of neuroscience
Extensive neuroanatomical, neurophysiological, and behavioral evidence demonstrates that GABAergic neurons inhibit endogenous dopamine release in the mammalian corpus striatum. Positron emission tomography (PET) studies in adult female baboons, using the dopamine D2-specific radiotracer 11C-raclopride, were undertaken to assess the utility of this imaging technique for measuring these dynamic interactions in vivo. 11C-raclopride binding was imaged prior to and following the administration of either gamma-vinyl-GABA (GVG), a specific suicide inhibitor of the GABA-catabolizing enzyme GABA transaminase, or lorazepam, a clinically prescribed benzodiazepine agonist. Striatal 11C-raclopride binding increased following both GVG and lorazepam administration. This increase exceeded the test/retest variability of 11C-raclopride binding observed in the same animals. These findings confirm that changes in endogenous dopamine concentrations resulting from drug-induced potentiation of GABAergic transmission can be measured with PET and 11C-raclopride. Finally, this new strategy for noninvasively evaluating the functional integrity of neurophysiologically linked transmitter systems with PET supports its use as an approach for assessing the multiple mechanisms of drug action and their consequences in the human brain
— id: 67825, year: 1992, vol: 12, page: 3773, stat: Journal Article,

The value of "the putrescine experience"
Fowler JS; Wolf AP; Volkow ND; Brodie JD; Hiesiger E
1992 Sep;33(9):1720-1721, Journal of nuclear medicine
— id: 61606, year: 1992, vol: 33, page: 1720, stat: Journal Article,

Is [1-11C]putrescine useful as a brain tumor marker? [see comments]
Hiesiger EM; Fowler JS; Logan J; Brodie JD; MacGregor RR; Christman DR; Wolf AP
1992 Feb;33(2):192-200, Journal of nuclear medicine
Our experience with 11C-putrescine underscores the difficulty of finding a selective brain tumor tracer, uniquely incorporated by neoplastic glia or metastatic cells within brain, but not by the proliferating, nontransformed cells which constitute a normal pathophysiological reaction to various disease processes. Thirty-three patients with 36 lesions were studied with 11C-putrescine to determine the specificity of labeled putrescine for tumor tissue. The uptake of 11C-putrescine was correlated with local cerebral glucose metabolic rate in various lesions, including different types of tumors, to assess the relationship between 11C-putrescine uptake and tumor biology. Carbon-11-putrescine uptake was similar in malignant tumor and benign, non-neoplastic lesions with blood-brain barrier breakdown, illustrating the lack of tumor specificity of this tracer. Carbon-11-putrescine was not well incorporated into poorly enhancing lesions, regardless of their pathology, emphasizing the requirement of a disrupted blood-brain barrier for 11C-putrescine uptake. The ratio of 11C concentration within lesions, compared to that in a region of interest in the contralateral brain, weakly correlated with an analogous ratio for local cerebral glucose metabolic rate in various lesions. Physiological processes not unique to tumors are associated with polyamine active transport and metabolism and contribute to the lack of tumor specificity of 11C-putrescine. Carbon-11-putrescine appear to have less diagnostic utility than 18FDG in brain tumors. The potential of 11C-putrescine for evaluating the effect of antineoplastic therapy and providing prognostic information on brain tumors remains to be investigated
— id: 13698, year: 1992, vol: 33, page: 192, stat: Journal Article,

Spatial low frequency pattern analysis in positron emission tomography: a study between normals and schizophrenics
Levy, A V; Gomez-Mont, F; Volkow, N D; Corona, J F; Brodie, J D; Cancro, R
1992 Feb;33(2):287-295, Journal of nuclear medicine
Using the two-dimensional Fourier transform and the brain's centroidal principal axis, a method is developed for the analysis of PET metabolic brain images without the use of predefined anatomic regions of interest. We applied the method to images from a group of 11 normal and 12 medicated schizophrenics tested under resting conditions and under a visual task. A cortical/subcortical spatial pattern was found to be significant in two directions; anterior/posterior and chiasmatic (left-anterior/right-posterior). The best individual clinical classification (Jackknife classification) occurred under visual task at two axial brain levels: at the basal ganglia with correct classification rates of 91% and 84%, while the cerebellum had rates of 82% and 92%. These high classification rates were obtained using only the four coefficients of the lowest spatial frequency. These results point to the generalized brain dysfunction of regional glucose metabolism in chronic medicated schizophrenics both at rest and at a visual image-tracking task
— id: 144614, year: 1992, vol: 33, page: 287, stat: Journal Article,

Low cerebellar metabolism in medicated patients with chronic schizophrenia
Volkow, N D; Levy, A; Brodie, J D; Wolf, A P; Cancro, R; Van Gelder, P; Henn, F
1992 May;149(5):686-688, American journal of psychiatry
Because of the frequent association of cerebellar structural defects with schizophrenia, the authors reanalyzed the metabolic brain images of patients with chronic schizophrenia to assess if they had abnormalities in cerebellar metabolism. They used carbon-11-2-deoxyglucose and positron emission tomography to study 18 medicated patients with chronic schizophrenia and 12 normal comparison subjects. Patients with schizophrenia showed significantly lower absolute and relative metabolism in the cerebellum than normal subjects
— id: 144613, year: 1992, vol: 149, page: 686, stat: Journal Article,

Negative symptoms and hypofrontality in chronic schizophrenia
Wolkin A; Sanfilipo M; Wolf AP; Angrist B; Brodie JD; Rotrosen J
1992 Dec;49(12):959-965, Archives of general psychiatry
Frontal lobe dysfunction is widely suspected to underlie negative symptoms of schizophrenia. This hypothesis is based largely on long-standing observations of the similarities between the effects of frontal lobe lesions and negative symptoms. However, there is little direct evidence specifically for such an association in schizophrenic patients. We measured the relationship between decreased relative prefrontal cortex glucose metabolism (hypofrontality) using positron emission tomography and evaluated the severity of negative symptoms in 20 chronic schizophrenics who underwent scanning while not receiving neuroleptic drugs. We found a close relationship between negative symptoms and prefrontal hypometabolism, particularly in the right dorsolateral convexity. This association was regionally specific. Furthermore, there was no evidence that this relationship was an artifact of age, cerebral atrophy, or severity of positive symptoms
— id: 57503, year: 1992, vol: 49, page: 959, stat: Journal Article,

Stability of resting deoxyglucose metabolic values in PET studies of schizophrenia
Bartlett EJ; Barouche F; Brodie JD; Wolkin A; Angrist B; Rotrosen J; Wolf AP
1991 May;40(1):11-20, Psychiatry research
Positron emission tomography (PET) and the deoxyglucose method were used to determine the test-retest stability of regional cerebral glucose metabolism in 8 male schizophrenic patients and 11 normal control subjects, scanned twice under baseline (resting) conditions. Normal and schizophrenic subjects showed comparable stability of regional metabolism. When the regional values were scaled to compensate for the effects of changes in whole brain metabolism, the resulting mean regional changes were reduced to about 1-2% in both groups. This study demonstrates that the baseline resting state is an appropriate reference state for schizophrenic subjects in deoxyglucose PET experiments
— id: 14038, year: 1991, vol: 40, page: 11, stat: Journal Article,

Importance of pharmacologic control in PET studies: effects of thiothixene and haloperidol on cerebral glucose utilization in chronic schizophrenia
Bartlett EJ; Wolkin A; Brodie JD; Laska EM; Wolf AP; Sanfilipo M
1991 Oct;40(2):115-124, Psychiatry research
This study compares the effects of two neuroleptic drugs with different pharmacologic characteristics (thiothixene and haloperidol) on cerebral glucose utilization in chronic schizophrenic inpatients. Positron emission tomographic (PET) scans were obtained from all subjects in a neuroleptic-free condition and again after 4-6 weeks of neuroleptic treatment. Eight subjects were treated with thiothixene and 12 with haloperidol. Thiothixene and haloperidol had different metabolic effects. For example, all thiothixene-treated subjects showed increased whole brain glucose utilization; all but one haloperidol-treated subject showed decreased utilization. Different patterns of relative prefrontal and striatal metabolism were also observed. These results highlight the importance of controlling for the effects of neuroleptic treatment and indicate the difficulty of interpreting data from studies with complex or poorly defined drug regimens
— id: 13887, year: 1991, vol: 40, page: 115, stat: Journal Article,

Amphetamine induced decreases in (18F)-N-methylspiroperidol binding in the baboon brain using positron emission tomography (PET)
Dewey, S L; Logan, J; Wolf, A P; Brodie, J D; Angrist, B; Fowler, J S; Volkow, N D
1991 Apr;7(4):324-327, Synapse
— id: 76236, year: 1991, vol: 7, page: 324, stat: Journal Article,

The spectral signature method for the analysis of PET brain images
Levy, A V; Laska, E; Brodie, J D; Volkow, N D; Wolf, A P
1991 Mar;11(2):A103-A113, Journal of cerebral blood flow & metabolism
We introduce the concept of the metabolic centroid spectrum as the feature space to characterize the distribution of metabolic activity in three-dimensional brains. The method computes the metabolic centroid of a brain subvolume for each increment of metabolic activity occurring in the whole brain. The result is the metabolic spectral signature, a continuous three-dimensional curve whose shape reflects the distribution of metabolic rates in the brain. The method's sensitivity to metabolic distribution asymmetries is greatly increased over that of the metabolic centroid method, while retaining its advantages; it is almost invariant to head size, head positioning, photon scatter, and the positron emission tomography (PET) camera's full width at half-maximum. It does not require magnetic resonance, computed tomography, or x-ray images. To test the method we analyzed the metabolic PET images of 40 normal subjects and 20 schizophrenics. The results show a unification of several metabolic characteristics of schizophrenic brains, such as laterality, hypofrontality, cortical/subcortical abnormalities, and overall brain hypometabolism, which were identified by different laboratories in separate studies using differing methodologies. Here they are presented by a single automatic objective method
— id: 140511, year: 1991, vol: 11, page: A103, stat: Journal Article,

THE EFFECT OF ENDOGENOUS DOPAMINE ON FLUORINE-18 N METHYLSPIROPERIDOL BINDING IS PREDICTED TO BE GREATER IN-VIVO THAN IN-VITRO
LOGAN J; DEWEY S L; WOLF A P; BRODIE J D; ANGRIST B; FOWLER J S; VOLKOW N D
1991 ;32(5 SUPPL):1071-1072, Journal of nuclear medicine
— id: 106732, year: 1991, vol: 32, page: 1071, stat: Journal Article,

Effects of endogenous dopamine on measures of [18F]N-methylspiroperidol binding in the basal ganglia: comparison of simulations and experimental results from PET studies in baboons
Logan, J; Dewey, S L; Wolf, A P; Fowler, J S; Brodie, J D; Angrist, B; Volkow, N D; Gatley, S J
1991 Nov;9(3):195-207, Synapse
The effect of endogenous dopamine on PET measures of radioligand binding is important to the measurement of receptor density (or availability) and neurotransmitter interactions in vivo. We recently reported that pretreatment with amphetamine, a drug which stimulates dopamine release, significantly reduced NMS binding in the baboon brain as determined by the product lambda k3 derived from the graphical analysis method for irreversible systems (lambda is the ratio of the forward to reverse plasma to tissue transport constants and k3 is proportional to receptor density) (Dewey et al.: Synapse 7:324-327, 1991). The purpose of this work is twofold: to evaluate the sensitivity and stability of the analysis method used for the NMS data and from simulation studies which include the competitive effects of dopamine on NMS binding to predict the effect of dopamine on the in vivo PET experiment. Using a measured plasma [18F]-NMS input function from a control study in a baboon, simulation data was numerically generated explicitly allowing competition between NMS and dopamine in the calculation. This data was analyzed using the same techniques as used for the experimental data and the results were compared to in vitro calculations. The following conclusions were reached: 1) The effect of dopamine on specific binding was found to be greater in vivo than in vitro because the in vitro equilibrium experiment is controlled only by the relative Kd's of tracer and dopamine while the in vivo experiment also depends upon the halftime of tracer in tissue which is controlled by the tissue-to-plasma transport constant; 2) Experimental evidence from rodent studies (Seeman et al.: Synapse 3:96-97, 1989) and the agreement between PET studies (Wong et al.: Science 234:1558-1563, 1986a) and postmortem human studies (Seeman et al.: Science 225:728-731, 1984) in schizophrenics suggest that NMS is not likely to be affected by normal levels of endogenous dopamine. From the calculations reported here the effective in vivo Kd of dopamine for the NMS binding site would have to be on the order of or greater than 100 nM, assuming a synaptic dopamine concentration of 20 nM, in order that this concentration of dopamine have little effect on NMS binding
— id: 76235, year: 1991, vol: 9, page: 195, stat: Journal Article,

Positron emission tomography: basic principles and applications in psychiatric research
Volkow, N D; Brodie, J; Bendriem, B
1991 ;620:128-144, Annals of the New York Academy of Sciences
— id: 144619, year: 1991, vol: 620, page: 128, stat: Journal Article,

Mapping muscarinic receptors in human and baboon brain using [N-11C-methyl]-benztropine
Dewey SL; MacGregor RR; Brodie JD; Bendriem B; King PT; Volkow ND; Schlyer DJ; Fowler JS; Wolf AP; Gatley SJ; et al.
1990 ;5(3):213-223, Synapse
The muscarinic cholinergic system has been mapped in vivo in human and baboon brain using [N-11C-methyl]-benztropine and high resolution positron emission tomography (PET). [N-11C-methyl]-benztropine uptake was observed in frontal, parietal, occipital, and temporal cortices as well as in subcortical structures including the corpus striatum and thalamus. Uptake continued to increase in baboon and human brain in all areas over an 80 minute experimental period with the exception of the cerebellum where the accumulation of radioactivity began to decrease by 25 minutes postinjection. The ratio of incorporation of [N-11C-methyl]-benztropine between corpus striatum/cerebellum was 1.53 and 1.46 in humans and baboons, respectively, at 60 minutes. Blocking studies in baboons using the muscarinic cholinergic antagonists scopolamine and benztropine and the muscarinic cholinergic agonist pilocarpine combined with blocking studies in humans using benztropine indicate that the binding of this compound is specific for the muscarinic cholinergic system. Pretreatment with the potent dopamine reuptake blocker nomifensine produced no effect on the incorporation of radioactivity in any baboon brain region examined. Analysis of labelled plasma metabolites indicates that in humans, the rate of metabolism of [N-11C-methyl]-benztropine is slow (83.0% unchanged at 30 minutes postinjection) differing quite dramatically from the rate of metabolism observed in baboons (43.4% unchanged at 30 minutes postinjection). These data combined with postmortem studies in humans and primates demonstrate that [N-11C-methyl]-benztropine is a suitable muscarinic cholinergic ligand for use in humans and baboons with PET
— id: 62298, year: 1990, vol: 5, page: 213, stat: Journal Article,

Positron emission tomography (PET) studies of dopaminergic/cholinergic interactions in the baboon brain
Dewey, S L; Brodie, J D; Fowler, J S; MacGregor, R R; Schlyer, D J; King, P T; Alexoff, D L; Volkow, N D; Shiue, C Y; Wolf, A P
1990 ;6(4):321-327, Synapse
Interactions between the dopaminergic D2 receptor system and the muscarinic cholinergic system in the corpus striatum of adult female baboons (Papio anubis) were examined using positron emission tomography (PET) combined with [18F]N-methylspiroperidol [( 18F]NMSP) (to probe D2 receptor availability) and [N-11C-methyl]benztropine (to probe muscarinic cholinergic receptor availability). Pretreatment with benztropine, a long-lasting anticholinergic drug, bilaterally reduced the incorporation of radioactivity in the corpus striatum but did not alter that observed in the cerebellum or the rate of metabolism of [18F]NMSP in plasma. Pretreatment with unlabelled NMSP, a potent dopaminergic antagonist, reduced the incorporation of [N-11C-methyl]benztropine in all brain regions, with the greatest effect being in the corpus striatum greater than cortex greater than thalamus greater than cerebellum, but did not alter the rate of metabolism of the labelled benztropine in the plasma. These reductions in the incorporation of either [18F]NMSP or [N-11C-methyl]benztropine exceeded the normal variation in tracer incorporation in repeated studies in the same animal. This study demonstrates that PET can be used as a tool for investigating interactions between neurochemically different yet functionally linked neurotransmitters systems in vivo and provides insight into the consequences of multiple pharmacologic administration
— id: 67824, year: 1990, vol: 6, page: 321, stat: Journal Article,

THE METABOLIC CENTROID METHOD FOR PET BRAIN IMAGE-ANALYSIS - REPLY
Levy, AV; Brodie, JD; Russell, JAG; Volkow, ND; Laska, EM; Wolf, AP
1990 May;10(3):439-440, Journal of cerebral blood flow & metabolism
— id: 31949, year: 1990, vol: 10, page: 439, stat: Journal Article,

D2-RECEPTOR OCCUPANCY AND PLASMA-CONCENTRATION OF ANTIPSYCHOTICS - RESPONSE
LOGAN, J; SCHLYER, DJ; WOLF, AP; FOWLER, JS; BRODIE, JD
1990 DEC 15 ;28(12):1068-1070, Biological psychiatry
— id: 51750, year: 1990, vol: 28, page: 1068, stat: Journal Article,

The metabolic centroid method for PET brain image analysis
Levy, A V; Brodie, J D; Russell, A G; Volkow, N D; Laska, E; Wolf, A P
1989 Jun;9(3):388-397, Journal of cerebral blood flow & metabolism
The method of centroids is an approach to the analysis of three-dimensional whole-brain positron emission tomography (PET) metabolic images. It utilizes the brain's geometric centroid and metabolic centroid so as to objectively characterize the central tendency of the distribution of metabolic activity in the brain. The method characterizes the three-dimensional PET metabolic image in terms of four parameters: the coordinates of the metabolic centroid and the mean metabolic rate of the whole brain. These parameters are not sensitive to spatially uniform random noise or to the position of the subject's head within a uniform PET camera field of view. The method has been applied to 40 normal subjects, 22 schizophrenics who were treated with neuroleptics, and 20 schizophrenics who were neuroleptic-free. The mean metabolic centroid of the normal subjects was found to be superior to the mean geometric centroid of the brain. The mean metabolic centroid of chronic schizophrenics is lower and more posterior to the mean geometric centroid than is that of normals. This difference is greater in medicated than in unmedicated schizophrenics. The posterior and downward displacement of the mean metabolic centroid is consistent with the concepts of hypofrontality, hyperactivity of subcortical structures, and neuroleptic effect in schizophrenics
— id: 140512, year: 1989, vol: 9, page: 388, stat: Journal Article,

Dopamine blockade and clinical response: evidence for two biological subgroups of schizophrenia
Wolkin A; Barouche F; Wolf AP; Rotrosen J; Fowler JS; Shiue CY; Cooper TB; Brodie JD
1989 Jul;146(7):905-908, American journal of psychiatry
Because CNS neuroleptic concentration cannot be directly measured in patients, the relation between clinical response and extent of dopamine receptor blockade is unknown. This relationship is critical in ascertaining whether nonresponse to neuroleptics is the result merely of inadequate CNS drug levels or of more basic biological differences in pathophysiology. Using [18F]N-methylspiroperidol and positron emission tomography, the authors assessed dopamine receptor occupancy in 10 schizophrenic patients before and after treatment with haloperidol. Responders and nonresponders had virtually identical indices of [18F]N-methylspiroperidol uptake after treatment, indicating that failure to respond clinically was not a function of neuroleptic uptake or binding in the CNS
— id: 8395, year: 1989, vol: 146, page: 905, stat: Journal Article,

Dopamine receptor occupancy and plasma haloperidol levels
Wolkin A; Brodie JD; Barouche F; Rotrosen J; Wolf AP; Smith M; Fowler J; Cooper TB
1989 May;46(5):482-484, Archives of general psychiatry
— id: 23596, year: 1989, vol: 46, page: 482, stat: Journal Article,

Reproducibility of cerebral glucose metabolic measurements in resting human subjects
Bartlett EJ; Brodie JD; Wolf AP; Christman DR; Laska E; Meissner M
1988 Aug;8(4):502-512, Journal of cerebral blood flow & metabolism
Positron emission tomography with 11C-2-deoxyglucose was used to determine the test-retest variability of regional cerebral glucose metabolism in 22 young normal right-handed men scanned twice in a 24-h period under baseline (resting) conditions. To assess the effects of scan order and time of day on variability, 12 subjects were scanned in the morning and afternoon of the same day (a.m.-p.m.) and 10 in the reverse order (p.m.-a.m.) with a night in between. The effect of anxiety on metabolism was also assessed. Seventy-three percent of the total subject group showed changes in whole brain metabolism from the first to the second measurement of 10% or less, with comparable changes in various cortical and subcortical regions. When a scaling factor was used to equate the whole brain metabolism in the two scans for each individual, the resulting average regional changes for each group were no more than 1%. This suggests that the proportion of the whole brain metabolism utilized regionally is stable in a group of subjects over time. Both groups of subjects had lower morning than afternoon metabolism, but the differences were slight in the p.m.-a.m. group. One measure of anxiety (pulse at run 1) was correlated with run 1 metabolism and with the percentage of change from run 1 to run 2. No significant run 2 correlations were observed. This is the first study to measure test-retest variability in cerebral glucose metabolism in a large sample of young normal subjects. It demonstrates that the deoxyglucose method yields low intrasubject variability and high stability over a 24-h period
— id: 11005, year: 1988, vol: 8, page: 502, stat: Journal Article,

Regional glucose metabolism in chronic schizophrenia
Brodie JD; Wolkin A; Wolf AP; Volkow N; Russell JA; Van Gelder P; Jaeger J; Fowler J; Rotrosen J; Cancro R
1988 ;3(1):54-54, American journal of physiologic imaging
— id: 11210, year: 1988, vol: 3, page: 54, stat: Journal Article,

DIFFICULTIES IN DIFFERENTIATING RECURRENT TUMOR FROM TREATMENT RELATED NECROSIS BY POSITRON EMISSION TOMOGRAPHY SCANNING WITH [11C]2-DEOXY-D-GLUCOSE - THE ISSUE OF MIXED LESIONS
HIESIGER, EM; BUDZILOVICH, G; LOGAN, J; FOWLER, JS; BRODIE, JD; WOLF, AP; MACGREGOR, RR; CHRISTMAN, DR; FLAMM, E
1988 MAR ;29(4):171-171, Proceedings (American Association for Cancer Research)
— id: 41772, year: 1988, vol: 29, page: 171, stat: Journal Article,

Serial [18F]N-methylspiroperidol PET studies to measure changes in antipsychotic drug D-2 receptor occupancy in schizophrenic patients
Smith M; Wolf AP; Brodie JD; Arnett CD; Barouche F; Shiue CY; Fowler JS; Russell JA; MacGregor RR; Wolkin A; et al.
1988 Apr 1;23(7):653-663, Biological psychiatry
An indirect approach to the relationship among drug dose, plasma level, and the competition between a labeled neuroleptic drug [18F]N-methylspiroperidol (18F-NMS) for binding sites in striatal tissue in normal and schizophrenic subjects is described. The slope of the line plotting the ratio of activity in the striatum (As) to activity in the cerebellum (Ac) versus time up to 5 hr postinjection of 18F-NMS is taken as a marker of site occupancy. An inverse relation between labeled competitor uptake and drug plasma level has been demonstrated for the classes of antipsychotic drug studied. Striatal uptake studies showed a progressive increase in all subjects following drug withdrawal up to 156 hr postwithdrawal. Uptake and clearance of 18F-NMS in cerebellar tissue was not appreciably affected by antipsychotic medication or drug withdrawal
— id: 62153, year: 1988, vol: 23, page: 653, stat: Journal Article,

Brain interactions in chronic schizophrenics under resting and activation conditions
Volkow, N D; Wolf, A P; Brodie, J D; Cancro, R; Overall, J E; Rhoades, H; Van Gelder, P
1988 Jan-Feb;1(1):47-53, Schizophrenia research
The metabolic patterns of correlation among brain images obtained during resting conditions and during an eye tracking task were investigated in 12 controls and 18 chronic schizophrenics using positron emission tomography (PET) and deoxy[11C]glucose. Analyses of the interaction between brain regions revealed highly significant differences between groups under both test conditions. Schizophrenics showed lower correlations between anterior and posterior areas and between thalamus and cortical areas than the normals and less change between the baseline and the task than the normals. The schizophrenic subjects showed derangements in the pattern of interactions among brain areas, both under baseline and under activation as compared to the control group
— id: 144634, year: 1988, vol: 1, page: 47, stat: Journal Article,

Low frontal glucose utilization in chronic schizophrenia: a replication study
Wolkin A; Angrist B; Wolf A; Brodie JD; Wolkin B; Jaeger J; Cancro R; Rotrosen J
1988 Feb;145(2):251-253, American journal of psychiatry
Frontal/posterior ratios of cerebral glucose metabolism as determined by positron emission tomography were significantly lower in 13 chronic schizophrenic patients than in eight normal control subjects, as were absolute metabolic rates in both the frontal and posterior regions. The differences were not accounted for by cerebral atrophy
— id: 11197, year: 1988, vol: 145, page: 251, stat: Journal Article,

Correlations between glucose metabolic rates in brain regions of healthy male adults at rest and during language stimulation
Bartlett EJ; Brown JW; Wolf AP; Brodie JD
1987 Sep;32(1):1-18, Brain & language
This study examines the effect of different behavioral conditions on patterns of correlation between regional cerebral metabolic rates for glucose. Cerebral glucose metabolism was determined with positron emission tomography and (11C)-deoxyglucose in 29 normal subjects between the ages of 23 and 55. Seventeen subjects were studied in an unstimulated (resting) condition and 12 subjects during a phoneme monitoring language stimulation. Partial correlation coefficients, controlling for whole brain glucose metabolism, were calculated for pairs of metabolic rates in 14 cortical and 2 subcortical regions. Both stimulated and unstimulated subjects showed statistically significant correlations between left and right hemisphere homologs. The stimulated subjects also showed significant within-hemisphere correlations between left but not right hemisphere regions. These included left perisylvian regions classically associated with language functions (left inferior frontal, left superior temporal and left transverse temporal cortical regions) as well as other regions. Significant correlations between left regions and a right superior temporal region were also found. In general, these findings show a pattern of cross-hemisphere symmetry at rest and of hemisphere asymmetry during stimulation. Moreover, the asymmetry observed during stimulation appears to be superimposed upon a pattern of cross-hemisphere symmetry similar to that observed in the unstimulated state
— id: 11376, year: 1987, vol: 32, page: 1, stat: Journal Article,

PET STUDIES IN SCHIZOPHRENIA
Brodie, JD; Wolf, AP; Bartlett, E; Wolkin, A; Vangelder, P; Volkow, N
1987 Apr;32(1-2):788-788, International journal of neuroscience
— id: 31395, year: 1987, vol: 32, page: 788, stat: Journal Article,

PET STUDIES IN SCHIZOPHRENIA
Brodie, JD; Wolf, AP; Wolkin, A; Arnett, CD; Angrist, B; Fowler, J; Smith, M; Russell, J; Logan, J; Christman, D; Rotrosen, J; Volkow, N
1987 Apr;32(1-2):445-445, International journal of neuroscience
— id: 31391, year: 1987, vol: 32, page: 445, stat: Journal Article,

Positron emission tomography studies of normal aging: a replication of PET III and 18-FDG using PET VI and 11-CDG
de Leon MJ; George AE; Tomanelli J; Christman D; Kluger A; Miller J; Ferris SH; Fowler J; Brodie JD; van Gelder P; et al
1987 Jul-Aug;8(4):319-323, Neurobiology of aging
Using PET VI and 11-CDG we replicated our earlier PET III and 18-FDG normal aging findings. Examination of young and old normal volunteers revealed the absence of any absolute regional age-related changes in glucose utilization. For the combined sample (N = 81) we did find evidence to suggest a relative hypofrontal change with increasing age. A strong relationship between age and ventricular size (CT) was also found. These findings suggest the preserved glucose metabolism of the resting aging brain in the presence of structural atrophic changes.
— id: 9473, year: 1987, vol: 8, page: 319, stat: Journal Article,

Serial PET studies of human cerebral malignancy with [1-11C]putrescine and [1-11C]2-deoxy-D-glucose
Hiesiger E; Fowler JS; Wolf AP; Logan J; Brodie JD; McPherson D; MacGregor RR; Christman DR; Volkow ND; Flamm E
1987 Aug;28(8):1251-1261, Journal of nuclear medicine
Serial PET measurements of [1-11C]putrescine ([11C]PUT) uptake and glucose metabolic rate (GMR) using [1-11C]2-deoxy-D-glucose ([11C]2DG) were made on eight human subjects with a radiological and, in most cases, pathological diagnosis of primary or metastatic brain tumor. Blood-to-brain influx constants (Ki) were calculated for [11C]PUT. Tumor uptake of 11C after [11C]PUT injection was unidirectional peaking at 15 min. The mean +/- s.d. Kis for [11C]PUT for tumor and normal brain tissue were 0.78 +/- 0.045 and 0.024 +/- 0.007 ml cc-1 min-1, respectively (average of ratio, 3.11) whereas the ratio of GMR for tumor and normal brain tissue was 1.2 +/- 0.5. The mean Ki for four active, high grade astrocytomas was 0.098 +/- 0.030 in contrast to 0.027 +/- 0.008 ml cc-1 min-1 for two patients with low grade astrocytoma. Active high grade astrocytomas also showed marked CT contrast enhancement and regional glucose hypermetabolism. In one subject with brain metastases, both [11C]PUT and GMR correlated with a declining clinical picture in repeated studies over a 4-mo period. PET studies with [11C]PUT provide a better signal:noise ratio than GMR measurements, are useful for locating small glycolytically hypometabolic tumors and, when used in longitudinal studies in a single subject, appear to provide an index of degree of malignancy
— id: 61607, year: 1987, vol: 28, page: 1251, stat: Journal Article,

Phenomenological correlates of metabolic activity in 18 patients with chronic schizophrenia
Volkow, N D; Wolf, A P; Van Gelder, P; Brodie, J D; Overall, J E; Cancro, R; Gomez-Mont, F
1987 Feb;144(2):151-158, American journal of psychiatry
Using [11C]-deoxy-D-glucose and positron emission tomography (PET), the authors measured brain metabolism in 18 patients with chronic schizophrenia to assess which of the metabolic measures from two test conditions was more closely related to the patients' differing clinical characteristics. The two conditions were resting and activation, and an eye tracking task was used. Patients with more negative symptoms showed lower global metabolic rates and more severe hypofrontality than did the patients with fewer negative symptoms. Differences among the patients were distinguished by the task: sicker patients failed to show a metabolic activation response. These findings suggest that cerebral metabolic patterns reflect clinical characteristics of schizophrenic patients
— id: 144637, year: 1987, vol: 144, page: 151, stat: Journal Article,

Effects of amphetamine on local cerebral metabolism in normal and schizophrenic subjects as determined by positron emission tomography
Wolkin A; Angrist B; Wolf A; Brodie J; Wolkin B; Jaeger J; Cancro R; Rotrosen J
1987 ;92(2):241-246, Psychopharmacology
The effects of d-amphetamine (0.5 mg/kg PO) on regional cerebral glucose utilization were measured with Positron Emission Tomography (PET). Subjects included ten chronic schizophrenics and six controls who received amphetamine, and six chronic schizophrenics and nine controls who received placebo or no treatment. Amphetamine decreased glucose metabolism in all regions studied (frontal, temporal, and striatal) in normal and schizophrenic subjects. The metabolic effects of amphetamine were correlated with plasma level of the drug. Cortical atrophy was associated with a blunted metabolic response
— id: 23614, year: 1987, vol: 92, page: 241, stat: Journal Article,

EFFECTS OF AMPHETAMINE ON LOCAL CEREBRAL METABOLISM IN NORMAL AND SCHIZOPHRENIC SUBJECTS AS DETERMINED BY POSITRON EMISSION TOMOGRAPHY USING [C-11-1] 2-DEOXY-D-GLUCOSE (C-11-2DG)
BRODIE, JD; WOLKIN, A; ANGRIST, B; WOLF, AP; JORDAN, B; JAEGER, J; CANCRO, R; ROTROSEN, J
1986 JUN ;27(6):901-901, Journal of nuclear medicine
— id: 41433, year: 1986, vol: 27, page: 901, stat: Journal Article,

Putrescine metabolism in human brain tumors
Goldman, S S; Volkow, N D; Brodie, J; Flamm, E S
1986 ;4(1):23-29, Journal of neuro-oncology
The metabolism of the polyamines, putrescine, spermidine and spermine, was studied in human brain and brain tumors. Samples of brain and tumors were incubated with 3H-putrescine and the amounts of labeled polyamines were measured. The amount of putrescine conversion was found to be greater in tumors that in normal brain samples. Furthermore, the metabolism of putrescine in brain tumors was related to tumor type and appeared to correlate with the degree of malignancy. The significance of these findings with regard to positron emission tomographic scanning and therapy of patients with malignant gliomas is discussed
— id: 123879, year: 1986, vol: 4, page: 23, stat: Journal Article,

SERIAL PET STUDIES OF HUMAN CEREBRAL MALIGNANCY WITH [1-C-11] PUTRESCINE (C-11-PUT) AND [1-C-11]2-DEOXY-D-GLUCOSE (C-11-2DG)
HIESIGER, E; LOGAN, J; WOLF, AP; BRODIE, JD; MCPHERSON, D; MACGREGOR, RR; FOWLER, JS; CHRISTMAN, DR; FLAMM, E
1986 JUN ;27(6):889-889, Journal of nuclear medicine
— id: 41432, year: 1986, vol: 27, page: 889, stat: Journal Article,

IMAGING OF HUMAN-BRAIN TUMORS BY POSITRON EMISSION TOMOGRAPHY (PET) USING (1-C-11) PUTRESCINE (C-11-PU) AND (1-C-11)-2-DEOXY-D-GLUCOSE (C-11-2DG)
HIESIGER, EM; FOWLER, J; BRODIE, JD; LOGAN, L; MACGREGOR, R; CHRISTMAN, D; FLAMM, EJ; WOLF, AP
1986 MAR ;27(2):155-155, Proceedings (American Association for Cancer Research)
— id: 41427, year: 1986, vol: 27, page: 155, stat: Journal Article,

SERIAL [F-18] N-METHYLSPIROPERIDOL (F-18 NMS) PET STUDIES MEASURE CHANGES IN ANTIPSYCHOTIC DRUG D2 RECEPTOR OCCUPANCY IN SCHIZOPHRENICS
SMITH, M; WOLF, AP; SHIUE, CY; FOWLER, JS; RUSSELL, JAG; MACGREGOR, R; ARNETT, C; LOGAN, J; WOLKIN, A; ROTROSEN, J; BRODIE, JD
1986 JUN ;27(6):880-880, Journal of nuclear medicine
— id: 41431, year: 1986, vol: 27, page: 880, stat: Journal Article,

Brain metabolism in patients with schizophrenia before and after acute neuroleptic administration
Volkow, N D; Brodie, J D; Wolf, A P; Angrist, B; Russell, J; Cancro, R
1986 Oct;49(10):1199-1202, Journal of neurology neurosurgery & psychiatry
Positron emission tomography (PET) with 11C-2-deoxyglucose (11DG) was used to compare regional brain metabolism in four patients with chronic schizophrenia who had no history of psychotropic medication and in 12 normal controls. Patients had a second PET scan after an injection of thiothixene to evaluate the effects of acute neuroleptics on glucose metabolism. The patients showed higher glucose metabolic values than the normals and did not show the metabolic hypofrontality reported in chronic medicated patients with schizophrenia. Administration of the neuroleptic did not have a significant effect in the metabolic pattern of the patients. These results give support to the hypothesis that prolonged medication may contribute to the metabolic hypofrontal pattern seen in patients with schizophrenia
— id: 106693, year: 1986, vol: 49, page: 1199, stat: Journal Article,

Brain organization in schizophrenia
Volkow, N D; Brodie, J D; Wolf, A P; Gomez-Mont, F; Cancro, R; Van Gelder, P; Russell, J A; Overall, J
1986 Aug;6(4):441-446, Journal of cerebral blood flow & metabolism
Brain metabolism was measured with positron emission tomography and [11C]deoxyglucose during baseline and during a visual task in 12 normal subjects and 18 schizophrenic patients. Global measures of metabolism for 11 brain regions were transformed into relative values by dividing them by the metabolic value for whole brain. Factor analysis was accomplished on the matrix of intercorrelations among the relative regional values for the normal and for the schizophrenic patients under baseline and under the task. Four factors that revealed independently varying metabolism in frontal, occipital, left-versus-right hemisphere, and subcortical structures were obtained. The frontal and subcortical factors discriminated between normal subjects and schizophrenic patients, whereas the occipital factor discriminated between baseline and task. Although activity in these individual regions varied significantly, it was the pattern of differences in regional metabolic activity that best discriminated between diagnostic groups and testing conditions
— id: 144640, year: 1986, vol: 6, page: 441, stat: Journal Article,

SYNTHESIS AND BIODISTRIBUTION OF NO-CARRIER-ADDED [1-11C PUTRESCINE
MCPHERSON, DW; FOWLER, JS; WOLF, AP; ARNETT, CD; BRODIE, JD; VOLKOW, N
1985 ;26(10):1186-1189, Journal of nuclear medicine
— id: 41143, year: 1985, vol: 26, page: 1186, stat: Journal Article,

SYNTHESIS AND BIODISTRIBUTION OF NO-CARRIER-ADDED [1-C-11] PUTRESCINE
Mcpherson, DW; Fowler, JS; Wolf, AP; Arnett, CD; Brodie, JD; Volkow, N
1985 ;26(5):P127-P128, Journal of nuclear medicine
— id: 30742, year: 1985, vol: 26, page: P127, stat: Journal Article,

Persistence of cerebral metabolic abnormalities in chronic schizophrenia as determined by positron emission tomography
Wolkin A; Jaeger J; Brodie JD; Wolf AP; Fowler J; Rotrosen J; Gomez-Mont F; Cancro R
1985 May;142(5):564-571, American journal of psychiatry
Local cerebral metabolic rates were determined by positron emission tomography and the deoxyglucose method in a group of 10 chronic schizophrenic subjects before and after somatic treatment and in eight normal subjects. Before treatment, schizophrenic subjects had markedly lower absolute metabolic activity than did normal controls in both frontal and temporal regions and a trend toward relative hyperactivity in the basal ganglia area. After treatment, their metabolic rates approached those seen in normal subjects in nearly all regions except frontal. Persistence of diminished frontal metabolism was manifested as significant relative hypofrontality. These findings suggest specific loci of aberrant cerebral functioning in chronic schizophrenia and the utility of positron emission tomography in characterizing these abnormalities
— id: 23625, year: 1985, vol: 142, page: 564, stat: Journal Article,

Patterns of metabolic activity in the treatment of schizophrenia
Brodie JD; Christman DR; Corona JF; Fowler JS; Gomez-Mont F; Jaeger J; Micheels PA; Rotrosen J; Russell JA; Volkow ND; et al.
1984 ;15 Suppl(3-4):S166-S169, Annals of neurology
Six patients with chronic schizophrenia were studied with positron emission tomography (PET) before and after neuroleptic treatment, using fluorine-18-labeled fluorodeoxyglucose. After treatment, the mean whole-slice glucose metabolic rate at the level of the basal ganglia showed a 25% increase. However, patterns of frontal hypometabolism observed with the schizophrenic patients were not altered by medication. Pattern analysis using the fast Fourier transform was applied to a set of 422 images from a mixed group of normal, depressed, and schizophrenic subjects. Reconstruction of the images with low-frequency coefficients was excellent, reducing considerably the number of variables needed to characterize each image. Hierarchical cluster analysis categorized the transformed images according to anatomical level and subject group (patient versus control). The results suggest the utility of this procedure for the classification and characterization of metabolic PET images from psychiatric patients
— id: 23635, year: 1984, vol: 15 Suppl, page: S166, stat: Journal Article,

REGIONAL GLUCOSE-METABOLISM IN CHRONIC-SCHIZOPHRENIA
Brodie, JD; Wolkin, A; Wolfe, AP; Jaeger, J; Fowler, J; Rotrosen, J; Cancro, R
1984 ;2(3):226-226, International journal of psychophysiology
— id: 30978, year: 1984, vol: 2, page: 226, stat: Journal Article,

Positron emission tomography and computed tomography assessments of the aging human brain
de Leon MJ; George AE; Ferris SH; Christman DR; Fowler JS; Gentes CI; Brodie J; Reisberg B; Wolf AP
1984 Feb;8(1):88-94, Journal of computer assisted tomography
The relationship between alterations in brain structure and brain function was studied in vivo in both young and elderly human subjects. Computed tomography revealed significant age-related ventricular and cortical sulcal dilatation. The cortical changes were most closely related to age. Positron emission tomography failed to show regional changes in brain glucose metabolic rate. The results suggest that the normal aging brain undergoes structural atrophic changes without incurring regional metabolic changes. Examination of the correlations between the structural and the metabolic measures revealed no significant relationships. These data are discussed with respect to the significant structure-function relationships that have been reported in Alzheimer disease.
— id: 9482, year: 1984, vol: 8, page: 88, stat: Journal Article,

REGIONAL BRAIN GLUCOSE-METABOLISM IN CHRONIC-SCHIZOPHRENIA - A POSITRON EMISSION TRANSAXIAL TOMOGRAPHIC STUDY
FARKAS, T; WOLF, AP; JAEGER, J; BRODIE, JD; CHRISTMAN, DR; FOWLER, JS; MACGREGOR, RR; DELEON, MJ; DEFINA, P; GOLDMAN, A; YONEKURA, Y; BRILL, AB; SCHWARTZ, M; LOGAN, J; CANCRO, R
1984 ;41(3):293-300, Archives of general psychiatry
— id: 41102, year: 1984, vol: 41, page: 293, stat: Journal Article,

Positron emission tomographic studies of aging and Alzheimer disease
de Leon MJ; Ferris SH; George AE; Christman DR; Fowler JS; Gentes C; Reisberg B; Gee B; Emmerich M; Yonekura Y; Brodie J; Kricheff II; Wolf AP
1983 May-Jun;4(3):568-571, AJNR. American journal of neuroradiology
In this study the positron emission tomographic (PET)-18F-2-deoxy-2-fluoro-D-glucose (FDG) technique was used to study both normal aging and senile dementia. The results derived from 15 young normal subjects (mean age, 26 +/- 5 years) and 22 elderly normal subjects (mean age, 66 +/- 7 years) failed to indicate significant metabolic changes associated with age. A group of 24 patients with senile dementia (mean age, 73 +/- 7 years) showed consistent diminutions in regional glucose use relative to the elderly normals. Across all brain regions the diminutions were 17%-24%. There were also significant correlations between the measures of glucose use and the measures of cognitive functioning. Discriminant function classification analysis results indicate that better than 80% classification accuracy can be achieved for individual PET measures. These data suggest a possible future diagnostic use of PET in senile dementia.
— id: 9486, year: 1983, vol: 4, page: 568, stat: Journal Article,

Labeled putrescine as a probe in brain tumors
Volkow, N; Goldman, S S; Flamm, E S; Cravioto, H; Wolf, A P; Brodie, J D
1983 Aug 12;221(4611):673-675, Science
The polyamine metabolism of transplanted N-nitrosomethylurea-derived rat glioma was determined with radiolabeled putrescine used as a marker for malignancy. The uptake of putrescine in vivo was complete within 5 minutes and was specific for tumor tissue. The conversion of putrescine to spermine and other metabolites by the tumor was rapid, in contrast to the case for adjacent normal brain. These results suggest that putrescine labeled with carbon-11 may be used as a positron-emission tomographic tracer for the selective metabolic imaging of brain tumor and may be used in an appropriate model as a marker for tumor growth rate
— id: 118098, year: 1983, vol: 221, page: 673, stat: Journal Article,

Margaret B : a "typical" Bellevue case
Brodie JD; Rohrs CC
1978 ;15:35-43, Psychiatric opinion
— id: 105407, year: 1978, vol: 15, page: 35, stat: Journal Article,

Mechanism and prevention of tachyphylaxis and cyanide toxicosis after nitroprusside-induced hypotension
Cottrell JE; Casthely P; Brodie JD; Patel K; Klein A; Turndorf H
1978 ;29:308-310, Surgical forum
— id: 11456, year: 1978, vol: 29, page: 308, stat: Journal Article,

Prevention of nitroprusside-induced cyanide toxicity with hydroxocobalamin
Cottrell JE; Casthely P; Brodie JD; Patel K; Klein A; Turndorf H
1978 May 13;298(15):809-811, New England journal of medicine
To investigate hydroxocobalamin's role in preventing cyanide intoxication from sodium nitroprusside, we studied two groups of patients. One group received nitroprusside alone, and the other received nitroprusside and hydroxocobalamin. Red-cell and plasma cyanide levels were 83.44 +/- 23.12 and 3.51 +/- 1.01 microgram per 100 ml after nitroprusside alone and were 33.18 +/- 17.29 and 2.18 +/- 0.65 microgram per 100 ml after nitroprusside plus hydroxocobalamin. Acidosis developed in patients with red-cell cyanide levels higher than 75 microgram per 100 ml. When hydroxocobalamin infusion was stopped before sodium nitroprusside infusion was discontinued, blood cyanide levels and base deficit increased in a manner similar to that in the untreated group. The dose of nitroprusside used in each group did not differ statistically. These data show that hydroxocobalamin prevents cyanide transfer from red cells and plasma to tissue after nitroprusside metabolism, and thereby prevents cyanide toxicity from large intravenous doses of the drug
— id: 45859, year: 1978, vol: 298, page: 809, stat: Journal Article,

PREVENTION OF CYANIDE INTOXICATION FOLLOWING SODIUM NITROPRUSSIDE INDUCED HYPOTENSION
Cottrell, JE; Casthely, P; Brodie, JD; Patel, K; Klein, A; Turndorf, H
1978 ;6(2):108-108, Critical care medicine
— id: 29851, year: 1978, vol: 6, page: 108, stat: Journal Article,

Cleavage of coenzyme B 12 by methylmalonyl coenzyme A mutase
Babior, B M; Woodams, A D; Brodie, J D
1973 Feb 25;248(4):1445-1450, Journal of biological chemistry
— id: 132253, year: 1973, vol: 248, page: 1445, stat: Journal Article,

FAST AND SLOW INHIBITORS OF OX HEART SUCCINATE DEHYDROGENASE ACTION OF OXAL ACETATE AND ITS FLUORO ANALOGUES
KAPPEN L S; BRODIE J D; NICHOLLS P
1973 ;1(4):877-880, Transactions (Biochemical Society (Great Britain))
— id: 105406, year: 1973, vol: 1, page: 877, stat: Journal Article,

Subcellular distribution of methylmalonyl CoA carbonylmutase in human liver extracts
Morrow, G 3rd; Brodie, J D; Strimpler, A; Barness, L A
1973 Oct;8(2):240-248, Biochemical medicine
— id: 105388, year: 1973, vol: 8, page: 240, stat: Journal Article,

Proton magnetic resonance of vitamin B 12 derivatives. Functioning of B 12 coenzymes
Brodie, J D; Poe, M
1972 Jun 20;11(13):2534-2542, Biochemistry
— id: 105389, year: 1972, vol: 11, page: 2534, stat: Journal Article,

Proton magnetic resonance studies of vitamin B12. Proton magnetic resonance spectra of some cobalamins and cobinamides
Brodie, J D; Poe, M
1971 Mar 2;10(5):914-922, Biochemistry
— id: 132254, year: 1971, vol: 10, page: 914, stat: Journal Article,

Mechanism of mammalian cobalamin-dependent methionine biosynthesis
Burke, G T; Mangum, J H; Brodie, J D
1971 Aug 3;10(16):3079-3085, Biochemistry
— id: 132255, year: 1971, vol: 10, page: 3079, stat: Journal Article,

Metabolism and enzymology of fluorosuccinic acids. I. Interactions with the succinate oxidase system
Brodie, J D; Nicholls, P
1970 Mar 18;198(3):423-437, Biochimica & biophysica acta
— id: 105391, year: 1970, vol: 198, page: 423, stat: Journal Article,

Methylcobalamin as an intermediate in mammalian methionine biosynthesis
Burke, G T; Mangum, J H; Brodie, J D
1970 Oct 27;9(22):4297-4302, Biochemistry
— id: 105392, year: 1970, vol: 9, page: 4297, stat: Journal Article,

Metabolism and enzymology of flurosuccinic acids. II. Substrate and inhibitor effects with soluble succinate dehydrogenase
Tober, C L; Nicholls, P; Brodie, J D
1970 Jun;138(2):506-514, Archives of biochemistry & biophysics. ABB
— id: 132256, year: 1970, vol: 138, page: 506, stat: Journal Article,

On the mechanism of catalysis by vitamin B12
Brodie, J D
1969 Feb;62(2):461-467, Proceedings of the National Academy of Sciences of the United States of America
The requirements for alkylation and binding of nitrogenous ligands to cobalamins and cobinamides suggest that the central cobalt atom can exist either approximately in the plane of the corrin or axially displaced above this plane. Distortion of the normal octahedral complex by axial displacement results when the dimethylbenzimidazole moiety of the coenzyme is prevented from coordinating with the cobalt. A general hypothesis of B(12) coenzyme catalysis that involves the potential of Co(III)-R([unk]) and Co(I)-R([unk]) transitions is proposed on the basis of these considerations
— id: 105390, year: 1969, vol: 62, page: 461, stat: Journal Article,

Enzymatic and metabolic behavior of fluorosuccinic acids
Brodie, J D; Nicholls, P
1968 Sep 30;32(6):1071-1077, Biochemical & biophysical research communications
— id: 105393, year: 1968, vol: 32, page: 1071, stat: Journal Article,

Origin of photolabile methyl groups in methionine biosynthesis
Brodie, J D
1967 Feb 8;26(3):261-264, Biochemical & biophysical research communications
— id: 105394, year: 1967, vol: 26, page: 261, stat: Journal Article,

Interrelationship of adenosyl methionine and methyl-B12 in the biosynthesis of methionine
Kerwar, S S; Mangum, J H; Scrimgeour, K G; Brodie, J D; Huennekens, F M
1966 Sep 26;116(1):305-318, Archives of biochemistry & biophysics. ABB
— id: 132257, year: 1966, vol: 116, page: 305, stat: Journal Article,

ENZYME-BOUND INTERMEDIATES IN THE BIOSYNTHESIS OF MEVALONIC AND PALMITIC AICDS
BRODIE, J D; WASSON, G; PORTER, J W
1964 May;239:1346-1356, Journal of biological chemistry
— id: 105387, year: 1964, vol: 239, page: 1346, stat: Journal Article,

The formation of malonyl-enzyme and its conversion to fatty acids and beta-hydroxy, beta-methyl glutaryl coenzyme A
BRODIE, J D; WASSON, G W; PORTER, J W
1963 Jul 10;12:27-33, Biochemical & biophysical research communications
— id: 105386, year: 1963, vol: 12, page: 27, stat: Journal Article,

The participation of malonyl coenzyme A in the biosynthesis of mevalonic acid
BRODIE, J D; WASSON, G; PORTER, J W
1963 Apr;238:1294-1301, Journal of biological chemistry
— id: 105385, year: 1963, vol: 238, page: 1294, stat: Journal Article,

MALONYL COA - A NEW INTERMEDIATE IN FORMATION OF MEVALONIC ACID
BRODIE, JD; PORTER, JW; WASSON, GW
1962 ;8(1-2):76-&, Biochemical & biophysical research communications
— id: 105404, year: 1962, vol: 8, page: 76, stat: Journal Article,

STUDIES ON A MEVALDIC ACID REDUCTASE OF RAT LIVER
KNAUSS, HJ; BRODIE, JD; PORTER, JW
1962 ;3(2):197-&, Journal of lipid research
— id: 105403, year: 1962, vol: 3, page: 197, stat: Journal Article,

THE SYNTHESIS OF MEVALONIC ACID BY NON-PARTICULATE AVIAN AND MAMMALIAN ENZYME SYSTEMS
BRODIE, J; PORTER, JW
1960 ;3(2):173-177, Biochemical & biophysical research communications
— id: 105405, year: 1960, vol: 3, page: 173, stat: Journal Article,