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Sex Differences in Regional Brain Glucose Metabolism Following Opioid Withdrawal and Replacement

Santoro, Giovanni C; Carrion, Joseph; Patel, Krishna; Vilchez, Crystal; Veith, Jennifer; Brodie, Jonathan D; Dewey, Stephen L
Methadone and buprenorphine are currently the most common pharmacological treatments for opioid dependence. Interestingly, the clinical response to these drugs appears to be sex-specific. That is, females exhibit superior therapeutic efficacy, defined as extended periods of abstinence and longer time to relapse, compared to males. However, the underlying metabolic effects of opioid withdrawal and replacement have not been examined. Therefore, using 18FDG and microPET, we measured differences in regional brain glucose metabolism in males and females following morphine withdrawal and subsequent methadone or buprenorphine replacement. In both males and females, spontaneous opioid withdrawal altered glucose metabolism in regions associated with reward and drug dependence. Specifically, metabolic increases in the thalamus, as well as metabolic decreases in insular cortex and the periaqueductal grey were noted. However, compared to males, females exhibited increased metabolism in the preoptic area, primary motor cortex, and the amygdala, and decreased metabolism in the caudate/putamen and medial geniculate nucleus. Methadone and buprenorphine initially abolished these changes uniformly, but subsequently produced their own regional metabolic alterations that varied by treatment and sex. Compared to sex-matched control animals undergoing spontaneous opioid withdrawal, male animals treated with methadone exhibited increased caudate/putamen metabolism, whereas buprenorphine produced increased ventral striatum and motor cortex metabolism in females, and increased ventral striatum and somatosensory cortex metabolism in males. Notably, when treatment effects were compared between sexes, methadone-treated females showed increased cingulate cortex metabolism, while buprenorphine-treated females showed decreased metabolism in cingulate cortex and increased metabolism in the globus pallidus. Perhaps the initial similarities in males and females underlie early therapeutic efficacy, while these post-treatment sex differences contribute to clinical treatment failure more commonly experienced by the former.Neuropsychopharmacology accepted article preview online, 10 April 2017. doi:10.1038/npp.2017.69.
PMID: 28393895
ISSN: 1740-634x
CID: 2528102

A Novel Strategy for Attenuating Opioid Withdrawal in Neonates

Santoro, Giovanni C; Shukla, Samarth; Patel, Krishna; Kaczmarzyk, Jakub; Agorastos, Stergiani; Scherrer, Sandra; Choi, Yoon Young; Veith, Christina; Carrion, Joseph; Silverman, Rebecca; Mullin, Danielle; Ahmed, Mohamed; Schiffer, Wynne K; Brodie, Jonathan D; Dewey, Stephen L
The rate of Neonatal Abstinence Syndrome (NAS) has drastically increased over the past decade. The average hospital expense per NAS patient has tripled, while the number of babies born to opioid-dependent mothers has increased to 5 in 1000 births. Current treatment options are limited to opioid replacement and tapering. Consequently, we examined the efficacy of prenatal, low-dose and short-term vigabatrin (gamma-vinyl GABA, GVG) exposure for attenuating these symptoms as well as the metabolic changes observed in the brains of these animals upon reaching adolescence. Pregnant Sprague-Dawley rats were treated in one of four ways: 1) saline; 2) morphine alone; 3) morphine+GVG at 25 mg/kg; 4) morphine+GVG at 50 mg/kg. Morphine was administered throughout gestation, while GVG administration occurred only during the last 5 days of gestation. On post-natal day 1, naloxone-induced withdrawal behaviours were recorded in order to obtain a gross behaviour score. Approximately 28 days following birth, 18FDG microPET scans were obtained on these same animals (Groups 1, 2, and 4). Morphine-treated neonates demonstrated significantly higher withdrawal scores than saline controls. However, GVG at 50 but not 25 mg/kg/day significantly attenuated them. Upon reaching adolescence, morphine treated animals showed regionally specific changes in 18FDG uptake. Again, prenatal GVG exposure blocked them. These data demonstrate that low-dose, short-term prenatal GVG administration blocks naloxone-induced withdrawal in neonates. Taken together, these preliminary findings suggest that GVG may provide an alternative and long-lasting pharmacologic approach for the management of neonatal and adolescent symptoms associated with NAS.
PMID: 28078167
ISSN: 2155-6105
CID: 2400822

(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
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
PMID: 22128851
ISSN: 1520-4804
CID: 150262

Application of neuroimaging in relationship to competence to stand trial and insanity

Chapter by: Kolla, Nathan J; Brodie, Jonathan D
in: Neuroimaging in forensic psychiatry: From the clinic to the courtroom by Simpson, Joseph R [Eds]
[S.l.] : Wiley-Blackwell, 2012
pp. 147-162
ISBN: 978-0-470-97699-9
CID: 2160642

Integrating molecular imaging and behavioral neuroscience: Seeing animal models in a new light [Meeting Abstract]

Schiffer W.; Carrion J.; Eidelberg D.; Brodie J.D.
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 (<sup>11</sup>C-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)
ISSN: 1536-1632
CID: 119244

Randomized, Double-Blind, Placebo-Controlled Trial of Vigabatrin for the Treatment of Cocaine Dependence in Mexican Parolees [Case Report]

Brodie, Jonathan D; Case, Brady G; Figueroa, Emilia; Dewey, Stephen L; Robinson, James A; Wanderling, Joseph A; Laska, Eugene M
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
PMID: 19651710
ISSN: 1535-7228
CID: 101865

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
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
PMID: 19439595
ISSN: 1529-2401
CID: 109179

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
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
PMID: 19016239
ISSN: 1098-2396
CID: 95221

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
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
PMID: 18720383
ISSN: 1098-2396
CID: 95222

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
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
PMID: 18063319
ISSN: 0376-8716
CID: 76198