Jonathan D. Brodie

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 with 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 gray, were noted. However, compared with 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 with 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, whereas 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, whereas these posttreatment sex differences contribute to clinical treatment failure more commonly experienced by the former.

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.

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 (γ-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.

Positron emission tomography studies in drug-addicted patients have shown that exposure to drug-related cues increases striatal dopamine, which displaces binding of the D₂ligand, [¹¹C]-raclopride. However, it is not known if animals will also show cue-induced displacement of [¹¹C]-raclopride binding. In this study, we use [¹¹C]-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 [¹¹C]-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. [¹¹C]-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 [¹¹C]-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 [¹¹C]-raclopride binding correlated with preference in the ventral striatum (R²= −0.87;p= 0.003). In this region, animals who showed little or no preference exhibited little or no change in [¹¹C]-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.

Preventing relapse poses a significant challenge to the successful management of methamphetamine (METH) dependence. Although no effective medication currently exists for its treatment, racemic γ 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. Synapse 63:87–94, 2009.

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. Synapse 62:870–872, 2008.

Brain imaging is one of the most remarkable technological advances towards understanding the relationship of behavior to brain anatomy and physiology. Brain images provide insight to understanding behavior. Additionally, the images themselves carry great impact, particularly when used to show differences in either the anatomy or the biological functioning of two different brains. For these reasons, brain images have increasingly been used in both criminal and civil trials.After describing some general features of brain imaging, we will focus on functional magnetic imaging (fMRI), as many believe this technology has the most potential for advancing our understanding of how parts of the brain function, including perhaps linking specific functions with cognition and behavior. Brain imaging as a field is vast and therefore our discussion will be limited. First, we will assess the advantages and limitations of fMRI, including research efforts towards standardizing equipment thereby assuring reliability and reproducibility.

Research from JAMA Ophthalmology — Short-term Treatment of Cocaine and/or Methamphetamine Abuse With Vigabatrin — Ocular Safety Pilot Results

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, ¹⁸FDG, 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 ¹⁸FDG 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 ¹⁸FDG 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 ¹⁸FDG 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.