During the present reporting period, no progress was made on this research project due to extremely severe cuts in budget, personnel, and research resources. We had previously found that the gamma-aminobutyric acid (GABA) transaminase inhibitor gamma-vinyl-GABA (GVG, Vigabatrin) dose-dependently inhibits cocaine-triggered relapse to cocaine-seeking behavior in laboratory rats who have been pharmacologically detoxified and behaviorally extinguished from their prior cocaine-taking habits. We further found that gamma-vinyl-GABA also dose-dependently inhibits sucrose-induced reinstatement of reward-seeking behavior in rats. By using in vivo brain microdialysis, we additionally found that gamma-vinyl-GABA dose-dependently elevates extracellular GABA levels in the nucleus accumbens of the limbic forebrain. However, gamma-vinyl-GABA, when administered either systemically or locally into the nucleus accumbens, fails to inhibit either basal or cocaine-enhanced nucleus accumbens dopamine in either drug-naive rats or in cocaine-extinction rats. We additionally found that gamma-vinyl-GABA increases nonvesicular release of GABA and glutamate in the nucleus accumbens of laboratory rats via action on anion channels and on GABA transporters. This is an important discovery, as it points toward an understanding of the mechanism(s) by which gamma-vinyl-GABA may exert its anti-addiction effects. This is especially timely, as gamma-vinyl-GABA has now entered human clinical trials to assess its anti-addiction efficacy at the human level. We interpret our prior findings with gamma-vinyl-GABA to suggest that: 1) gamma-vinyl-GABA appears to possess significant anti-addiction efficacy;2) gamma-vinyl-GABA's mechanism(s) of action in the brain may differ significantly from those of other GABAmimetic compounds. This may well explain our previous findings that systemic administration of gabapentin (another putative GABAmimetic compound claimed in some previous reports from other research groups to have anti-cocaine-addiction properties) has no effect on cocaine-triggered relapse to cocaine-seeking behavior, that gabapentin also fails to alter intravenous cocaine self-administration under fixed-ratio reinforcement in laboratory rats, and that gabapentin fails to alter either basal or cocaine-enhanced dopamine levels in the nucleus accumbens as measured by in vivo brain microdialysis. When added to our prior extensive findings with gamma-vinyl-GABA in a very wide variety of addiction-related preclinical animal models, such findings suggest that gamma-vinyl-GABA may have anti-addiction, anti-craving, and anti-relapse efficacy in human drug addiction, and that it may differ significantly from other GABAmimetic drugs with respect to mechanism(s) of action in the brain. We are currently interested in obtaining and testing a new and novel GABA aminotransferase inhibitor - CPP-115 (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid, and negotiations to obtain this compound are in progress.
|Peng, Xiao-Qing; Gardner, Eliot L; Xi, Zheng-Xiong (2010) Gamma-vinyl GABA increases nonvesicular release of GABA and glutamate in the nucleus accumbens in rats via action on anion channels and GABA transporters. Psychopharmacology (Berl) 208:511-9|
|Xi, Zheng-xiong; Spiller, Krista; Gardner, Eliot L (2009) Mechanism-based medication development for the treatment of nicotine dependence. Acta Pharmacol Sin 30:723-39|
|Peng, Xiao-Qing; Li, Xia; Gilbert, Jeremy G et al. (2008) Gamma-vinyl GABA inhibits cocaine-triggered reinstatement of drug-seeking behavior in rats by a non-dopaminergic mechanism. Drug Alcohol Depend 97:216-25|
|Peng, Xiao-Qing; Li, Xia; Li, Jie et al. (2008) Effects of gabapentin on cocaine self-administration, cocaine-triggered relapse and cocaine-enhanced nucleus accumbens dopamine in rats. Drug Alcohol Depend 97:207-15|