GABAergic compounds for treating drug addiction: Preclinical models

点击翻译按钮获取中文摘要

During the period 01 Oct 09 to 30 Sept 10, significant progress was made on this research project. 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. During the present reporting period, 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 uinderstanding 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 current findings (together with our previous 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 previous extensive findings with gamma-vinyl-GABA in a very wide variety of addiction-related preclinical animal models, the present 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.