GABAergic compounds for treating drug addiction: Preclinical models

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During the period 01 Oct 07 to 30 Sept 08, significant progress was made on this research project. We 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 interpret these findings to suggest that: 1) gamma-vinyl-GABA significantly inhibits cocaine- or sucrose-triggered relapse to reward-seeking behavior; and 2) a GABAergic-, but not dopaminergic-, dependent brain mechanism underlies the antagonism by gamma-vinyl-GABA of cocaine-triggered reinstatement of drug-seeking behavior, at least with respect to gamma-vinyl-GABA's action(s) within the nucleus accumbens. In contrast to gamma-vinyl-GABA, systemic administration of gabapentin (another putative GABAmimetic compound claimed in some previous reports from other research groups to have anti-cocaine-addiction properties) was found to have no effect on cocaine-triggered relapse to cocaine-seeking behavior. Gabapentin also failed to alter intarvenous cocaine self-administration under fixed-ratio reinforcement in laboratory rats. In vivo brain microdialysis experiments showed that gabapentin produces a modest (50%) increase in extracellular GABA levels in the nucleus accumbens, but fails to alter either basal or cocaine-enhanced dopamine levels in the nucleus accumbens. 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. However, gabapentin appears to lack significant anti-addiction, anti-craving, or anti-relapse efficacy.