A pharmacologic strategy for the treatment of nicotine addiction

Like many psychostimulant drugs, nicotine elevates extracellular and synapt ic dopamine (DA) concentrations in the nucleus accumbens (NAc). This elevat ion has been linked to its reinforcing properties. Dopaminergic transmissio n within the NAc is modulated by gamma-aminobutyric acid (GABA). Therefore, we examined the utility of gamma vinyl-GABA (GVG, Vigabatrin) for inhibiti ng nicotine's biochemical effects on NAc DA as well as its effects on behav iors associated with these biochemical changes. Given 2.5 hours prior to ni cotine, GVG (75 mg/kg) had no effect on nicotine-induced increases in extra cellular NAc DA. However, at 90 mg/kg, GVG significantly inhibited nicotine -induced increases by approximately 50% while at 100 or 150 mg/kg, GVG comp letely abolished nicotine-induced increases in both naive and chronically n icotine-treated animals, When given 12 or 24 hours prior to nicotine admini stration at a dose of 100 mg/kg, GVG-induced inhibition was diminished or a bolished, respectively. In addition, at a dose of 18.15 mg/kg GVG abolished the expression of nicotine-induced conditioned place preference (CPP) whil e a dose of 75 mg/kg abolished the acquisition phase of CPP. Finally, using positron emission tomography (PET) and C-11-raclopride in primates, GVG (1 00 mg/kg) abolished nicotine-induced increases in synaptic DA while having no effect on the rate of metabolism of the radiotracer or its regional dist ribution. Together, these data suggest that GVG may be useful for the treat ment of nicotine addiction and further support the strategy of targeting th e GABAergic system with a suicide inhibitor of GABA-transaminase for the tr eatment of drug addiction. Synapse 31:76-86, 1999. (C) 1999 Wiley-Liss, Inc .