Inhibition of Aldehyde Dehydrogenase-2 (ALDH-2) Suppresses Nicotine Self-Administration in Rats

Introduction. Aldehyde dehydrogenase-2 (ALDH-2) inhibitors have been shown to reduce cocaine and alcohol intake in rats. The mechanism of action appears to be due to inhibition of drug-induced dopamine (DA) production in the ventral tegmental area (VTA) and DA release in the nucleus accumbens. The purpose of this study was to explore the potential of a selective ALDH-2 inhibitor to reduce self-administration of nicotine. Materials and methods. Adult male rats were trained to self-administer nicotine intravenously. After acquiring a stable baseline for nicotine intake, rats were given one of the three oral gavage doses (5, 10 or 30 mg eq/kg, calculated based on parent drug) of the prodrug GS-6637 of an ALDH-2 inhibitor or vehicle one hour before a nicotine self-administration session. Results. Our data showed that acute administration of GS-6637 at 10 mg eq/kg and 30 mg eq/kg significantly reduced nicotine self-administration. Similarly, subchronic administration of GS-6637 for seven days significantly reduced nicotine self-administration at 10 mg eq/kg and 30 mg eq/kg without inducing tolerance. In order to compare GS-6637 with varenicline, rats were given single doses of varenicline at 1.6, 3.2, and 6.4 mg/kg. Consistent with previous reports, significant inhibitions of nicotine self-administration was observed at the 3.2 mg/kg and 6.4 mg/kg doses but less than observed with GS-6637. Discussion and conclusions. Our data suggest that selective ALDH-2 inhibition appears to have therapeutic potentials as novel therapy for smoking cessation.