Inhibition of aldehyde dehydrogenase-2 (ALDH-2)‎ suppresses nicotine self-administration in rats

Abstract EN

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 30mg 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 30mg eq/kg significantly reduced nicotine self-administration.

Similarly, subchronic administration of GS-6637 for seven days significantly reduced nicotine self-administration at 10mg 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 3.2mg/kg and 6.4mg/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.