Aldehyde Dehydrogenase 2 Anti-Sense in the Ventral Tegmental Area Reduces Alcohol Drinking

Abstract

Background: We have reported that aldehyde dehydrogenase 2 (ALDH2) inhibitors suppress alcohol seeking and drinking in rats even in the absence of alcohol and acetaldehyde. These behavioural changes suggest that ALDH2 in brain could be a target for ANS-6637 inhibition to suppress alcohol seeking and drinking. Here we ask whether ALDH2-RNA anti-sense administered directly into the Ventral Tegmental Area (VTA) also reduces alcohol drinking. Methods: A recombinant adenoviral vector expressing rat AGS3 and specific RNA antisense against ALDH2 was injected into the VTA of actively drinking alcohol-preferring (iP) rats in a 2-bottle choice study with 10% alcohol (v/v) and water. Controls received scrambled RNA. Alcohol consumption was assayed before and after adenoviral injection. Histology confirmed cannulae implantation. Results: ALDH2 antisense microinjected in the VTA of alcohol-drinking iP rats reduces alcohol intake when compared with baseline drinking prior to antisense microinjection. Controls are unaffected. Reduction occurs between days 5 and 12 post-ALDH2 antisense microinjection with maximal effects on days 7 and 9 (31% from baseline). Rats recover baseline alcohol intake values by day 16. Conclusions: The major finding is that ALDH2 antisense in the VTA appears to reduce alcohol drinking. Consistent with previous results suggesting that ALDH2 inhibitors might reduce drinking by acting in the brain, this observation with ALDH2 antisense suggests that ALDH2 in the VTA may be an important target for pharmacologic ALDH2 inhibitors.