Some of the polymorphisms associated with vulnerability for the binge/intoxication stage interfere with drug metabolism. For example, specific alleles for genes that encode alcohol dehydrogenase (ADH1B) and acetaldehyde dehydrogenase (ALDH2; enzymes involved in the metabolism of alcohol) are reportedly protective against alcoholism.160 Intriguingly, an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1) has been identified in the ventral tegmental area.161 GABA co-release is modulated by binge-like doses of alcohol administered to mice, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. Similarly, polymorphisms in the genes for cytochrome P450 2A6 and 2D6 (enzymes involved in nicotine and opioid metabolism, respectively) are reportedly protective against nicotine addiction.162
