The ADH2*2 allele represents a functional polymorphism encoding an enzyme of enhanced catalytic activity, leading presumably to a more rapid metabolism of ethanol and transient accumulation of acetaldehyde. It is this transient and aversive effect of acetaldehyde that is thought to confer a dose dependent protective effect by limiting the amount of ethanol ingested, but their protective effects against alcohol abuse and dependence are thought to be subtler than those of ALDH2 variants and are poorly understood. However, this exclusively pharmacokinetic mechanism of genetic protection from alcoholism has not been directly confirmed and has been recently challenged. ALDH2*2 heterozygotes and homozygotes did exhibit an enhanced reactivity to ethanol, but primarily for positive rather than negative attributes of intoxication. We propose that genetically conferred protection for the ADH2*2 alleles is conferred at a pharmacodynamic rather than pharmacokinetic level. Specifically, we propose that the association of ADH2*2 alleles and drinking behavior is expressed as individual differences in positive and negative experiences to ethanol and their neural correlates, but not blood ethanol or acetaldehyde concentration. It is proposed further that these acetaldehyde-independent non-reinforcing or negatively reinforcing experiences decrease motivations for future ethanol ingestion, thereby decreasing risk for alcohol-related problems. Functional brain imaging approaches offer the unique opportunity to define objectively the distributed neural processing related to the psychopharmacometrics of ethanol and thus provide a potentially powerful and novel endophenotype for exploring the genetics of risk for alcoholism.
