CLINICAL PHARMACOLOGY OF ETHANOL
Alcohol is the cause of more preventable morbidity and mortality than all other drugs combined with the exception of tobacco. The search for specific etiologic factors or the identification of significantpredisposing variables for alcohol abuse has generally led to disap-pointing results. Personality type, severe life stresses, psychiatric disorders, and parental role models are not reliable predictors of alcohol abuse. Although environmental factors clearly play a role, evidence suggests that there is a large genetic contribution to the development of alcoholism. Not surprisingly, polymorphisms in alcohol dehydrogenase and aldehyde dehydrogenase that lead to increased aldehyde accumulation and its associated facial flushing, nausea, and hypotension appear to protect against alcoholism. Much attention in genetic mapping experiments has focused on membrane-signaling proteins known to be affected by ethanol and on protein constituents of reward pathways in the brain. Polymorphisms associated with a relative insensitivity to alcohol and presumably thereby a greater risk of alcohol abuse have been identified in genes encoding an α subunit of the GABAA receptor, an M2 muscarinic receptor, a serotonin transporter, adenylyl cyclase, and a potassium channel. The link between a polymor-phism in an opioid receptor gene and a blunted response to naltrexone raises the possibility of genotype-guided pharmaco-therapy for alcohol dependence.