Serotonin‐Ethanol Interactions and the Pharmacotherapy of Alcoholism

Serotonin (5‐HT) reuptake inhibitors have been reported to reduce ethanol consumption in rats and humans. Because of the potential therapeutic value of this effect, it is useful to examine the possible mechanisms underlying it. 5‐HT neurons project to almost every part of the neuraxis and affect almost all its functions. Therefore 5‐HT agonists could theoretically decrease ethanol intake by: (1) their anorexiant effect on non‐protein calorie sources, (2) stimulation of perferential water intake, (3) reduction of ethanol preference by central angiotensin mechanisms, (4) attenuation of anxiolytic or other reinforcing effects of ethanol, (5) increased aversiveness of ethanol, (6) facilitation of tolerance to the reinforcing effects of ethanol. Conversely, it is possible that ethanol alters the turnover or receptor binding of 5‐HT in some way that results in aversive effects. Evidence for and against these possibilities is discussed. Serotonin does have aversive effects, as revealed by conditioned aversion to novel tastes paired with 5‐HTP, and the aversion is greater when 5‐HTP is paired with ethanol than with other tastes. However, it is not yet clear that 5‐HT is actually involved in the anti‐alcohol effects of various 5‐HT reuptake inhibitors. In humans, zimelidine increased the number of alcohol‐free days during a clinical trial but did not reduce the mean daily consumption. It appears to prolong the latency to initiate drinking, but not to decrease the rate when drinking starts. Major advances in pharmacotherapy of alcoholism will probably arise from a better understanding of the neurobiology of reinforcement by alcohol.