Selective serotonin reuptake inhibitors: effects of chronic treatment on ethanol-reinforced behavior in mice

Several lines of evidence suggest that aspects of ethanol drinking are mediated, at least in part, by serotonergic (5-HT) neurotransmitter systems. Ethanol-preferring animals show decreases in serotonin function and receptor densities. In addition, serotonin uptake inhibitors have been shown to decrease ethanol consumption in animal models and in humans. However, the time course of these effects and their duration remain undetermined. In the present studies, C57BL/6J male mice were treated with one of three selective 5-HT reuptake inhibitors (SSRIs): fluoxetine, sertraline, or paroxetine. All three drugs produced initial decreases in operant lever pressing behavior for ethanol followed by a return to baseline on subsequent days. Immediately following 14 days of this initial treatment, subsequent treatment with higher SSRI doses was ineffective in decreasing ethanol-reinforced behavior. However, after a several week "washout period," SSRI pretreatment again produced an initial decrease in responding for ethanol, again followed by a return to baseline. Thus, suppression of ethanol drinking may be related to immediate changes in 5-HT function following treatment with SSRIs, and tolerance to this effect appears to develop rapidly.