Severity of drinking as a predictor of efficacy of the combination of ondansetron and topiramate in rat models of ethanol consumption and relapse

Rationale Alcohol dependence is the third leading cause of preventable death in the USA. While single-agent pharmacotherapies have variable efficacy, medication combinations may produce additive effects by modulating multiple neural pathways. Objectives Here, we examined in animal models of ethanol consumption and relapse the combined effects of ondansetron (a serotonin-3 antagonist) and topiramate (a GABA/ glutamate modulator), two medications with demonstrated efficacy for treating alcohol dependence, hypothesizing that their combination would produce a more efficacious response. Methods The effects of acutely administered ondansetron (0-0.01 mg/kg) and topiramate (0-10 mg/kg) alone and in combination on ethanol consumption were examined in alcohol preferring (P) rats (N=20) and in rats from their background strain (Wistars, N=20) using a 24-h access free-choice paradigm. Next, we examined their ability to prevent an increase in ethanol consumption following a deprivation period (i.e., an animal model of relapse). Results Whether administered alone or combined with ondansetron, topiramate produced a similar modest but persistent reduction in ethanol consumption. However, an analysis of efficacy by drinking level revealed that the combination was superior to topiramate alone in heavydrinking P rats, but was without effect in lighter-drinking P rats and Wistar rats. Both topiramate alone and the combination blocked the alcohol deprivation effect in both Wistar and P rats with the combination tending to produce a greater decrease than topiramate alone. Conclusions The combination of ondansetron and topiramate may be a promising treatment for preventing relapse and for treating alcohol dependence in heavy-, but not lighter-drinkers.