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 heavy-drinking 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.