The efficacy of a low dose combination of topiramate and naltrexone on ethanol reinforcement and consumption in rat models

Abstract

Rationale Combined medication approaches, by targeting multiple neurotransmitter systems involved in alcohol use disorders (AUDs), may be more efficacious than single-medication approaches. Objectives We examined, in animals models of consumption and reinforcement, the combined effects of naltrexone (an opioid antagonist) and topiramate (a GABA/glutamate modulator), two medications that have shown promise for treating AUDs, hypothesizing that their combination would be more efficacious than either alone. Methods The effects of naltrexone and topiramate on ethanol consumption were examined in alcohol preferring (P) rats (N=10) and in rats from their background strain (Wistar, N=9) using conditions that induce high levels of consumption (24-hr, 3-bottle, free-choice procedure). Low doses of each medication (1 mg/kg, naltrexone; 10 mg/kg, topiramate) were selected in an attempt to maximize their combined efficacy while minimizing potential side-effects. Their effects on ethanol reinforcement were assessed under a progressive-ratio schedule in additional groups of (N=22) P rats. A moderate dose of topiramate (20 mg/kg) was also included to verify topiramate’s efficacy on its own. Results In P rats, but not Wistar rats, the combination effectively and persistently reduced consumption; whereas, neither dose alone was effective. The combination and naltrexone alone were equally effective at reducing ethanol reinforcement; however, with the combination, but not naltrexone alone, this effect was selective for ethanol. All treatments produced a similar decrease in home-cage food consumption. The 20 mg/kg dose of topiramate also effectively reduced ethanol consumption and reinforcement. Conclusions With greater efficacy and fewer side-effects, the combination shows promise as a treatment for AUDs.

Alcohol preferring (P) rats as a model for examining sex differences in alcohol use disorder and its treatment

“…All compounds were dissolved in 0.9% sodium chloride and sterile water. Doses of naltrexone (1 mg/kg) and topiramate (10, 20 g/kg) were chosen based on previous studies demonstrating the ability of these doses to reduce ethanol consumption/reinforcement in male P rats (Lynch et al 2011; Moore et al 2014). …”

“…Sex differences in ethanol consumption were examined under prolonged 24-hr / day access as previously described (Moore et al 2014). Briefly, all animals were given access to two concentrations of ethanol solution (8 and 16% v/v) along with the bottle containing water.…”

“…Ethanol’s reinforcing effects were examined in males and females ( n ’s=23; 1 male and 1 female were lost to health complications) following the ethanol consumption period under a FR1 schedule as described previously (Moore et al 2014). Briefly, ethanol was removed from the home cages and rats were trained to self-administer 10% v/v ethanol in operant testing chambers 6 days/week.…”

“…Once responding stabilized under FR1 conditions (defined as variation less than 20% over three consecutive days), animals were placed on a PR schedule to measure motivation to obtain 0.1 ml deliveries of 10% v/v ethanol using methods previously described (Moore et al 2014). With this schedule, animals must respond for deliveries of ethanol and water at higher levels for each subsequent delivery in the following steps: 1, 2, 4, 6, 9, 12, 15, 20, 25, 32, etc.…”

“…Finally, we were interested in the effects of two pharmacological treatments for AUDs, naltrexone and topiramate, on the reinforcing effects of ethanol as these have shown promise in treating AUDs in humans, but whether their efficacy varies based on sex/gender is still unclear. We have shown previously that the combination of topiramate and naltrexone, as well as a 20 mg/kg dose of topiramate alone decreases ethanol consumption in males ( Moore et al 2014 ), potentially through decreasing ethanol’s reinforcing effects. Following baseline responding for ethanol, these medications, alone and in combination, were tested for sex-specific differences in reducing ethanol’s reinforcing effects as assessed under a PR schedule.…”