Effects of naltrexone and Ro 15-4513 on a multiple schedule of ethanol and Tang self-administration

Background: Both the opioid antagonist, naltrexone, and GABA_A/benzodiazepine-site negative modulator, Ro 15-4513, decrease ethanol self-administration in rodents and nonhuman primates. However, the selectivity of these drugs for decreasing ethanol self-administration relative to reducing responding maintained by other reinforcers in primates is not clear. The present study used a multiple schedule self-administration procedure in cynomolgus monkeys to examine the selectivity of naltrexone and Ro 15-4513 for reducing ethanol self-administration relative to an orange flavored sugar-free sweetened solution (Sugar-free Tang). Methods: Six adult cynomolgus monkeys were trained to self-administer 4% (w/v) ethanol and 4% or 6% (w/v) Tang under a multiple schedule of liquid access. The effect of acute administration of naltrexone (0.1, 0.3, 1, 3 mg/kg) was examined. The effect of 15 days of chronic, 1 mg/kg naltrexone on ethanol and Tang self-administration was then examined in four monkeys. Acute administration of Ro 15-4513 (0.01, 0.03, 0.1, 0.3 mg/kg) as well as 15 days of chronic administration of 0.1 mg/kg Ro 15-4513 was also examined in four monkeys. Results: Ethanol and Tang were self-administered at similar volumes and patterns under baseline conditions. Acute naltrexone administration significantly decreased total session ethanol and Tang intake as well as the number and volume of ethanol and Tang drinks. Chronic naltrexone also significantly decreased ethanol and Tang intake. Ethanol, but not Tang, drink volume was significantly decreased by chronic 1 mg/kg naltrexone pretreatment. The number of ethanol and Tang drinks and drink duration were not significantly decreased by chronic naltrexone. Acute Ro 15-4513 pretreatment significantly decreased ethanol and Tang intake, mean drinks and median drink duration. Chronic 0.1 mg/kg Ro 15-4513 pretreatment significantly decreased total ethanol intake only during the first week of pretreatment, but it significantly decreased Tang intake for all 3 pretreatment weeks. Conclusions: Similar to rodent studies, acute and chronic naltrexone and Ro 15-4513 reduced ethanol and Tang intake in cynomolgus monkeys. However, unlike rodent studies, neither drug showed selectivity for reducing ethanol intake compared with a comparison reinforcer. These differences highlight the need for testing putative ethanol abuse treatment drugs under diverse conditions and multiple species before undertaking human clinical trials.