Conditioned effects produced by naltrexone doses that reduce ethanol-reinforced responding in rhesus monkeys

Clinical trials have shown that naltrexone is effective in treating alcohol dependence; nausea and dysphoria have been reported as "side effects" in many of these studies. In primates, naltrexone reduces reinforced responding for oral ethanol, sucrose, and phencyclidine. This study was designed to determine if naltrexone reduces reinforced responding for various solutions by producing an interoceptive stimulus that may result in a conditioned taste aversion. Four opioid antagonist-naive rhesus monkeys responded for solutions from a two-spout operant panel for 30 min per day. During a conditioning phase, the monkeys received novel Kool-Aid solutions paired with either saline or naltrexone (0.32 mg/kg) given 30 min before the session. The monkeys then had seven choice sessions between the saline-paired solution or the naltrexone-paired solution. During the conditioning phase, the naltrexone reduced responding after five naltrexone/solution pairings. In addition, a conditioned taste aversion was produced; the naltrexone-paired solution maintained significantly less responding than did the saline-paired solution during the choice phase. In the next phase, the saline and naltrexone were given "unpaired" from any distinct part of the operant session, and another seven choice sessions followed. Naltrexone had no effect when given "unpaired" from the operant session. Then, another conditioning phase was undertaken followed by another series of choice sessions. During the replication of the conditioning, naltrexone reduced responding by the second pairing, although no conditioned aversion was observed in the subsequent choice sessions. Thus, given in the same manner (dose, route, and pretreatment time) as situations in which naltrexone reduces oral ethanol-, sucrose-, and phencyclidine-reinforced responding, naltrexone produced a conditioned taste aversion. These results suggest that naltrexone-induced nausea and its conditioned effects should be considered in naltrexone's effect in alcoholics.