Suppression of ethanol-reinforced behavior by naltrexone is associated with attenuation of the ethanol-induced increase in dialysate dopamine levels in the nucleus accumbens

The opiate antagonist naltrexone suppresses ethanol-reinforced behavior in animals and decreases ethanol intake in humans. However, the mechanisms und erlying these actions are not well understood. Experiments were designed to test the hypothesis that naltrexone attenuates the rewarding properties of ethanol by interfering with ethanol-induced stimulation of dopamine activi ty in the nucleus accumbens (NAcc). Simultaneous measures of the effects of naltrexone on dialysate dopamine levels in the NAcc and on operant respond ing for oral ethanol were used. Male Wistar rats were trained to self-admin ister ethanol (10-15%, w/v) in 0.2% (w/v) saccharin during daily 30 min ses sions and were surgically prepared for intracranial microdialysis. Experime nts began after reliable self-administration was established. Rats were inj ected with naltrexone (0.25 mg/kg, s.c.) or saline and 10 min later were pl aced inside the operant chamber for a 20 min waiting period with no ethanol available, followed by 30 min of access to ethanol. A transient rise in di alysate dopamine levels was observed during the waiting period, and this ef fect was not altered by naltrexone. Ethanol self-administration reliably in creased dopamine levels in controls. Naltrexone significantly suppressed et hanol self-administration and prevented ethanol-induced increases in dialys ate dopamine levels. Subsequent dose-effect analyses established that the l atter effect was not merely a function of reduced ethanol intake but that n altrexone attenuated the efficacy of ethanol to elevate dialysate dopamine levels. These results suggest that suppression of ethanol self-administrati on by opiate antagonists is the result of interference with dopamine-depend ent aspects of ethanol reinforcement, although possible additional effects via nondopaminergic mechanisms cannot be eliminated as a factor in opiate a ntagonist-induced reduction of ethanol intake.