The naltrexone-ethanol interaction on oral-reinforced responding in rhesus monkeys.

Abstract

The opioid antagonist naltrexone (NTX) reduces ethanol drinking and responding for ethanol. In spite of reducing many consummatory behaviors, NTX has beneficial therapeutic effects on alcohol-dependent patients. NTX might act through the mu- or delta-opioid receptor to block the ethanol-induced opioid activity, reduce palatability, or cause an aversive interoceptive state. The purpose of these studies was to clarify the behavioral and receptor mechanisms by which NTX interacts with ethanol self-administration. In all experiments, rhesus monkeys had opportunities to respond for oral reinforcers from 2 spouts. Also, in Chapter 2, a separate group of monkeys responded for intravenous ethanol deliveries. NTX pretreatments (0.1-0.32 mg/kg) reduced responding for oral and intravenous deliveries of ethanol at many different concentrations or doses. The ethanol concentration- and dose-effect curves were shifted down which indicated an insurmountable antagonism of responding for ethanol. In addition, NTX was not selective for ethanol; NTX reduced responding for sucrose when offered concurrently with water. Opioid antagonists selective for the $\mu$-(clocinnamox), $\kappa$-(nor-binaltorphimine), or $\delta$-receptor (naltrindole) were given prior to operant sessions wherein oral ethanol and water were available. At doses that were behaviorally active in other assays, these receptor selective antagonist failed to reduce responding for ethanol in a manner that would suggest involvement of the $\mu$-, $\kappa$-, or $\delta$-receptor. Exploring the environmental determinants for NTX's ethanol-selective effects, we tested NTX at different ethanol concentrations where responding for ethanol was less than (at 32% ethanol), greater than (at 2% ethanol), or equal to (at 8% ethanol) responding for the concurrently available water. NTX reduced responding for whichever fluid maintained the greater amount of fluid deliveries. Because NTX's selectivity for ethanol depended upon experimental conditions, we hypothesized that NTX reduces responding for oral reinforcers by inducing an aversive interoceptive state. In the final experiment, NTX, at the same dose and pretreatment time as the previous experiments, was given to opioid naive monkeys prior to access to novel Kool-Aid$\sp\circler$ solutions. Under these conditions, NTX produced a conditioned taste aversion. The results of these experiments indicate that NTX may reduce ethanol-reinforced responding by inducing an aversive interoceptive state, rather than by blocking ethanol-induced opioid activity or affecting palatability.