Effects of naltrexone on cocaine and sucrose seeking behavior in response to associated stimuli in rats

The endogenous opioid system has been implicated in different aspects of dependence to non-opioid drugs of abuse. Recent reports have shown that the non-selective opioid antagonist naltrexone reduces cocaine-induced reinstatement of drug-seeking behavior in rats. Considering the hypothetical role of environmental stimuli associated with drug self-administration in the induction of drug-seeking behavior in abstinent subjects, the current study sought to determine whether opioid receptor activity is also involved in cocaine-seeking behavior induced by drug-associated stimuli in abstinent rats. Adult male rats were trained either to self-administer cocaine or to press a lever for sucrose pellets. Responses for either substance were differentially reinforced in the presence of a discriminative stimulus. Reinforcers were available under an FR1 schedule of reinforcement, and were followed by a response-cue signaling 20-s time-out (conditioned stimulus). After a period of extinction, re-exposure to cocaine-associated cues selectively elicited robust responding at the previously active lever, while sucrose-pellet-associated cues revived seeking-behavior but less markedly. Pre-treatment with naltrexone (0.25-1-2.5 mg/kg s.c., 20 min before reinstatement tests) dose-dependently attenuated cocaine-seeking behavior, compared to saline-treated subjects. The dose of 2.5 mg/kg naltrexone did not affect the degree of cues-induced sucrose-seeking behavior. These results provide evidence that naltrexone influences cocaine-seeking induced by conditioned stimuli; this effect seems selective for cocaine reinstatement as opposed to a non-drug reinforcer.