Effect of selective blockade of mu(1) or delta opioid receptors on reinstatement of alcohol-seeking behavior by drug-associated stimuli in rats

Abstract

This study examined the effects of a nonselective opiate antagonist and antagonists selective for the mu(1) versus delta opioid receptor on ethanol-seeking behavior induced by alcohol-related environmental stimuli in an animal model of relapse. Rats were trained to self-administer ethanol (10% w/v) or water on an FR 1 schedule in 30-min daily sessions. The availability of ethanol was signaled by an olfactory discriminative stimulus (S(+)). A different olfactory stimulus (S(-)) signaled water availability. In addition, each lever-response resulting in delivery of ethanol was paired with illumination of a visual cue for 5 s (SC(+)), whereas a 5-s white noise (SC(-)) was associated with water. The rats were then subjected to a 20-day extinction phase where lever presses had no programmed consequences. Reexposure to the S(+)/CS(+) stimulus condition in the absence of further ethanol availability elicited strong recovery of responding. No effect was observed following presentation of S(-)/CS(-). Subsequently, ethanol-seeking behavior associated with the S(+)/CS(+) stimulus condition was studied in rats treated with the nonselective opiate antagonist naltrexone (0.25-1 mg/kg, SC), the delta selective antagonist naltrindole (1-5 mg/kg, IP), and the mu(1) selective antagonist naloxonazine (1-15 mg/kg, IP). Naltrexone (1 mg/kg) and naltrindole (5 mg/kg) selectively inhibited alcohol-seeking behavior. Naloxonazine (15 mg/kg) also reduced ethanol-seeking behavior but produced some nonselective behavioral suppression as well. The results provide evidence that selective blockade of either mu(1) or delta opioid receptors inhibits ethanol-seeking behavior elicited by drug-related environmental stimuli. Moreover, the data suggest that drugs aimed at the delta opioid receptor may offer advantages in the treatment and prevention of relapse compared with agents that also block the mu(1) receptor.