m-Opioid Receptor Knockout Mice Do Not Self-Administer Alcohol

Opioid peptides long have been hypothesized to play a role in ethanol reinforcement. Neuropharmacological studies have shown that opioid receptor antagonists decrease ethanol selfadministration in rodents and prevent relapse in humans. However, the exact mechanism for such powerful effects has remained elusive. The availability of m-opioid receptor knockout mice has made possible the direct examination of the role of the m-opioid receptor in mediating ethanol self-administration. In the present experiments, both nosepoke and lever operant ethanol self-administration and several tests of two bottlechoice ethanol drinking were studied in these genetically engineered mice. In no case did knockout mice show evidence of ethanol self-administration, and, in fact, these mice showed evidence of an aversion to ethanol under several experimental conditions. These data provide new evidence for a critical role for m-opioid receptors in ethanol self-administration assessed with a variety of behavioral paradigms and new insights into the neuropharmacological basis for ethanol reinforcement. Opioid peptides acting via the m-opioid receptor have been implicated in the reinforcing effects of ethanol (Froehlich, 1995; Ulm et al., 1995; Herz, 1997). Evidence for this implication has come from both correlational and pharmacological studies. In the correlational approach, opioid peptide levels and opioid receptor levels are compared between strains or lines of rodents differing in their ethanol intake. m-Opioid receptor densities have been shown to be higher in ethanolpreferring strains in brain regions such as the extended amygdala postulated to mediate the rewarding effects of drugs of abuse. For example, densities of m-receptors were higher in the alcohol-preferring AA rats relative to their nonpreferring ANA counterparts in the nucleus accumbens (shell region) and ventral tegmental area (de Waele et al., 1995; Soini et al., 1999). The alcohol-preferring P rats had a greater number of m-opioid recognition sites in the nucleus accumbens and amygdaloid nuclei than alcohol-nonpreferring NP rats (McBride et al., 1998). Furthermore, alcoholaccepting C57BL/6J mice showed higher levels of m-receptor labeling in the amygdala than the alcohol-avoiding DBA/2J mice (de Waele and Gianoulakis, 1997). These results suggest a link between m-receptor binding potential (greater receptor densities and/or higher binding affinities) and alco-