The role of endogenous beta-endorphin and enkephalins in ethanol reward.

Substantial evidence has implicated the endogenous opioid system in alcohol reinforcement. However, the role of each opioid peptide in alcohol reinforcement and, particularly, reward is not fully characterized. In this study, using the conditioned place preference (CPP) paradigm as an animal model of reward, we determined the role of endogenous β-endorphin and enkephalins in the rewarding action of ethanol. Female mice lacking beta-endorphin and/or the proenkephalin gene as well as their respective wild-type controls were tested for baseline place preference on day 1, conditioned with ethanol versus saline on days 2-4 and were then tested under a drug-free state for postconditioning place preference on day 5. On each test day, mice were placed in the central neutral chamber and allowed to freely explore all three CPP chambers. The amount of time that mice spent in each chamber was recorded. We also studied the effect of naloxone, a non-selective opioid receptor antagonist, on ethanol CPP, in which wild-type mice were treated with saline or naloxone 10 min prior to ethanol or saline conditioning. Our results showed that the absence of β-endorphin or enkephalins alone failed to alter the acquisition of ethanol-induced CPP. However, the absence of both β-endorphin and enkephalins significantly reduced the CPP response. Interestingly, high but not low dose naloxone blunted ethanol CPP. These findings provide the first evidence illustrating that ethanol induces its rewarding action, at least in part, via a joint action of β-endorphin and enkephalins, possibly involving both mu and delta opioid receptors.