Rewarding and aversive effects of ethanol in High Drinking in the Dark selectively bred mice.

Both rewarding and aversive effects contribute to alcohol consumption. Animals genetically predisposed to be high drinkers show reduced sensitivity to the aversive effects of alcohol, and in some instances, increased sensitivity to alcohol's rewarding effects. The present studies tested the high drinking in the dark (HDID) selected lines, a genetic model of drinking to intoxication, to determine whether intake in these mice was genetically related to sensitivity to alcohol aversion or reward. Male HDID mice from the first and second replicate lines (HDID-1 and HDID-2, respectively) and mice from the heterogeneous progenitor control population (HS/Npt, or HS) were conditioned for a taste aversion to a salt solution using two doses of alcohol, and lithium chloride (LiCl) and saline controls. In separate experiments, male and female HDID-1, HDID-2 and HS mice were conditioned for place preference using alcohol. HDID mice were found to have an attenuated sensitivity to alcohol at a moderate (2 g/kg) dose compared to HS mice, but did not differ on conditioned taste aversion to a high (4 g/kg) dose or LiCl or saline injections. HDID and HS mice showed comparable development of alcohol-induced conditioned place preference. These results indicate that high blood alcohol levels after drinking in the HDID mice is genetically related to attenuated aversion to alcohol, while sensitivity to alcohol reward is not altered in these mice. Thus, HDID mice may find a moderate dose of alcohol to be less aversive than control mice and consequently may drink more because of this reduced aversive sensitivity.

Time-dependent negative reinforcement of ethanol intake by alleviation of acute withdrawal.

BACKGROUND: Drinking to alleviate the symptoms of acute withdrawal is included in diagnostic criteria for alcoholism, but the contribution of acute withdrawal relief to high alcohol intake has been difficult to model in animals. METHODS: Ethanol dependence was induced by passive intragastric ethanol infusions in C57BL/6J (B6) and DBA/2J (D2) mice; nondependent control animals received water infusions. Mice were then allowed to self-administer ethanol or water intragastrically. RESULTS: The time course of acute withdrawal was similar to that produced by chronic ethanol vapor exposure in mice, reaching a peak at 7 to 9 hours and returning to baseline within 24 hours; withdrawal severity was greater in D2 than in B6 mice (experiment 1). Postwithdrawal delays in initial ethanol access (1, 3, or 5 days) reduced the enhancement in later ethanol intake normally seen in D2 (but not B6) mice allowed to self-infuse ethanol during acute withdrawal (experiment 2). The postwithdrawal enhancement of ethanol intake persisted over a 5-day abstinence period in D2 mice (experiment 3). D2 mice allowed to drink ethanol during acute withdrawal drank more ethanol and self-infused more ethanol than nondependent mice (experiment 4). CONCLUSIONS: Alcohol access during acute withdrawal increased later alcohol intake in a time-dependent manner, an effect that may be related to a genetic difference in sensitivity to acute withdrawal. This promising model of negative reinforcement encourages additional research on the mechanisms underlying acute withdrawal relief and its role in determining risk for alcoholism.