Kappa opioid regulation of depressive-like behavior and reward seeking during acute and protracted withdrawal from ethanol

Withdrawal from alcohol is often characterized by enhanced negative affect, such as symptoms of depression and anxiety, and increased reward seeking. These behavioral changes can be long-lasting in nature, which further contributes to the challenge of the long-term management of alcoholism. Recent evidence from animal models suggests that the increased activity of the dynorphin (DYN)/kappa opioid receptor (KOR) system leads to an increase in depressive-like behaviors and reward seeking following withdrawal from ethanol. The objective of the present experiments was to determine the role of the KOR system in the regulation of depression-related behaviors and saccharin reward following chronic exposure to ethanol. In the first experiment, male Wistar rats were fed an ethanol or control liquid diet for approximately four weeks. To assess the ability of the KOR antagonist nor-BNI to attenuate increases in depressive-like behavior, animals were examined in the forced swim test. Immediately after removal of the diet, rats were injected with nor-BNI (20 mg/kg, i.p.), and 24 h later, were exposed to a 10 min session of forced swim stress. The following day, rats were given a 5 min forced swim session that was recorded and examined for time spent immobile. In the second set of experiments, male Wistar rats were trained to self-administer saccharin, and following stable intake, were exposed to an ethanol or control liquid diet as described above. The ability of the nor-BNI to decrease saccharin self-administration was examined during acute withdrawal and protracted abstinence from ethanol. Following removal of the diet, rats were injected with saline, and 24 h later, were allowed to self-administer saccharin. Immediately following this initial self-administration session, animals were pretreated with nor-BNI (20 mg/kg, i.p.), and were again allowed to self-administer saccharin 24 h later. This saccharin self-administration procedure was repeated three weeks later after rats received injections of saline and nor-BNI as described. In the forced swim test, ethanol dependent rats displayed a characteristic increase in time spent immobile compared to controls, an effect that was reversed by pretreatment with nor-BNI. nor-BNI also selectively decreased saccharin intake in ethanol dependent rats without affecting responding in controls at 48 h and 3 weeks following withdrawal. These results suggest that KOR blockade reverses depression-related behaviors and general reward seeking associated with withdrawal from ethanol following both acute and protracted periods of abstinence. Supported by: R15 AA018213 from NIAAA (GRV). SKJ was supported by the Ronald E. McNair Scholars Program at GVSU