nor-BNI Antagonism of Kappa Opioid Agonist-Induced Reinstatement of Ethanol-Seeking Behavior.

Recent work suggests that the dynorphin (DYN)/kappa opioid receptor (KOR) system may be a key mediator in the behavioral effects of alcohol. The objective of the present study was to examine the ability of the KOR antagonist norbinaltorphimine (nor-BNI) to attenuate relapse to ethanol seeking due to priming injections of the KOR agonist U50,488 at time points consistent with KOR selectivity. Male Wistar rats were trained to self-administer a 10% ethanol solution, and then responding was extinguished. Following extinction, rats were injected with U50,488 (0.1-10 mg/kg, i.p.) or saline and were tested for the reinstatement of ethanol seeking. Next, the ability of the nonselective opioid receptor antagonist naltrexone (0 or 3.0 mg/kg, s.c.) and nor-BNI (0 or 20.0 mg/kg, i.p.) to block U50,488-induced reinstatement was examined. Priming injections U50,488 reinstated responding on the previously ethanol-associated lever. Pretreatment with naltrexone reduced the reinstatement of ethanol-seeking behavior. nor-BNI also attenuated KOR agonist-induced reinstatement, but to a lesser extent than naltrexone, when injected 24 hours prior to injections of U50,488, a time point that is consistent with KOR selectivity. While these results suggest that activation of KORs is a key mechanism in the regulation of ethanol-seeking behavior, U50,488-induced reinstatement may not be fully selective for KORs.

Protracted withdrawal from ethanol and enhanced responsiveness stress: regulation via the dynorphin/kappa opioid receptor system.

Although recent work suggests that the dynorphin/kappa opioid receptor (DYN/KOR) system may be a key mediator in the stress-related effects of alcohol, the regulation of long-term changes associated with protracted withdrawal from ethanol via the DYN/KOR system has yet to be explored. The objective of the present study was to determine the role of the DYN/KOR system in the regulation of anxiety-related behaviors during an extended period of abstinence from ethanol in animals with a history of ethanol dependence. Male Wistar rats (n = 94) were fed an ethanol or control liquid diet for 25-30 days. Six weeks after its removal, rats were exposed to 20 min of immobilization, and the ability of the KOR antagonist nor-binaltorphimine (nor-BNI) (0-20 mg/kg, intraperitoneal [i.p.]) to attenuate the enhanced responsiveness to stress observed in rats chronically exposed to ethanol was investigated using the elevated plus maze. In addition, the ability of U50,488 (0-10 mg/kg, i.p.) to prime anxiety-like behavior during protracted withdrawal was also examined. Rats with a history of ethanol dependence showed a significant decrease in open-arm exploration after exposure to restraint, indicating an anxiety-like state, compared to similarly treated controls, an effect that was blocked by nor-BNI. nor-BNI also selectively decreased center time and open-arm approaches in ethanol-exposed rats. The highest dose of U50,488 decreased open-arm exploration and the total number of arm entries in ethanol-exposed and control rats. Although lower doses of U50,488 did not affect open-arm exploration in either group, the 0.1 mg/kg dose selectively decreased motor activity in the ethanol-exposed rats when compared to similarly pretreated controls. These findings further support the hypothesis that behaviors associated with withdrawal from ethanol are in part regulated by the DYN/KOR system, and suggest that these effects may be long lasting in nature.

κ opioid regulation of anxiety-like behavior during acute ethanol withdrawal.

Withdrawal is one of the defining characteristics of alcohol dependence, and is often characterized by impaired physiological function and enhanced negative affect. Recent evidence suggests that the dynorphin (DYN)/kappa opioid receptor (KOR) system may be a key mediator in the negative affect often associated with drugs of abuse. The objective of the present experiments was to determine the role of the DYN/KOR system in the regulation of anxiety-related behavior during acute withdrawal from ethanol. Rats were fed an ethanol liquid diet and following removal, the ability of the KOR antagonist nor-BNI to attenuate the increased anxiogenic-like response characteristic of ethanol withdrawal was investigated using the elevated plus maze. A comparison study was also conducted examining anxiety-related behavior following direct activation of KORs via injections of the KOR agonist U50,488. Rats experiencing ethanol withdrawal showed a significant decrease in open arm exploration compared to controls, an effect that was blocked by nor-BNI. Similar decreases in open arm exploration were observed following injections with the KOR agonist, U50,488, an effect also reversed by pretreatment with nor-BNI. These results suggest that similar mechanisms are involved in the regulation of ethanol withdrawal- and KOR agonist-induced changes in behavior. Given the potential role of enhanced negative affect in persistent ethanol drinking, understanding the role of the DYN/KOR system in regulating anxiety associated with withdrawal may be critical in understanding the factors associated with the nature of alcohol dependence.