Kelli Gillett ACF Abstract FY13

"Protracted withdrawal from ethanol and the enhanced responsiveness to mild stress: Regulation via the dynorphin/kappa opioid receptor system"

Society for Neuroscience Annual Meeting: Neuroscience 2012

Withdrawal is one of the defining characteristics of alcohol dependence, and is often characterized by impaired physiological function and enhanced negative affect. These alterations in mood can be long-lasting in nature, as abstinent alcoholics show symptoms of anxiety for months and even years after their last drink. When examined under animal models of alcoholism, laboratory animals with a history of ethanol dependence show an enhanced responsiveness to mild stressors and alterations in neurobiological stress systems for weeks after they are no longer given access to ethanol. The biological mechanisms underlying these changes, however, have yet to be fully explored. 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 kappa opioid system in the regulation of anxiety-related behaviors during protracted withdrawal from ethanol. Male Wistar rats ( n=76) were fed an ethanol or control liquid diet for 28 days. Six weeks after removal of the diet, rats were exposed to a mild stressor (20 minutes of immobilization), and the ability of the KOR antagonist nor-BNI to attenuate increases in anxiety-like behavior in the elevated plus maze was investigated. A comparison study was also conducted following direct activation of the DYN/KOR system. Six weeks after removal of the liquid diet, rats received injections of U50,488 (0.1 or 1.0 mg/kg, i.p.) or saline10 minutes prior to testing in the elevated plus maze. Rats with a history of ethanol dependence showed a significant decrease in open arm exploration compared to controls when exposed to the mild stressor, an effect that was blocked by nor-BNI. Interestingly, injections of U50,488, which has previously been shown to enhance stress-related behaviors in laboratory animals, did not lead to an anxiety-like response in rats with a history of dependence. There were no effects of treatment on locomotor activity. These results suggest that preventing KOR activation may be sufficient in attenuating the enhanced responsiveness to stress observed during long-term withdrawal from ethanol. However, the KOR/DYN system may not be necessary in producing this anxiety-like state. Further investigation will aid in clarifying the role of the kappa opioid receptor system in protracted abstinence from ethanol. Supported by: R15 AA018213 from NIAAA.