A role for KOR in ethanol-induced aversion?

PAUTASSI RM

Sapporo

Congreso; 2012 International Society for Biomedical Research on Alcoholism (ISBRA) World Congress; 2012

Science Council of Japan

The motivational effects of ethanol result from the interaction of ethanol?s appetitive and aversive effects. Substantial data indicates that the appetitive effects of ethanol are modulated by μ and δ opioid receptors. For instance, conditioned place preference by ethanol is blocked by general (e.g., naloxone) and specific µ and δ opioid antagonists. Less is known, however, about the central mechanisms underlying the aversive effects of ethanol. Intracerebral administration of ethanol facilitates the release of dynorphin, the endogenous ligand of kappa opioid receptors (KOR), which is involved in the mediation of dysphoria and other aversive effects. Kappa antagonists have been observed to reduce some aversive effects of ethanol (e.g., hypothermia). In the present study we assessed the role of KOR in a second-order schedule of ethanol-induced conditioned place preference and in ethanol-induced motor activation. Both paradigms are considered to measure the appetitive effects of ethanol. The hypothesis was that ethanol-induced aversion is partially mediated by KOR activation. Therefore, we expected kappa agonism and antagonism to block and promote ethanol?s appetitive effects, respectively. Consistent with previous reports, prolonged spiradoline (U62,066E)-induced activation of the KOR system promoted the emergence of ethanol-induced appetitive reinforcement. This result probably reflects negative reinforcing (i.e., anxiolytic) effects of ethanol. Administration of U62,066E just before conditioning tended to decrease ethanol-induced CPP, although the effect was not statistically significantly. KOR agonism did block, however, ethanol- induced motor stimulation during the rising limb of the blood ethanol curve. Perhaps more important, high-dose ethanol (2.0 g/kg) induced appetitive reinforcement only in rats injected with the KOR antagonist kappa 5?-guanidinylnaltrindole dihydrochloride (GNTI) before conditioning. The results underscore the role of the KOR system in ethanol reinforcement and support the hypothesis that KOR antagonism can result in lessened expression of ethanol?s aversive effects and, therefore, greater expression of ethanol?s appetitive effects. Acknowledgements: Grants PIP CONICET 2010-2012 and PICT-PRH3 (Argentina) and support from SUNY Res. Foundation.