The Mu1-opioid receptors and ethanol-stimulated mesolimbic dopamine release

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DESCRIPTION (provided by applicant): Ethanol is a widely abused drug with a huge socio-economic impact, yet the mechanisms of ethanol reinforcement are still not clear. The mesolimbic system, which includes the dopaminergic pathway from the ventral tegmental area (VTA) to the ventral striatum, is proposed to play a major role in ethanol reinforcement. Mesolimbic dopamine activity is modulated by the opioid peptide system (which includes endogenous opioid peptide ligands and their corresponding receptor subtypes), and is affected by exogenous opiates. Naltrexone, an opioid receptor antagonist, is used in the clinical management of alcoholism but its mechanism is not firmly established. However, it is known that naltrexone causes a decrease in mesolimbic dopamine. Naltrexone is a non-selective opioid receptor antagonist, and it is therefore important to determine the effects of more selective opioid antagonists on mesolimbic dopamine release. This will enable us to characterize the contributions of individual opioid receptor subtypes to ethanol reinforcement, and also enable the development of more selective opioid antagonists for possible use in the clinical management of alcoholism. Recent evidence suggests that mu-opioid receptors in both the VTA and ventral striatum may be involved in reinforcement and mesolimbic dopamine release. Our long term goal is to determine the mechanism of ethanol-opioid-dopamine interaction. Ethanol is hypothesized to cause an increase of beta-endorphin, in both the VTA and ventral striatum, leading to an activation of mu-opioid receptor populations in these regions, which results in an increase in mesolimbic dopamine release, which may lead to reinforcement. Of the mu-opioid receptor subtypes, the mu1-opioid receptor is the most studied. The specific aims of this study are to determine if the mu1-opioid receptors in the VTA and the ventral striatum are involved in ethanol-stimulated dopamine release. The proposed experiments involve determination of the effect of selective blockade of mu1 opioid receptor subtype in the VTA and ventral striatum, on ethanol- stimulated mesolimbic dopamine release. C57BL/6J mice will be used in all experiments, and dialysate dopamine and ethanol concentrations will be determined using in vivo microdialysis. The results of this study will increase our understanding of the mechanism of ethanol-stimulated opioid mediated dopamine release. The results could also lead to the development of more effective pharmacological agents for the management of alcoholism.