Ethanol Regulation of Neuronal Nicotinic Receptor Expression in Reward Circuitry

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Neuronal nicotinic acetylcholine receptors are ligand-gated cation channels activated by the endogenous neurotransmitter, acetylcholine (ACh), as well as the highly addictive component of tobacco, nicotine. Expression of neuronal nAChRs in the dopaminergic mesocorticolimbic pathways (the 'reward' pathways) are necessary for nicotine's rewarding properties, but they have also been implicated in the reinforcing effects of alcohol. Ethanol, like all drugs of abuse, increases dopamine (DA) release in nucleus accumbens which is associated with reinforcement. Blocking nAChRs prevents DA release, and inhibits both locomotor stimulation and ethanol self-administration. How may alcohol interact with nAChRs to contribute to reinforcement? Interestingly, ethanol has been proposed to increase ACh release in the VTA thereby increasing the activity of nAChRs expressed in DAergic neurons. In addition, ethanol has been shown to directly either potentiate or inhibit the nAChR response to ACh depending on the subunit composition of the receptor. Together, these data suggest that chronic exposure to ethanol may chronically activate nAChRs. Since it is known that chronic activation of nAChRs by nicotine modulates expression, we hypothesize that ethanol has the potential to regulate nAChR expression, as well. In Aim 1, we will utilize quantitative real time RT-PCR to analyze mRNA expression changes in all 12 neuronal nAChR genes in key mouse brain areas implicated in addiction after acute or chronic ethanol exposure. Quantitative immunoblotting will also be used to measure changes in nAChR protein expression with alcohol exposure. A biophysical approach will be utilized in Aim 2 to measure changes in nAChR function with acute or chronic ethanol exposure in key midbrain areas. We anticipate that the results from this study will not only identify nAChR subtypes regulated by ethanol in reward circuitry, but also lead to a potential molecular target for alcohol cessation therapeutics. PUBLIC HEALTH RELEVANCE: Alcoholism is the third largest cause of preventable mortality in the world. The goal of the proposed project is to understand how alcohol may regulate expression and function of neuronal nicotinic acetylcholine receptors, key proteins critically involved in the addictive properties of both alcohol and nicotine. The insights gained from this project should help elucidate the molecular mechanism underlying alcoholism, as well as identify molecular targets for alcohol cessation therapeutics.