Grant: $205,104 - National Institutes of Health - Sep. 9, 2009
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Award Description: 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. In Aim 3, we will obtain genetically engineered knockout mice (KOs) that do not express nAChRs identified in Aims 1 and 2, and measure ethanol consumption, preference, and reward compared to wild-type animals, to test the hypothesis that ethanol regulated nAChRs are critical for the reinforcing properties of alcohol. 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.
Project Description: We were awarded this grant on September 10. In the last 20 days we have purchased mice and bought reagents for this project. In addition, a graduate student has begun experiments.
Jobs Summary: N/A (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Sep. 9, 2009. Help expand these official descriptions using the wiki below.