Binge drinking is associated with significant short- and long-term health problems including impaired judgment, mood swings, and heart disease. Heavy alcohol users who frequently binge drink exhibit increased stimulant and rewarding responses to alcohol. Thus, understanding the molecular bases of alcohol reward and binge drinking should lead to identification of novel molecular targets for therapeutics designed to decrease alcohol consumption. Like nicotine and other drugs of abuse, alcohol activates dopaminergic (DAergic) neurons in the ventral tegmental area (VTA), which ultimately yields an increase in dopamine (DA) concentrations in the nucleus accumbens (NAc), a phenomenon widely associated with the rewarding or reinforcing properties of the drug. Previously, utilizing a combination of neuronal nicotinic acetylcholine receptor (nAChR) mouse models, pharmacology, behavioral assays, and electrophysiology, we determined that nAChRs containing the alpha4 subunit (denoted """"""""alpha4* nAChRs""""""""), previously found to be paramount in initiating nicotine dependence, are also involved in the rewarding properties of ethanol and binge drinking. Building upon previous studies, we will test the hypothesis that alpha4* nAChRs specifically in the ventral tegmental area (VTA) contribute to alcohol reward, consumption, and alcohol-mediated activation of VTA dopaminergic (DAergic) neurons. This hypothesis will be tested by re-expressing alpha4 nAChR subunits specifically in the VTA of alpha4 knock- out (KO) mice via viral-mediated gene delivery and measuring alcohol reward, binge drinking, and alcohol-mediated activation of VTA DAergic neurons compared to control KO mice. In addition, alpha4 subunits that are hypersensitive to agonist will be expressed selectively in distinct neuronal subpopulations within the VTA to determine how nAChR expression within VTA micro-circuitry affects alcohol reward and acute consumption.
In aim 2, we will use molecular and biophysical approaches to test the hypothesis that ethanol-mediated activation of DAergic VTA neurons also involves nAChRs that contain the alpha6 subunit. Finally, aim 3 will determine how alpha6* nAChRs are involved in alcohol reward and consumption using a combination of mouse genetics and pharmacology. It is anticipated that the results from these experiments will yield valuable insight into the molecular underpinnings of alcohol reward and binge drinking, as well as identify potential targets for alcohol cessation therapeutics.
Alcohol abuse is the third largest cause of preventable mortality in the world. The goal of the proposed project is to understand how the known molecular targets of nicotine, nicotinic acetylcholine receptors, contribute to the rewarding effects of alcohol and binge drinking. The insights gained from this project should help identify novel molecular targets for therapeutics designed to reduce alcohol consumption.
|Ji, Xincai; Saha, Sucharita; Kolpakova, Jenya et al. (2017) Dopamine Receptors Differentially Control Binge Alcohol Drinking-Mediated Synaptic Plasticity of the Core Nucleus Accumbens Direct and Indirect Pathways. J Neurosci 37:5463-5474|
|Ji, Xincai; Saha, Sucharita; Gao, Guangping et al. (2017) The Sodium Channel ?4 Auxiliary Subunit Selectively Controls Long-Term Depression in Core Nucleus Accumbens Medium Spiny Neurons. Front Cell Neurosci 11:17|
|Slater, Cassandra A; Jackson, Asti; Muldoon, Pretal P et al. (2016) Nicotine Enhances the Hypnotic and Hypothermic Effects of Alcohol in the Mouse. Alcohol Clin Exp Res 40:62-72|
|Guildford, Melissa J; Sacino, Anthony V; Tapper, Andrew R (2016) Modulation of ethanol reward sensitivity by nicotinic acetylcholine receptors containing the ?6 subunit. Alcohol 57:65-70|
|Ngolab, Jennifer; Liu, Liwang; Zhao-Shea, Rubing et al. (2015) Functional Upregulation of ?4* Nicotinic Acetylcholine Receptors in VTA GABAergic Neurons Increases Sensitivity to Nicotine Reward. J Neurosci 35:8570-8|
|Zhao-Shea, Rubing; Liu, Liwang; Pang, Xueyan et al. (2013) Activation of GABAergic neurons in the interpeduncular nucleus triggers physical nicotine withdrawal symptoms. Curr Biol 23:2327-35|
|Liu, Liwang; Zhao-Shea, Rubing; McIntosh, J Michael et al. (2013) Nicotinic acetylcholine receptors containing the ?6 subunit contribute to ethanol activation of ventral tegmental area dopaminergic neurons. Biochem Pharmacol 86:1194-200|
|Liu, Liwang; Hendrickson, Linzy M; Guildford, Melissa J et al. (2013) Nicotinic acetylcholine receptors containing the ?4 subunit modulate alcohol reward. Biol Psychiatry 73:738-46|
|Liu, Liwang; Zhao-Shea, Rubing; McIntosh, J Michael et al. (2012) Nicotine persistently activates ventral tegmental area dopaminergic neurons via nicotinic acetylcholine receptors containing ?4 and ?6 subunits. Mol Pharmacol 81:541-8|
|Hendrickson, Linzy M; Gardner, Paul; Tapper, Andrew R (2011) Nicotinic acetylcholine receptors containing the ýý4 subunit are critical for the nicotine-induced reduction of acute voluntary ethanol consumption. Channels (Austin) 5:124-7|
Showing the most recent 10 out of 17 publications