Every year, tobacco use is attributed to approximately 400,000 deaths in the United States. Withdrawal from nicotine elicits aversive symptoms that interfere with normal behavior and prevent many smokers from quitting. Nicotine, the psychoactive compound in tobacco is known to act upon the major brain reward circuit, the mesocorticolimbic pathway. With other drugs of abuse, the activity of the inhibitory GABAergic neurons of the Ventral Tegmental Area (VTA) is altered. Nicotinic acetylcholine receptors (nAChRs) are upregulated in VTA GABAergic neurons with chronic nicotine use, specifically nAChRs containing both the ?4 and ?2 nAChR subunits. However, little is known regarding how increased expression of nAChRs on GABAergic neurons contributes to nicotine dependence. Utilizing a viral mediated, cell specific gene expression system to selectively express nicotine hypersensitive ?4 subunit-containing nAChRs in GABAergic VTA neurons, I propose to elucidate the role of VTA GABAergic neurons in nicotine withdrawal.
In Aim 1, I will test the hypothesis that chronic activation/desensitization of ?4 nAChRs in VTA GABAergic neurons is sufficient to elicit withdrawal symptoms upon nicotine cessation.
In Aim 2, using biophysical approaches, I will investigate the mechanism by which chronic treatment of and withdrawal from nicotine modulates GABAergic neuronal activity. The results from these experiments will provide a better understanding of the cellular components involved in nicotine dependence, and provide insight into developing more focused nicotine cessation therapies.

Public Health Relevance

The use of tobacco is the number one preventable cause of death in the Western world. Although not the primary cause of death, nicotine, the addictive substance in tobacco, reinforces continual and unstoppable use. This project aims to understand the molecular and cellular interactions in neurons and between neuronal subpopulations in behaviors of nicotine dependence. The results gained from this project will hopefully be used to formulate new therapies for smoking cessation. !

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Babecki, Beth
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University of Massachusetts Medical School Worcester
Schools of Medicine
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Pang, Xueyan; Liu, Liwang; Ngolab, Jennifer et al. (2016) Habenula cholinergic neurons regulate anxiety during nicotine withdrawal via nicotinic acetylcholine receptors. Neuropharmacology 107:294-304
Ngolab, Jennifer; Liu, Liwang; Zhao-Shea, Rubing et al. (2015) Functional Upregulation of α4* Nicotinic Acetylcholine Receptors in VTA GABAergic Neurons Increases Sensitivity to Nicotine Reward. J Neurosci 35:8570-8
Weismann, Cara M; Ferreira, Jennifer; Keeler, Allison M et al. (2015) Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan. Hum Mol Genet 24:4353-64