Alpha4* Nicotinic Receptor in Dopaminergic System

Institution:	California Institute of Technology
Investigator(s):	Cheng Xiao, Ph.D.
Award Cycle:	2007 (Cycle 16)	Grant #: 16FT-0066	Award: $75,000
Subject Area:	Nicotine Dependence
Award Type:	Postdoctoral Fellowship Awards

Abstracts

Initial Award Abstract

Nicotine is the compound in tobacco that causes addiction. Nicotine activates nicotinic acetylcholine receptors (nAChRs) widely expressed in the brain, and causes the behaviors of nicotine addiction. Mesolimbic and nigrostriatal dopamine systems are important brain areas for these events. Chronic nicotine exposure results in long-term alterations in these brain areas, and these alterations may underlie the diffuclties in smoking cessation. This project seeks to understand the alterations in both nigrostriatal and mesolimbic dopamine systems following chronic nicotine exposure. There are several subtypes of nAChRs in the brain. Among them, the nAChRs containing alpha4beta2 subunits are the most abundant nAChRs in these two dopamine systems, and are activated by nicotine at the concentrations as low as in cerebrospinal fluid of smokers (0.1 - 1 microM). In previous experiments, a fluorescent protein (YFP) was introduced into the alpha4 nAChR subunit. Then, an alpha4-YFP knock-in mouse line was generated. This mouse line facilitates the visualization of nAChRs containing alpha4 subunit in the brain. The data showed that nAChRs containing the alpha4 subunit are upregulated in both number and function by chronic nicotine exposure in both nigrostriatal and mesolimbic dopamine systems. Interestingly, the upregulation specifically occurs in certain cell types in these systems. This project will examine the functional changes following the upregulation of alpha4 nAChRs at both the cellular and the neuronal circuitry levels. If funded and successful, this project will broaden our knowledge of physiological alterations induced by chronic nicotine exposure. Preventing or reversing may partially or fully disrupt nicotine addiction, which would be valuable for designing therapeutic strategies for nicotine cessation.

Publications

*Chronic nicotine enhanced alpha4 nicotine acetylcholine recptors in nigrostriatal dopamine system.**
Periodical: Journal of Neuroscience			Index Medicus:
Authors: Xiao, C. Nashmi R. McKinney S, Cai H, Lester HA				ART
Yr:	Vol:	Nbr:	Abs:	Pg:

*Chronic nicotine enhanced alpha4 nicotine acetylcholine recptors in nigrostriatal dopamine system.**
Periodical: Journal of Neuroscience			Index Medicus:
Authors: Xiao, C. Nashmi R. McKinney S, Cai H, Lester HA				ART
Yr:	Vol:	Nbr:	Abs:	Pg: