Tobacco addiction has a significant negative impact on the health and economic status of the individual and society. Nicotine is considered to be the primary reinforcing component responsible for tobacco addiction in human smokers [2]. Nicotine's main site of action in the brain is the nicotinic acetylcholine receptor (nAChR), which is composed of discrete combinations of various subunits. The a5 subunit has garnered recent attention based on genetic linkage studies suggesting polymorphisms in the a5 nAChR subunit gene (CHRNA5) increase susceptibility to nicotine dependence in human smokers [11, 12]. Further, insertion of this subunit into certain nAChR subtypes has been shown to alter receptor desensitization and activation kinetics in Xenopus oocytes [5]. The objective of this proposal is to determine the role ofaS-containing nAChRs in nicotine reward, dependence and withdrawal in mice. The intravenous self-administration procedure is considered to be the most reliable measure of the reinforcing properties of drugs of abuse.
In Specific Aim I, I will examine the role of the a5 subunit in nicotine reward by examining intravenous nicotine self-administration in wildtype (WT) mice and mice with a null mutation of the a5 nAChR subunit gene (a5-/-). The intracranial self-stimulation procedure (ICSS) is considered to be a direct measure of the functioning of the brain's natural reward pathways. Thus, in Specific Aim II, I will investigate the role of a5- containing nAChRs in regulating the stimulatory effects of acutely administered nicotine on brain reward systems by measuring nicotine-induced lowering of ICSS thresholds in WT and a5-/- mice. Finally, in Specific Aim III, I will examine the role of the aS-containing nAChRs in the expression of reward deficits during spontaneous nicotine withdrawal in WT and a5-/- mice;elevation of ICSS thresholds during spontaneous nicotine withdrawal will serve as a measure of the reward deficit associated with nicotine withdrawal. I hypothesize that aS-containing nAChRs play an important role in regulating the actions of nicotine on the brain reward circuits, and thereby regulate nicotine self-administration behavior, the acute reward-enhancing effects of nicotine, and the reward deficit associated with nicotine withdrawal. Together, these data may reveal fundamental insights into the neurobiological mechanisms underlying nicotine reward, dependence and withdrawal. Importantly, these findings could lead to the development of novel therapeutics efficacious for smoking cessation and/or relapse prevention in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DA026693-03
Application #
8035346
Study Section
Special Emphasis Panel (ZRG1-F02A-C (20))
Program Officer
Babecki, Beth
Project Start
2009-04-01
Project End
2012-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
3
Fiscal Year
2011
Total Cost
$58,682
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Ochoa, Vanessa; Loeffler, Annalee J; Fowler, Christie D (2015) Emerging Role of the Cerebrospinal Fluid - Neuronal Interface in Neuropathology. Neuro 2:92-98
Fowler, Christie D; Kenny, Paul J (2012) Utility of genetically modified mice for understanding the neurobiology of substance use disorders. Hum Genet 131:941-57
Fowler, Christie D; Kenny, Paul J (2012) Habenular signaling in nicotine reinforcement. Neuropsychopharmacology 37:306-7
Fowler, Christie D; Kenny, Paul J (2011) Intravenous nicotine self-administration and cue-induced reinstatement in mice: effects of nicotine dose, rate of drug infusion and prior instrumental training. Neuropharmacology 61:687-98
Tuesta, Luis M; Fowler, Christie D; Kenny, Paul J (2011) Recent advances in understanding nicotinic receptor signaling mechanisms that regulate drug self-administration behavior. Biochem Pharmacol 82:984-95
Fowler, Christie D; Lu, Qun; Johnson, Paul M et al. (2011) Habenular ?5 nicotinic receptor subunit signalling controls nicotine intake. Nature 471:597-601