Nicotine is the addictive substance that is primarily responsible for the maintenance of smoking, despite the negative health consequences associated with smoking. Nicotine elicits its effects through nicotinic acetylcholine receptors and one of the most prevalent is the receptor composed of alpha4 and beta2 subunits in the brain. Although 90 percent of nicotine binding occurs at this receptor, its function remains unknown. Recent data indicate, however, that alpha4beta2 receptors stimulate the release of the inhibitory neurotransmitter GABA in many brain regions. Evidence also indicates that a1pha4 receptors may mediate seizures induced by high doses of nicotine and that these receptors originate in the hippocampus. Although paradoxical, this may be explained by decreased GABA release due to desensitization of alpha4beta2 receptors. We hypothesize that receptors containing alpha4 subunits stimulate the release of GABA and mediate nicotine-induced seizures. Homologous recombination techniques will be used to generate mice in which deletions of alpha4 subunits can be induced in selective brain regions, using the Cre recombinase/loxP system for site-specific recombination. Mice with a null mutation of alpha4 as well as regional deletions of alpha4 will be assessed using nicotine- evoked [3H]GABA release and seizures induced by intraventricular injections of nicotine. Given evidence that indicates that sensitivity to nicotine seizures correlates with the maximum consumption of nicotine that inbred mouse strains will self administer, elucidating the role of alpha4-containing receptors may help elucidate the mechanism that regulates nicotine consumption.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS010830-02
Application #
6186729
Study Section
Special Emphasis Panel (ZRG1-MDCN-3 (01))
Program Officer
Baughman, Robert W
Project Start
2000-07-01
Project End
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
2
Fiscal Year
2000
Total Cost
$37,516
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
005436803
City
La Jolla
State
CA
Country
United States
Zip Code
92037
McGranahan, Tresa M; Patzlaff, Natalie E; Grady, Sharon R et al. (2011) ?4?2 nicotinic acetylcholine receptors on dopaminergic neurons mediate nicotine reward and anxiety relief. J Neurosci 31:10891-902