Tobacco use is a major health problem in the United States, where over 400,00 deaths and $50 billion in medical costs yearly are directly attributed to smoking (Epping-Jordan et al., 1998). Teenagers smoke 1.1 billion packs of cigarettes annually and will account for more than $200 billion in future health care costs (Woolf, 1997). Nicotine is the major component of tobacco that leads to addiction, but the underlying mechanisms remain unclear. This Program Project application takes a multi-level approach to understand nicotinic cholinergic systems and nicotine's effect on synaptic events, cardiovascular function, and behavior. Overall the Program will investigate the hypothesis that different nicotinic acetylcholine receptor (nAChR) subunits have special importance in the individual properties that contribute to nicotinic cholinergic functions in the nervous system. Three Projects have arisen from the production of mutant mice for nAChR subunits. The Mouse Core, headed by Dr. Beaudet, has already produced null mice lacking alpha3, alpha5, alpha7, beta3, or beta 4, and a mouse expressing in alpha7 L247T mutation that diminishes desensitization. The Morphology Core, headed by Dr. Armstrong, will do a systematic anatomical and histological screen of each mutant mouse, and will pursue further morphological investigations as warranted. The three Projects could not exist without the mutant mice, which are the fundamental tool used in each investigation. The Dani Project will directly study the altered nAChRs and the synaptic basis for nicotine's actions. The work is intended to provide basic biophysical and synaptic information that will be helpful when interpreting the results from all of the Projects. The De Biasi Project will use radio-telemetry to examine the effects of nicotine on the autonomic nervous system and cardiovascular functions. Among the specific goals is to understand how tolerance to nicotine develops more rapidly for increases in blood pressure than for increases in heart rate. The Paylor Project will use a battery of behavioral tests to examine the mutant mice with the aim of understanding how nAChR subunits regulate the sensitivity to nicotine and the development of tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA012661-02
Application #
6174942
Study Section
Special Emphasis Panel (ZDA1-RXL-E (23))
Program Officer
Pollock, Jonathan D
Project Start
1999-08-15
Project End
2004-06-30
Budget Start
2000-08-05
Budget End
2001-06-30
Support Year
2
Fiscal Year
2000
Total Cost
$1,047,242
Indirect Cost
Name
Baylor College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Adriaan Bouwknecht, J; Olivier, Berend; Paylor, Richard E (2007) The stress-induced hyperthermia paradigm as a physiological animal model for anxiety: a review of pharmacological and genetic studies in the mouse. Neurosci Biobehav Rev 31:41-59
McCallum, Sarah E; Collins, Allan C; Paylor, Richard et al. (2006) Deletion of the beta 2 nicotinic acetylcholine receptor subunit alters development of tolerance to nicotine and eliminates receptor upregulation. Psychopharmacology (Berl) 184:314-27
Bao, Jianxin; Lei, Debin; Du, Yafei et al. (2005) Requirement of nicotinic acetylcholine receptor subunit beta2 in the maintenance of spiral ganglion neurons during aging. J Neurosci 25:3041-5
Armstrong, Dawna Duncan (2005) Neuropathology of Rett syndrome. J Child Neurol 20:747-53
Arredondo, Juan; Chernyavsky, Alexander I; Marubio, Lisa M et al. (2005) Receptor-mediated tobacco toxicity: regulation of gene expression through alpha3beta2 nicotinic receptor in oral epithelial cells. Am J Pathol 166:597-613
Pidoplichko, Volodymyr I; Noguchi, Jun; Areola, Oluwasanmi O et al. (2004) Nicotinic cholinergic synaptic mechanisms in the ventral tegmental area contribute to nicotine addiction. Learn Mem 11:60-9
Chernyavsky, Alex I; Arredondo, Juan; Marubio, Lisa M et al. (2004) Differential regulation of keratinocyte chemokinesis and chemotaxis through distinct nicotinic receptor subtypes. J Cell Sci 117:5665-79
Salas, Ramiro; Cook, Kimberly D; Bassetto, Laura et al. (2004) The alpha3 and beta4 nicotinic acetylcholine receptor subunits are necessary for nicotine-induced seizures and hypolocomotion in mice. Neuropharmacology 47:401-7
Tritto, Theresa; McCallum, Sarah E; Waddle, Satori A et al. (2004) Null mutant analysis of responses to nicotine: deletion of beta2 nicotinic acetylcholine receptor subunit but not alpha7 subunit reduces sensitivity to nicotine-induced locomotor depression and hypothermia. Nicotine Tob Res 6:145-58
Marubio, L M; Paylor, R (2004) Impaired passive avoidance learning in mice lacking central neuronal nicotinic acetylcholine receptors. Neuroscience 129:575-82

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