Tobacco use has been implicated in a wide range of human diseases, including heart disease, emphysema, and cancer, which together result in millions of premature deaths each year. The addictive properties of nicotine are a major cause of persistent and compulsive tobacco use. Nicotine addiction is thought to result from long-term adaptive changes in the activity and expression of nicotinic acetylcholine receptors in the brain. However, the molecular and neuronal mechanisms that underlie these adaptive processes remain poorly understood. The goal of this research is to use genetic analysis in a simple animal model, the nematode Caenorhabditis elegans, to investigate the molecular basis of nicotine adaptation. C. elegans is highly amenable to molecular analysis of nervous system function: It has a simple and well-characterized nervous system, and its short generation time, small and largely sequenced genome, and accessibility to germline transformation make it ideal for classical and molecular genetic studies. C. elegans exhibits a striking and easily measurable response to nicotine, and long-term nicotine exposure leads to both nicotine tolerance and nicotine dependence. In this R21 exploratory/developmental project, genes required for nicotine adaptation in nematodes will be identified by screening for adaptation defective mutants. Detailed characterization of mutant phenotypes will provide insight into the roles of these genes in nicotine adaptation and other aspects of nervous system function. The results of this study will be used to support an RO1 proposal to determine the molecular functions of these nicotine adaptation genes, and to characterize the cellular pathways in which they function. The ultimate goal of this work is to provide a model for the general molecular mechanisms underlying nicotine adaptation in neurons, and to identify new proteins that participate in nicotine addiction in other animals, including vertebrates.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DA011556-01
Application #
2468019
Study Section
Human Development Research Subcommittee (NIDA)
Project Start
1998-02-01
Project End
2000-01-31
Budget Start
1998-02-01
Budget End
1999-01-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Kim, J; Poole, D S; Waggoner, L E et al. (2001) Genes affecting the activity of nicotinic receptors involved in Caenorhabditis elegans egg-laying behavior. Genetics 157:1599-610
Waggoner, L E; Hardaker, L A; Golik, S et al. (2000) Effect of a neuropeptide gene on behavioral states in Caenorhabditis elegans egg-laying. Genetics 154:1181-92
Waggoner, L E; Dickinson, K A; Poole, D S et al. (2000) Long-term nicotine adaptation in Caenorhabditis elegans involves PKC-dependent changes in nicotinic receptor abundance. J Neurosci 20:8802-11
Kerr, R; Lev-Ram, V; Baird, G et al. (2000) Optical imaging of calcium transients in neurons and pharyngeal muscle of C. elegans. Neuron 26:583-94