The molecular basis of drug addiction has recently been explored using knock-out mice. These studies have revealed that a number of molecules contribute to distinct aspects of addiction to stimulants, opiates, and ethanol. However, the molecular basis of nicotine addiction remains unclear despite the fact that addiction to nicotine and other drugs shares a common neuroanatomical basis. The transcription factor FosB and the protein phosphatase inhibitor DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) have been shown to be critical determinants for different aspects of behavioral responsiveness to cocaine in mice. These two intracellular molecules are unique in that their disruption makes animals more vulnerable to cocaine's behavioral effects. The present application is designed to test the hypothesis that these two molecules are also critical for nicotine addiction and that, if so, they play distinct roles in specific aspects of nicotine dependence. The experimental design is unique in three aspects. First, a number of behavioral models will be used to assess different aspects of nicotine addiction. They include tolerance, sensitization, conditioned place preference, withdrawal-associated conditioned place aversion, and self-administration. Second, an attempt will be made to assess the influence of genetic backgrounds on behavioral phenotypes. The dissimilar genetic backgrounds of knock-out and wild-type mice littermates have confounded the behavioral phenotypes of knock-out mice. Heterozygous mice will be repeatedly back-crossed to C57BL/6J mice to achieve a higher degree of similarity in the genetic backgrounds of knock-out mice and wild-type littermates (i.e., congenic mice). Third, anatomical analysis will determine the involvement of neuroanatomical adaptations in behavioral phenotypes. Based on the outcome of similar approaches to cocaine addiction, it is expected that these two genes contribute to specific aspects of nicotine addiction. If these molecules turn out to be important for vulnerability to nicotine addiction, this mouse study will provide a solid basis for genetic analysis of human addiction vulnerability.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA013232-05
Application #
6743777
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Pollock, Jonathan D
Project Start
2000-08-01
Project End
2006-04-30
Budget Start
2004-06-10
Budget End
2006-04-30
Support Year
5
Fiscal Year
2004
Total Cost
$250,500
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Hiroi, N; Scott, D (2009) Constitutional mechanisms of vulnerability and resilience to nicotine dependence. Mol Psychiatry 14:653-67
Zhu, Hongwen; Lee, MoonSook; Agatsuma, Soh et al. (2007) Pleiotropic impact of constitutive fosB inactivation on nicotine-induced behavioral alterations and stress-related traits in mice. Hum Mol Genet 16:820-36
Hiroi, N; Agatsuma, S (2005) Genetic susceptibility to substance dependence. Mol Psychiatry 10:336-44
Zhu, Hongwen; Lee, MoonSook; Guan, Fangxia et al. (2005) DARPP-32 phosphorylation opposes the behavioral effects of nicotine. Biol Psychiatry 58:981-9