The devastating effects of drug addiction on the lives of those who struggle with it, and the social and economic implications for society as a whole are staggering. Faced with this challenge, understanding the biological pathways that predispose individuals to addiction to cocaine (and other drugs) is a top priority in the research community. Genetic background is thought to influence an individual's predisposition to abuse drugs and this hypothesis is supported by studies in animal models, by clinical observations in humans, and by animal studies showing mouse inbred strain differences in behaviors that model addiction liability. While no animal model exists that recapitulates the entire spectrum of the drug abuse syndrome in humans, animal models do exist to examine specific drug?related behaviors. Locomotor response to drug administration models initial sensitivity to the stimulant effects of the drug. Rodents that exhibit increased locomotor response to psycho stimulants also show faster rates of acquisition in drug self?administration assays, which suggests that initial sensitivity to cocaine predicts liability to addiction. The goal of this proposal is to identify genetic loci involved in the regulation of cocaine locomotor response as an indication of drug sensitivity. Our strategy takes advantage of naturally occurring phenotypic variation between inbred mouse strains and haplotype association mapping, a genetic approach for mapping complex trait genes. In addition, gene expression paHerns in brain regions involved in drug response and addiction as well as pharmacokinetic properties of cocaine will be examined across strains to identify gene expression and pharmacokinetic differences that may contribute to phenotypic variation.

Public Health Relevance

An understanding of the biological pathways that predispose individuals to addiction to cocaine (and other drugs) has been a top priority in the research community. This application proposes to identify genes and gene pathways, through the use of animal models, underlying individual differences in the risk for abusing cocaine and other psychostimulants. The major goal of this application is to advance the knowledge of mechanisms underlying addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA023690-02
Application #
7894894
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Pollock, Jonathan D
Project Start
2009-08-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$551,492
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Psychiatry
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Roberts, Amanda J; Casal, Linzy; Huitron-Resendiz, Salvador et al. (2018) Intravenous cocaine self-administration in a panel of inbred mouse strains differing in acute locomotor sensitivity to cocaine. Psychopharmacology (Berl) 235:1179-1189
Thompson, Trey; Grabowski-Boase, Laura; Tarantino, Lisa M (2015) Prototypical anxiolytics do not reduce anxiety-like behavior in the open field in C57BL/6J mice. Pharmacol Biochem Behav 133:7-17
Wiltshire, T; Ervin, R B; Duan, H et al. (2015) Initial locomotor sensitivity to cocaine varies widely among inbred mouse strains. Genes Brain Behav 14:271-80
Eisener-Dorman, Amy F; Bailey, Janice S; Grabowski-Boase, Laura et al. (2013) Characterization of Highper, an ENU-induced mouse mutant with abnormal psychostimulant and stress responses. Psychopharmacology (Berl) 225:407-19
Eisener-Dorman, Amy F; Grabowski-Boase, Laura; Tarantino, Lisa M (2011) Cocaine locomotor activation, sensitization and place preference in six inbred strains of mice. Behav Brain Funct 7:29