Vulnerability to develop addiction to psychostimulants, including cocaine and amphetamine, as well as other drugs, like alcohol, is influenced by both genetic and environmental factors. Genetic factors may modulate differing initial responses to drugs of abuse in humans and this has been linked to the propensity to develop a drug abuse disorder. Abnormal adaptations in stress response pathways have also been implicated in the development of drug dependence and while this relationship is firmly established, the underlying neurobiological mechanisms are not well understood. While no animal model exists that reproduces the entire spectrum of the drug abuse syndrome in humans, animal models do exist for certain drug-related behaviors including acute locomotor activation, behavioral sensitization and conditioned place preference in response to drug treatment, as well as rates of drug self-administration. We have identified an ENU-induced mutant, Highper, that shows hyperlocomotion in a novel environment, an exaggerated locomotor response to the psychostimulants cocaine and methylphenidate and a prolonged release of corticosterone following an acute stressor. We believe that the abnormal stress and drug responses exhibited by these animals are related;our hypothesis is that the exaggerated locomotor response to psychostimulants is exacerbated by previous exposure to stressful events. Using single nucleotide polymorphism (SNP) genotyping, we have mapped the Highper mutation to a 59 megabase region on chromosome 12. This region contains 411 genes, none of which has previously been implicated in both drug and stress responses. Thus, Highper may represent a novel model for studying the relationship between the stress and drug response behavioral domains. In this proposal, we outline an experimental strategy to address our three primary goals: 1) to further characterize the Highper line to better understand the abnormal stress and psychostimulant responses and the link between the two 2) to fine map and identify the causative mutation and 3) to characterize the functional disruption caused by the gene mutation both in vivo and in vitro.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Pollock, Jonathan D
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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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
Tarantino, Lisa M; Eisener-Dorman, Amy F (2012) Forward genetic approaches to understanding complex behaviors. Curr Top Behav Neurosci 12:25-58
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
Eisener-Dorman, Amy F; Grabowski-Boase, Laura; Steffy, Brian M et al. (2010) Quantitative trait locus and haplotype mapping in closely related inbred strains identifies a locus for open field behavior. Mamm Genome 21:231-46
Bailey, Janice S; Grabowski-Boase, Laura; Steffy, Brian M et al. (2008) Identification of QTL for locomotor activation and anxiety using closely-related inbred strains. Genes Brain Behav :
Bailey, J S; Grabowski-Boase, L; Steffy, B M et al. (2008) Identification of quantitative trait loci for locomotor activation and anxiety using closely related inbred strains. Genes Brain Behav 7:761-9