Psychopharmacology (2003) 167:159–166 DOI 10.1007/s00213-003-1387-0 ORIGINAL INVESTIGATION Chris Downing · Kristina Rodd-Henricks · Rodney J. Marley · Bruce C. Dudek Genetic variation in the psychomotor stimulant properties of cocaine in Mus musculus Received: 18 July 2002 / Accepted: 14 December 2002 / Published online: 18 March 2003  Springer-Verlag 2003 Abstract Rationale: The psychomotor stimulant proper- ties of drugs are argued to be a key feature of abuse liability. Several studies, primarily using inbred strains of mice, have demonstrated genetic variation in the psycho- motor stimulant properties of cocaine. As of yet, however, no gene(s) has been identified which influences this phenotype. Objectives: The purpose of the present study was to examine a number of inbred strains of mice, including several closely related substrains, for cocaine- induced locomotor activation. Such substrain differences would suggest the possibility of a major gene effect. These data will also help to further characterize the range of genetic variation in response to cocaine. Methods: Mice from 11 inbred strains were initially injected with saline and activity monitored for 30 min; mice were then removed from the activity monitor, injected with saline or one of six doses of cocaine, and activity was monitored for an additional 30 min. Results: Compared to several other closely related C57BL substrains, we found the C57BL/10SnJ substrain to be significantly less activated following cocaine administration. In contrast, the C57BR/ cdJ and C57L/J substrains showed extremely high levels of cocaine-induced locomotor activation. Conclusions: The genetic similarity between C57BL/10SnJ and the other closely related C57BL substrains suggests the possibility that the aberrant behavioral response to cocaine observed in B10SnJ mice may be due to a major gene effect. Similarly, the differences found in the C57BR/cdJ and C57L/J substrains may also be influenced by a major gene. The strains examined in this study will be useful tools for identification of relevant quantitative trait loci. Keywords Cocaine · Behavior genetics · Inbred strains · Psychomotor stimulation Introduction Both environmental and genetic factors are known to contribute to individual differences in susceptibility to abuse drugs. Among human populations, twin and adoption studies have shown that vulnerability to cocaine abuse is a heritable trait (Kendler and Prescott 1998; Karkowski et al. 2000; Kendler et al. 2000). Animal studies have further demonstrated that many of cocaine’s neurobehavioral actions are influenced by genotype. Several phenotypes which are thought to reflect the rewarding or reinforcing properties of cocaine, including self-administration, conditioned place preference, and locomotor activation, are known to differ among inbred strains of mice and rats (Ruth et al. 1988; George and Ritz 1990; Seale and Carney 1991; Womer at al. 1994; Grahame and Cunningham 1995; Deroche et al. 1997; Henricks et al. 1997; Miner 1997; Rocha et al. 1998; Schlussman et al. 1998; Cunningham et al. 1999). The phenotype of psychomotor activation has received much attention in models of addiction (Wise and Bozarth 1987; Newlin and Thomson 1991). Successful selective breed- ing of mice for sensitivity and insensitivity to the psychomotor stimulant properties of cocaine provides further evidence for the role of genes in mediating behavioral responses to drugs of abuse (Smolen and Marks 1991; Marley et al. 1998). While inbred strain differences and selective breeding offer strong evidence for a general genetic influence on the psychomotor stimulant properties of cocaine, and quanti- tative trait locus (QTL) studies have identified several putative chromosomal regions influencing this phenotype (Tolliver et al. 1994; Miner and Marley 1995; Phillips et al. 1998; Jones et al. 1999; Boyle and Gill 2001), no single gene has been identified which has an effect on cocaine- induced psychomotor activation. Recent studies by Marley and colleagues (Henricks et al. 1997; Marley et al. 1998) C. Downing · K. Rodd-Henricks · R. J. Marley · B. C. Dudek State University of New York at Albany, NY, USA C. Downing ( ) ) Institute for Behavioral Genetics, University of Colorado at Boulder, Campus Box 447, Boulder, CO 80309-0447, USA e-mail: cdowninp@colorado.edu Tel.: +1-303-4922152