Differential cocaine sensitivity between two closely related substrains of C57BL mice

Abstract

While there is evidence that individual differences in response to cocaine are mediated, in part, by genetic factors, no single gene has been identified that can account for differential responsivity to cocaine. Recent studies in our laboratory may have moved us closer to identification of the gene(s) underlying cocaine sensitivity. We have identified several cocaine-related phenotypes on which two substrains of C57BL mice (6J and ByJ) differ. The genealogy of these two substrains leads to the expectation that they should be genetically very similar, differing at only a few loci. The large differences between the two substrains in cocaine sensitivity may be influenced by allelic differences at a major gene mediating the actions of cocaine. Naive ByJ mice are more resistant to cocaine-induced seizures than are 6J mice. Furthermore, among 6J mice repeated exposure to cocaine results in a decreased susceptibility to cocaine-induced seizure, while among ByJ mice, the same treatment gives rise to an increased susceptibility to seizures. In contrast to their lower sensitivity to cocaine-induced seizures, ByJ mice show a greater sensitivity to cocaine's locomotor stimulant effects. Furthermore, the repeated pairing of cocaine and the test environment results in the development of conditioned locomotion during subsequent exposure to that environment among 6J, but not ByJ, mice. Similarly, a greater degree of conditioned sensitization to the locomotor stimulant effects of cocaine develops in 6J mice.

Genetic variation in the psychomotor stimulant properties of cocaine in Mus musculus

“…One procedural factor differentiated the 11 strain doseresponse study and the smaller B6J/B6ByJ/F 1 study from the previously published work which reported B6J/B6ByJ differences (Henricks et al 1997;Marley et al 1998). The earlier studies of psychomotor stimulant effects of cocaine in these strains used mice purchased and shipped from JAX.…”

“…These follow-up studies examined fewer doses of cocaine and were designed as replication studies for particular outcomes seen in the larger study. The test protocol for the large dose-response study consisted of a one-day test as previously reported for studies of cocaine pharmacogenetics (Henricks et al 1997;Marley et al 1998). Mice were moved, in home cages, to a holding room adjacent to the testing room, for 1 h. Animals were then weighed, injected with saline (0.9% NaCl), and immediately placed into the activity monitors, where locomotion was measured for 30 min.…”

“…Recent studies by Marley and colleagues (Henricks et al 1997;Marley et al 1998) have suggested the possibility of a major gene effect on cocaine sensitivity. Those papers identified two closely related C57BL substrains of mice, C57BL/6J (B6J) and C57BL/6ByJ (B6ByJ), which may differ in locomotor activation and in a seizure kindling paradigm following cocaine administration.…”

“…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).…”

Individual Differences in Cocaine- and Amphetamine-Induced Activation of Male Sprague–Dawley Rats: Contribution of the Dopamine Transporter

“…However, considerable variability (eg different magnitudes) in the behavioral responsiveness of individual animals is often observed. These individual differences have been observed both in outbred and inbred strains of mice (Ruth et al, 1988;George and Ritz, 1990;Henricks et al, 1997;Marley et al, 1998;Rocha et al, 1998). Likewise, variability in COC-induced behaviors has been observed in rats, predominantly in the propensity of rats, often initially classified as either low or high responders to novelty, to self-administer drug (Glick et al, 1994;Piazza et al, 2000), or to become behaviorally sensitized (Hooks et al, 1991a;Hooks et al, 1992;Djano and Martin-Iverson, 2000;Chefer et al, 2003).…”