Sensitivity to cocaine and amphetamine among mice selectively bred for differential cocaine sensitivity

Abstract

Selective breeding of mice for differences in response to a drug offers a powerful means for testing hypotheses regarding underlying mechanisms and relationships between drug-induced behaviors. Starting from a heterogeneous stock of mice, we have selectively bred lines of mice for extreme differences in their locomotor response to 10 mg/kg cocaine HCl. Selection pressure has been maintained for 12 generations and has resulted in two cocaine sensitive (CAHI) and two cocaine insensitive (CALO) lines. Across the generations of selection, the CAHI lines showed progressively greater amounts of cocaine-induced locomotion, with mice from the S12 generation traveling over 21,000 cm/30 min. following 10 mg/kg cocaine. The CALO lines, in contrast, did not substantially diverge from control values until the S8 generation. By generation 12, however, the LO lines traveled no further following 10 mg/kg cocaine (7000 cm/30 min), than they did following an initial saline injection. Cocaine and amphetamine dose-response analyses were conducted on drug-naive mice from the tenth generation. The CAHI lines were extremely sensitive to the locomotor activating effects of all doses of cocaine, displaying from 2- to 6-fold greater amounts of cocaine-induced locomotion than the CALO lines. The CALO lines, in contrast, were completely insensitive to the psychomotor stimulant effects of cocaine. The CAHI lines were also more sensitive to the locomotor activating effects of amphetamine. Both lines showed dose-dependent amphetamine-induced locomotion that peaked at 3 mg/kg. However, at all doses, the CAHI lines showed a 2- to 4-fold greater amount of locomotion than CALO lines. Thus, the sensitivity to cocaine developed through selection using a single dose of cocaine has generalized to a range of doses of cocaine and to at least one other psychostimulant.

Behavioral genetic contributions to the study of addiction-related amphetamine effects

“…Similar results with respect to both line and replicate were found when FAST and SLOW mice were tested for stimulant response to cocaine (Bergstrom et al, 2003;Phillips and Shen, 1996). Further, two lines of mice bred for their large locomotor stimulant response to cocaine exhibited a larger stimulant response to d-amphetamine, compared to two lines bred for low cocaine response (Marley et al, 1998). Finally, Short Sleep mice bred for decreased sensitivity to the sedative-hypnotic effects of ethanol have been found to exhibit heightened sensitivity to the locomotor stimulant effects of (+)amphetamine, cocaine and ethanol, compared to Long Sleep mice, which were bred for increased sensitivity to the sedativehypnotic effects of ethanol (Hanania and Zahniser, 2002).…”

A role for neuronal nicotinic acetylcholine receptors in ethanol-induced stimulation, but not cocaine- or methamphetamine-induced stimulation

“…Similar to the FAST and SLOW mouse lines, the HMACT line was more stimulated by EtOH and COC compared to the LMACT line (Kamens et al 2005(Kamens et al , 2006. Furthermore, lines of mice selectively bred for sensitivity to COC's stimulatory effects also differed in response to amphetamine, such that the lines that were more stimulated by COC were more stimulated by amphetamine (Marley et al 1998). No data exist regarding sensitivity to EtOH in these lines.…”

“…Crabbe et al 1983Crabbe et al , 1994Downing et al 2006;Dudek et al 1991;Grisel et al 1997;Marley et al 1998;Phillips et al 1998). Sensitivity to druginduced behavioral stimulation has been suggested to be an important endophenotype for drug abuse (Gabbay 2005).…”

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).…”