SENSITIVITY TO COCAINE AND AMPHETAMINE AMONG MICE SELECTIVELY BRED FOR DIFFERENTIAL COCAINE SENSITIVITY

Selective breeding of mice for differences in response to a drug offer s a powerful means for testing hypotheses regarding underlying mechani sms and relationships between drug-induced behaviors. Starting from a heterogeneous stock of mice, we have selectively bred lines of mice fo r 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 show ed progressively greater amounts of cocaine-induced locomotion, with m ice 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 s ensitive to the locomotor activating effects of all doses of cocaine, displaying from 2- to 6-fold greater amounts of cocaine-induced locomo tion 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 loc omotion 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. Th us, the sensitivity to cocaine developed through selection using a sin gle dose of cocaine has generalized to a range of doses of cocaine and to at least one other psychostimulant.