Cocaine self-administration under fixed and progressive ratio schedules of reinforcement: comparison of C57BL/6J, 129X1/SvJ, and 129S6/SvEvTac inbred mice

Rationale Combining strains to generate mutant mice may obscure conclusions regarding the targeted gene. Specifically, cocaine may have reduced reinforcing effects in 129 substrains compared to the C57BL/6 strain, commonly used for ES cells and breeding, respectively. Objectives We tested the hypothesis that reinforcing effects of cocaine differ between the C57BL/6J strain and two substrains of 129, 129X1/SvJ and 129S6/SvEvTac. Methods To assess and reduce performance differences, operant responding was established with liquid food as a reinforcer and evaluated under fixed and progressive ratio schedules. Dose–effect functions for intravenous cocaine self-administration were then determined under both schedules. Finally, reinforced and nonreinforced manipulanda were reversed to assess acquisition of self-administration using a previously nonreinforced response. Results Relative to C57BL/6J mice, 129X1/SvJ mice showed decreased reinforcing effects of low-magnitude food and cocaine reinforcers. Dose–effect functions for cocaine self-administration were comparable between C57BL/6J and 129S6/SvEvTac mice, despite delayed acquisition of operant behaviors and rightward shifts in the food concentration–effect functions in 129S6/SvEvTac mice. A high cocaine dose clearly served as a positive reinforcer in all three strains in a reversal procedure. Conclusions Relative to C57BL/6J mice, the reinforcing effects of cocaine were diminished in 129X1/SvJ mice, but only for low cocaine doses, and a similar profile was observed with food reinforcement. 129S6/SvEvTac mice required more extensive operant training than C57BL/6J mice did, but after acquisition, reinforcing effects of cocaine were similar in the two strains. We suggest that comparable phenotypes observed in gene-targeting studies may result from genetic background, whereas more profound or qualitatively different phenotypes may be more confidently attributed to targeted mutations.