Rationale A key role has been identified for the circadian locomotor output cycles kaput (Clock) gene in the regulation of drug reward. Mice bearing a dominant negative mutation in the Clock gene (ClockΔ19 mice) exhibit increased cocaine-induced conditioned place preference, reduced anxiety- and depression-like behavior, increased sensitivity to intracranial self-stimulation, and increased dopaminergic cell activity in the ventral tegmental area. Objectives We sought to determine if this hyperhedonic phenotype extends to cocaine self-administration and measures of motivation. Methods Two separate serial testing procedures were carried out (n07-10/genotype/schedule). Testing began with acquisition of sucrose pellet self-administration, implantation of intravenous catheter, acquisition of cocaine self-administration, and dose-response testing (fixed ratio or progressive ratio). To evaluate diurnal variations in acquisition behavior, these sessions occurred at Zeitgeber 2 (ZT2) or ZT14. Results WT and ClockΔ19 mice exhibited similar learning and readily acquired food self-administration at both ZT2 and ZT14. However, only ClockΔ19 mice acquired cocaine self-administration at ZT2. A greater percentage of ClockΔ19 mice reached acquisition criteria at ZT2 and ZT14. ClockΔ19 mice self-administered more cocaine than WT mice. Using fixed ratio and progressive ratio schedules of reinforcement dose-response paradigms, we found that cocaine is a more efficacious reinforcer in ClockΔ19 mice than in WT mice. Conclusion Our results demonstrate that the Clock gene plays an important role in cocaine reinforcement and that decreased CLOCK function increases vulnerability for cocaine use.
Bibliographical noteFunding Information:
Acknowledgements This study was supported by NIH grants DA-07290 and AA-020452 (to ARO), DA-023988 (to CAM), and DA-010460 (to DWS). The authors thank Edgardo Falcon, Andrea Gill-man, Alexandria Nugent, Daniel Guzman, Elizabeth Gordon, and Ariel Ketcherside for technical help and advice. ClockΔ19 mice were a generous gift from Joseph Takahashi.
- Clock gene
- Cocaine self-administration
- Genetic animal models