Changes in the magnitude of drug-unconditioned stimulus during conditioning modulate cocaine-induced place preference in mice.

Drug reinforcement learning is relevant for the development of addiction. The present study investigated how changes in the magnitude of drug-unconditioned stimulus during associative learning modulate the acquisition and extinction of cocaine-induced conditioned place preference (CPP). B6;129S F2 mice were conditioned by three dosing schedules of cocaine: (1) ascending, (2) fixed and (3) descending daily doses. Following acquisition of CPP, extinction was induced by (1) context re-exposure, (2) reconditioning by saline and (3) reconditioning by descending doses of cocaine. The magnitude of CPP following conditioning by daily ascending doses of cocaine (2, 4, 8 and 16 mg/kg) was significantly higher than that obtained from conditioning by either a fixed daily dose (16 mg/kg × 4 days) or daily descending doses (24, 12, 6 and 3 mg/kg). Extinction following context re-exposure showed persistent CPP in the 'ascending' group compared to the other two groups. However, extinction via reconditioning by saline was equally effective in all groups. Interestingly, reconditioning by descending doses of cocaine (1) extinguished CPP and (2) resulted in partial resistance to the reinstatement of conditioned response by cocaine priming. Results underscore the significance of daily changes in cocaine dosage in the development and extinction of drug-induced conditioned response. Increase and decrease in cocaine dosage strengthens and weakens cocaine-associated memory, respectively. Moreover, extinction by 'tapering down' drug reward may be superior to extinction by saline.