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Rationale: The place conditioning procedure is increasingly used to study relapse in drug seeking in mice. However, the retention course of drug-induced place preference has not been systematically characterized., Methods: The effects of cocaine doses and number of conditioning trials on both the magnitude and the persistence of cocaine-induced conditioned place preference (CPP) were investigated in C57BL/6J mice. Twelve groups of animals were injected with saline, 4, 8 or 12 mg/kg cocaine (i.p.) and submitted to an unbiased counterbalanced place conditioning protocol including one, two or four drug-pairing sessions. Subsequently, the animals were tested at various time intervals after the last conditioning session., Results: One cocaine-pairing session was insufficient to induce a CPP. Two and four pairing sessions resulted in significant place preferences of similar magnitude for all tested doses of cocaine, the place preference induced by the greatest number of pairing sessions being the strongest. In the two-pairing groups, place preference lasted less than 14 days for any tested dose of cocaine. In contrast, all four-pairing groups still showed significant place preference 28 days after the last conditioning session. However, the magnitude of cocaine place preference slowly declined at a rate that was dependent upon cocaine dose. On the 35-day post-conditioning interval, only the 12-mg/kg cocaine group still displayed a significant place preference, whereas place preference was undetectable at 42 and 56 days post-conditioning for all groups., Conclusions: The number of cocaine-pairing sessions, but not cocaine dose, affected the magnitude of cocaine place preference in mice when tested 1 day after the last conditioning session. In contrast, both cocaine doses and the number of pairing sessions affected the persistence of cocaine place preference. Overall, these results demonstrate that cocaine-induced place preference is a long lasting phenomenon that is strongly affected by the number of drug-pairing trials.

The histaminergic system has been speculated to be involved in the inhibitory control of drug reward, H1 and H2 antagonists having been found to potentiate conditioned place preference induced by morphine or cocaine. In contrast, the role of H3 receptors in cocaine-induced place preference is still unknown. The present study tested the effects of thioperamide (0, 10 and 20 mg/kg, i.p.), an H3 autoreceptor antagonist, on the development of a conditioned place preference induced by cocaine (0, 2 and 8 mg/kg, i.p.) in C57BL/6J mice. Thioperamide was injected 10 min before each cocaine-pairing session. The activity scores recorded on the first cocaine-pairing session were also used to test the effects of thioperamide on cocaine-induced locomotor activity. Thioperamide alone had no reinforcing effects and did not affect the conditioned place preference induced by 8 mg/kg cocaine. However, thioperamide dose-dependently revealed a conditioned place preference induced by 2 mg/kg cocaine, a dose that was inactive per se. Finally, thioperamide dose-dependently potentiated the stimulant effects of cocaine, in spite of its slight hypolocomotor effect when given alone. Our results strongly suggest that H3 antagonists potentiate the stimulant and reinforcing effects of cocaine in mice.

It has been speculated that an individual's response to novelty is a reliable predictor of its vulnerability to develop addiction. However, the relationships between response to novelty and the development of drug-induced conditioned place preference are still unclear. The present study investigates the relationships between locomotor responses to novelty, cocaine-induced locomotor stimulation and conditioned place preference in C57BL/6J mice with multiple regression analyses. Four groups of mice receiving saline, 4, 8 or 12 mg/kg cocaine (i.p.) were submitted to an 8-day unbiased counterbalanced place conditioning protocol. Levels of locomotion on the pre-conditioning session were used as a score of locomotor response to a novel environment. The locomotor activity on the first cocaine-pairing session of the conditioning procedure served as a measure of the locomotion-activating response to a single injection of cocaine. Cocaine-induced dose-dependent locomotor stimulant effects and a significant place preference at all tested doses. A positive correlation was found between the locomotor responses to novelty and the locomotor stimulant effects of cocaine, but was significant only for the highest dose of cocaine (12 mg/kg). In contrast, there was a negative correlation between the locomotor response to novelty and the conditioned place preference induced by 4 mg/kg cocaine. Finally, the locomotor stimulant effects of cocaine do not correlate with cocaine-induced conditioned place preference at any tested dose of cocaine. The relationships between locomotor response to novelty and both cocaine-induced stimulant and rewarding effects can be differentially affected by the dose in inbred C57BL/6J mice.

The emergence of a conditioned cocaine-induced hyperlocomotion was examined in C57BL/6J mice using a procedure that has not been used previously. Two days after a session of preexposure to the test chambers under saline, a first group of mice (cocaine-cued) received five once-daily injections of 10-mg/kg s.c. cocaine every other day (on the odd days of the chronic treatment period) and a saline injection on the 5 days following each cocaine injection day (on the even days of the treatment period), in all cases before being placed in the test chamber. Another group of mice (saline-cued) received 10 injections of saline on both the even and the odd days in the same context, and a third group of mice (cocaine-uncued) received five injections of saline on the even days in the test context and five injections of cocaine on the odd days in an alternative context. On the odd days sessions, the cocaine-cued group showed significant repeated increases in locomotion without behavioural sensitisation being induced, whereas the saline-cued levels of locomotion remained on baseline levels. On the first even session, the three groups did not differ from each other and showed lower levels of locomotion than on the preexposure session. During the two following even sessions, the cocaine-cued group showed an increase in locomotion that levelled off on the two remaining sessions, whereas the saline-cued and the cocaine-uncued groups (which presented comparable values) exhibited significantly lower levels of locomotion. That pattern of successive placebo responses resembles the typical S-shaped development of a Pavlovian conditioned response, albeit the increase described here was quite rapid. The protocol used here may provide an additional method for the experimental analysis of stimulant-induced conditioned placebo activity.