Influence of individual differences and chronic fluoxetine treatment on cocaine-seeking behavior in rats

Rationale: Clinical studies examining the efficacy of the selective serotonin reuptake inhibitor, fluoxetine, in decreasing craving and cocaine use have been inconsistent. Objective: To understand better the effects of fluoxetine treatment on incentive motivation for cocaine, the present study assessed the effects of chronic fluoxetine treatment on cocaine-seeking behavior in rats following exposure to a cocaine self-administration environment or a cocaine priming injection. Methods: Rats were trained to press a lever for a cocaine reinforcer (0.5 mg/kg per 0.1 ml, IV) or received yoked administration of saline. They were then withdrawn from this regimen and given 20 daily injections of saline or fluoxetine (3.0 mg/kg, IP). Twenty-four hours after the last injection, the rats were placed in the self-administration environment and cocaine-seeking behavior (i.e., non-reinforced lever pressing) was measured for 90 min. Reinstatement of extinguished cocaine-seeking behavior was then measured for 60 min following a saline injection and for 90 min following a cocaine priming injection (15 mg/kg, IP). Results: Chronic fluoxetine treatment attenuated cocaine-seeking behavior following exposure to the self-administration environment in most rats (n=16), but enhanced cocaine-seeking behavior in two rats. Furthermore, the treatment failed to alter cocaine-seeking behavior following a cocaine priming injection. Interestingly, the amount of cocaine intake during self-administration training correlated with cocaine-seeking behavior following the cocaine priming injection. In fact, the priming injection reinstated cocaine-seeking behavior only in rats with high, but not low, cocaine intake based on a median split. Conclusions: These results suggest that chronic fluoxetine treatment decreases motivation for cocaine when animals are in a cocaine-free state. Furthermore, individual differences in cocaine use are related to individual differences in sensitivity to the incentive motivational effects of cocaine priming.