Serotonin depletion attenuates cocaine-seeking behavior in rats

Rationale: Alterations in serotonin (5-HT) neurotransmission during cocaine withdrawal may be involved in incentive motivation for cocaine. Objective: The present study examined the effects of 5-HT depletion on cocaine- and food-seeking behavior (i.e., non-reinforced operant responding). Methods: Separate groups of rats were trained to lever press for cocaine infusions (0.33 mg/kg/0.1 ml, i.v.) or for food pellets (45-mg Noyes food pellets) on a fixed-ratio one schedule of reinforcement during 14 daily 2-h sessions. Half of each group then received treatment with either saline or the tryptophan hydroxylase inhibitor para-chlorophenylalanine (p-CPA; 100 mg/kg, i.p.) on post-training day 5 and day 6. Twenty-four hours after their last treatment, rats were tested for cocaine- or food-seeking behavior by measuring operant responding in the absence of reinforcement until they reached an extinction criterion of no responses for 30 min. Animals were sacrificed 24 h after testing and brain 5-HT levels in various regions were quantified. Results: In cocaine-trained animals, p-CPA treatment significantly decreased cocaine-seeking behavior and produced a trend toward a decrease in extinction latency relative to saline treatment. In food- trained animals, p-CPA treatment failed to alter any of the behavioral measures during testing, suggesting that p-CPA treatment did not alter the animals' memory or ability to perform an operant response. p-CPA significantly depleted 5-HT by 73-85% in every brain region examined. Conclusion: The results suggest that decreasing 5-HT neurotransmission may decrease incentive motivation for cocaine.