Serotonin depletion attenuates cocaine seeking but enhances sucrose seeking and the effects of cocaine priming on reinstatement of cocaine seeking in rats.

RATIONALE: Acute serotonin (5-HT) depletion by the tryptophan hydroxylase inhibitor, para-chlorophenylalanine, attenuates cocaine seeking in rats. OBJECTIVE: The present study examined the effects of chronic 5-HT depletion on cocaine- and sucrose seeking using the 5-HT-selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). METHODS: Separate groups of rats were trained to lever press for cocaine infusions (0.33 mg/kg/0.1 ml, i.v.) or for sucrose pellets (45 mg Noyes) on a fixed ratio (FR) 1 schedule of reinforcement during daily 2-h sessions. Subsequently, animals received i.c.v. infusions of either vehicle or 5,7-DHT (150 microg/6 microl or 200 microg/20 microl). After a minimum of 10 days post-lesion, cocaine- and sucrose seeking were measured as lever presses in the absence of reinforcement (extinction). Some cocaine-trained animals were also assessed for the re-establishment of self-administration and reinstatement of extinguished cocaine seeking by i.v. cocaine priming injections and response-contingent presentations of cocaine-paired stimuli. RESULTS: 5-HT depletion by the 150 microg/6 microl dose of 5,7-DHT failed to alter cocaine- and sucrose seeking despite producing a 42-77% depletion of 5-HT in limbic terminal regions. The 200 microg/20 microl dose of 5,7-DHT attenuated cocaine seeking but enhanced sucrose seeking during extinction and produced a 55-85% depletion of 5-HT. In addition, cocaine-paired cues and cocaine priming reinstated cocaine-seeking behavior, and responding was enhanced in 5,7-DHT-treated animals relative to vehicle-treated controls at the 1 mg/kg/0.1 ml priming dose. However, re-establishment of cocaine self-administration was not altered by 5,7-DHT. CONCLUSION: The results suggest that 5-HT depletion may attenuate cocaine seeking but may enhance sucrose seeking when animals are tested during extinction. Furthermore, 5-HT depletion may enhance cocaine seeking produced by cocaine itself. Together these findings suggest that 5-HT depletion may have opposite effects on incentive motivation for cocaine during abstinence versus relapse.

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.