Attenuation of cocaine-induced reinstatement of drug seeking in squirrel monkeys by direct and indirect activation of 5-HT2C receptors

5-Hydroxytryptamine (5-HT) transport inhibitors can attenuate the abuse-related effects of cocaine, and the mechanisms underlying this attenuation may involve activation of 5-HT2C receptors. The objective of this study was to investigate the consequences of direct and indirect pharmacological activation of 5-HT2C receptors on reinstatement of cocaine-seeking behavior induced by cocaine priming and a cocaine-paired stimulus. Monkeys were trained to self-administer cocaine under a second-order schedule in which responding was maintained by i.v. cocaine injections and a cocaine-paired stimulus. Drug seeking was extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. During reinstatement tests, the animals received a priming injection of cocaine along with restoration of the cocaine-paired stimulus, but only vehicle was available for self administration. Pretreatment with either the 5-HT transport inhibitor fluoxetine (5.6 mg/kg) or the 5-HT2C receptor agonist Ro 60-0175 (1 mg/kg) attenuated reinstatement of drug seeking by cocaine priming. The reinstatement-attenuating effects of both drugs were reversed by the 5-HT2C receptor antagonist SB 242084 (0.03-0.56 mg/kg). Ro 60-0175 (1 mg/kg) attenuated cocaine-induced reinstatement of drug seeking regardless of whether priming injections were or were not accompanied by restoration of the cocaine-paired stimulus. Ro 60-0175 (0.56 mg/kg) was equally effective whether it was administered acutely or chronically. Finally, Ro 60-0175 (0.3-1 mg/kg) had observable behavioral effects suggestive of anxiolytic-like properties. 5-HT2C receptor mechanisms play a key role in the modulation of cocaine-induced reinstatement by fluoxetine and Ro 60-0175. Direct activation of 5-HT2C receptors may offer a novel, tolerance-free therapeutic strategy for the prevention of cocaine relapse.