Inhibition of Cocaine and 3,4-Methylenedioxypyrovalerone (MDPV) Self-Administration by Lorcaserin Is Mediated by 5-HT2C Receptors in Rats

Lorcaserin is a serotonin (5-HT)(2C) receptor-preferring agonist approved by the US Food and Drug Administration to treat obesity. Lorcaserin decreases cocaine self-administration in rats and monkeys. Although this effect is partially inhibited by a 5-HT(2C) receptor antagonist (SB242084), lorcaserin also has effects at 5-HT(2A) and 5-HT(1A) receptors, and the relative contribution of these receptors to its anti-cocaine effects has not been investigated. The goals of this study were to determine 1) the potency and effectiveness of lorcaserin to decrease self-administration of cocaine and 3,4-methylenedioxypyrovalerone (MDPV), a common “bath salts” constituent; and 2) the receptor(s) mediating the effects of lorcaserin on cocaine and MDPV self-administration. Male Sprague-Dawley rats (n = 6) were trained to self-administer MDPV under a progressive ratio schedule of reinforcement and maintained under this schedule with daily access to 0.32 mg/kg per infusion of cocaine or 0.032 mg/kg per infusion of MDPV. Dose-response curves for the effects of lorcaserin on cocaine and MDPV self-administration were generated by administering lorcaserin (0.1–5.6 mg/kg) 25 minutes before the start of the session. To assess the effects of 5-HT(2C) (SB242084, 0.1 mg/kg), 5-HT(2A) (MDL100907, 0.1 mg/kg), and 5-HT(1A) (WAY100635, 0.178 mg/kg) receptor antagonists, they were administered 15 minutes before lorcaserin. Lorcaserin decreased cocaine and MDPV self-administration with equal potency. Antagonism of 5-HT(2C) (but not 5-HT(1A) or 5-HT(2A)) receptors blocked the effects of lorcaserin on cocaine and MDPV self-administration. Taken together, these data provide additional support for further development of 5-HT(2C) receptor agonists, such as lorcaserin, for the treatment of stimulant abuse.