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, 364 (2), 359-366

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

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

Brenda M Gannon et al. J Pharmacol Exp Ther.

Abstract

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-HT2C receptor antagonist (SB242084), lorcaserin also has effects at 5-HT2A and 5-HT1A 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-HT2C (SB242084, 0.1 mg/kg), 5-HT2A (MDL100907, 0.1 mg/kg), and 5-HT1A (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-HT2C (but not 5-HT1A or 5-HT2A) receptors blocked the effects of lorcaserin on cocaine and MDPV self-administration. Taken together, these data provide additional support for further development of 5-HT2C receptor agonists, such as lorcaserin, for the treatment of stimulant abuse.

Figures

Fig. 1.
Fig. 1.
Dose-dependent attenuation of self-administration of 0.32 mg/kg per inf cocaine (circles) and 0.032 mg/kg per inf MDPV (squares) by lorcaserin in individual subjects (n = 6, first and second rows) and at the group level (bottom row). Abscissa: V represents vehicle pretreatment, whereas numbers refer to the dose of lorcaserin administered (intraperitoneally) 25 minutes before the self-administration session, expressed as milligrams per kilogram on a log scale. Ordinate: total number of infusions earned in the self-administration session. Filled symbols indicate the first dose of lorcaserin that decreased the number of infusions earned by ≥50% for each individual subject (i.e., dose X of lorcaserin).
Fig. 2.
Fig. 2.
The effect of dose X of lorcaserin (open symbols) and vehicle (gray symbols) on cocaine (circles) and MDPV (squares) self-administration under a progressive ratio schedule of reinforcement (n = 6). Abscissa: numbers refer to the unit dose of cocaine (left) or MDPV (right) available for infusion, expressed as milligram per kilogram per inf on a log scale. Ordinate: total infusions ± S.E.M. earned during the self-administration session.
Fig. 3.
Fig. 3.
The effect of selective 5-HT2C (top row), 5-HT2A (middle row), or 5-HT1A (bottom row) receptor antagonists on lorcaserin-induced decreases in 0.32 mg/kg per inf cocaine (left) and 0.032 mg/kg per inf MDPV (right) and self-administration (n = 6). Abscissa: V represents vehicle pretreatment, log-unit dose of lorcaserin relative to the first dose of lorcaserin that decreased the number of infusions earned by ≥50% for each individual subject (as shown in Fig. 1). Ordinate: total infusions ± S.E.M. earned in the self-administration session.

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