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J Pharmacol Exp Ther. 2015 Dec;355(3):381-5. doi: 10.1124/jpet.115.228148. Epub 2015 Sep 17.

Directly Observable Behavioral Effects of Lorcaserin in Rats.

Author information

1
Departments of Pharmacology (K.M.S., C.P.F.) and Psychiatry (C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas and Chemical Biology Research Laboratory, Department of Health and Human Services, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (K.C.R.).
2
Departments of Pharmacology (K.M.S., C.P.F.) and Psychiatry (C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas and Chemical Biology Research Laboratory, Department of Health and Human Services, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (K.C.R.) france@uthscsa.edu.

Abstract

(1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (lorcaserin) is approved by the United States Food and Drug Administration for treating obesity, and its therapeutic effects are thought to result from agonist activity at serotonin (5-HT)2C receptors. Lorcaserin has affinity for other 5-HT receptor subtypes, although its activity at those subtypes is not fully described. The current study compared the behavioral effects of lorcaserin (0.0032-32.0 mg/kg) to the effects of other 5-HT receptor selective agonists in rats (n = 8). The 5-HT2C receptor selective agonist 1-(3-chlorophenyl)piperazine (mCPP, 0.032-1.0 mg/kg) and lorcaserin induced yawning which was attenuated by the 5-HT2C receptor selective antagonist 6-chloro-5-methyl-N-(6-[(2-methylpyridin-3-yl)oxy]pydidin-3-yl)indoline-1-carboxamide (1.0 mg/kg). The 5-HT2A receptor selective agonist 2,5-dimethoxy-4-methylamphetamine (0.1-3.2 mg/kg) induced head twitching, which was attenuated by the 5-HT2A receptor selective antagonist R-(+)-2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol] (MDL 100907, 0.01 mg/kg), lorcaserin (3.2 mg/kg), and mCPP (3.2 mg/kg). In rats pretreated with MDL 100907 (1.0 mg/kg), lorcaserin also induced head twitching. At larger doses, lorcaserin produced forepaw treading, which was attenuated by the 5-HT1A receptor selective antagonist N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridyl)cyclohexanecarboxamide (0.178 mg/kg). While the behavioral effects of lorcaserin in rats are consistent with it having agonist activity at 5-HT2C receptors, these data suggest that at larger doses it also has agonist activity at 5-HT2A and possibly 5-HT1A receptors. Mounting evidence suggests that 5-HT2C receptor agonists might be effective for treating drug abuse. A more complete description of the activity of lorcaserin at 5-HT receptor subtypes will facilitate a better understanding of the mechanisms that mediate its therapeutic effects.

PMID:
26384326
PMCID:
PMC4658489
DOI:
10.1124/jpet.115.228148
[Indexed for MEDLINE]
Free PMC Article

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