Characterizing the effects of 5-HT2C receptor ligands on motor activity and feeding behaviour in 5-HT2C receptor knockout mice |
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Authors: | Paul J. Fletcher Maria Tampakeras Abdelmalik Slassi Methvin Isaac Guy A. Higgins |
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Affiliation: | a Section of Biopsychology, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8 b Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada c Department of Psychology, University of Toronto, Toronto, Ontario, Canada d NPS Pharmaceuticals, 101 College Street, South Tower, 8th Floor, Toronto, Ontario, Canada M5G 1L8 |
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Abstract: | 5-HT2C receptor agonists have considerable therapeutic potential, however there is little in vivo data to compare the potency and selectivity of 5-HT2C receptor agonists. Since 5-HT2C receptor agonists reduce locomotor activity and food intake, changes in these drug-induced behaviours in 5-HT2C receptor knockout mice could provide a means to examine receptor selectivity in-vivo. Initially this study compared older 5-HT2C agonists mCPP and MK212, to newer, apparently more selective compounds: Ro 60-0175, WAY161503, CP809,101 and lorcaserin (APD356) on motor activity in wild-type, and 5-HT2C receptor knockout mice. Two 5-HT2C receptor antagonists SB242084 and SDZ SER 082 were also examined. mCPP did not significantly alter activity in wild-type mice, but enhanced activity in knockout animals. MK212 (3 and 10 mg/kg) and Ro 60-0175 (1 and 3 mg/kg) reduced activity in wild-type but not knockout animals. At 10 mg/kg, Ro 60-0175 reduced activity in knockout animals, suggesting loss of 5-HT2C receptor selectivity. CP809,101 and lorcaserin reduced activity in wild-type but not knockout mice. In subsequent feeding studies, Ro 60-0175 and lorcaserin reduced food intake in wild-type animals only. Selectivity of effect for mCPP was marginal. The antagonist SB242084 increased activity in wild-type animals but not in knockout mice; SB242084 did not alter feeding in either genotype. SDZ SER 082 reduced activity in both genotypes implying poor selectivity for 5-HT2C receptors. The data demonstrate that studying food intake, and particularly motor behaviour, in the 5-HT2C receptor knockout mouse is a useful and relatively simple approach for screening 5-HT2C receptor ligands in vivo. |
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Keywords: | 5-HT2C receptor agonists 5-HT2C receptor antagonists 5-HT2C receptor knockout mouse Motor activity Feeding Lorcaserin 5-HT2 receptor selectivity |
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