Characterizing the effects of 5-HT(2C) receptor ligands on motor activity and feeding behaviour in 5-HT(2C) receptor knockout mice.
5-HT(2C) receptor agonists have considerable therapeutic potential, however there is little in vivo data to compare the potency and selectivity of 5-HT(2C) receptor agonists. Since 5-HT(2C) receptor agonists reduce locomotor activity and food intake, changes in these drug-induced behaviours in 5-HT(2C) receptor knockout mice could provide a means to examine receptor selectivity in-vivo. Initially this study compared older 5-HT(2C) 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-HT(2C) receptor knockout mice. Two 5-HT(2C) 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-HT(2C) 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-HT(2C) receptors. The data demonstrate that studying food intake, and particularly motor behaviour, in the 5-HT(2C) receptor knockout mouse is a useful and relatively simple approach for screening 5-HT(2C) receptor ligands in vivo.
Fletcher
Paul J
PJ
Section of Biopsychology, Centre for Addiction and Mental Health, Toronto, Ontario, Canada M5T 1R8. paul_fletcher@camh.net
Tampakeras
Maria
M
Sinyard
Judy
J
Slassi
Abdelmalik
A
Isaac
Methvin
M
Higgins
Guy A
GA
D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology; D020372:Dexfenfluramine / Q000008:administration & dosage / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D005021:Ethylamines / Q000008:administration & dosage / Q000494:pharmacology; D005247:Feeding Behavior / Q000187:drug effects* / Q000502:physiology; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009287:Naphthyridines / Q000008:administration & dosage / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*
C544865:4,5,7a,8,9,10,11,11a-octohydro-7H-10-methylindolol(1,7bc)(2,6)-napthyridine; C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; C502777:8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino(1,2-a)quinoxalin-5(6H)-one; D000631:Aminopyridines; D001552:Benzazepines; C518685:CP-809,101; D005021:Ethylamines; D007211:Indoles; D008024:Ligands; D009287:Naphthyridines; D010879:Piperazines; D011719:Pyrazines; D011810:Quinoxalines; D044405:Receptor, Serotonin, 5-HT2C; C103848:Ro 60-0175; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C014896:6-chloro-2-(1-piperazinyl)pyrazine; C506658:lorcaserin; D020372:Dexfenfluramine; C015068:1-(3-chlorophenyl)piperazine