The effects of antipsychotics with 5-HT(2C) receptor affinity in behavioral assays selective for 5-HT(2C) receptor antagonist properties of compounds.
Many antipsychotics have marked antagonist effects at 5-hydroxytryptamine (5-HT(2C)) receptors in vitro, which, however, have been difficult to show in behavioral assays. Here, we used two assays - hypolocomotion and hypophagia induced by the 5-HT(2C) receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) - to try to characterize the 5-HT(2C) receptor antagonist properties of antipsychotics in vivo. Clozapine, olanzapine, pipamperone, and trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz-[2,3:6, 7]oxepino[4,5-C] pyrrolidino maleate (ORG 5222), modestly, but significantly, attenuated mCPP (10 mg/kg)-induced hypolocomotion. In contrast, risperidone and loxapine were inactive. The putative antipsychotic ORG 5222 significantly attenuated mCPP (5 mg/kg)-induced hypophagia, whereas the other antipsychotics were inactive. Selective antagonists at dopamine D(2)-like receptors, alpha(1)-adrenoceptors, alpha(2)-adrenoceptors, or muscarinic receptors were not able to antagonize the effects of mCPP in either assay. The results suggest that mCPP-induced hypolocomotion can be used to characterize the 5-HT(2C) receptor antagonist properties of antipsychotics, whereas mCPP-induced hypophagia appeared to be sensitive only to compounds highly selective for 5-HT(2C) receptors. Together, these assays may help to characterize functional, in vivo, 5-HT(2C) receptor antagonist properties of antipsychotics.
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Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, 81106, Castres, France. eric.prinssen@pierre-fabre.com
Koek
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Kleven
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D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D014150:Antipsychotic Agents; D010879:Piperazines; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C015068:1-(3-chlorophenyl)piperazine