title: Biochemical evidence that the atypical antipsychotic drugs clozapine and risperidone block 5-HT(2C) receptors in vivo.
abstract: Clozapine and risperidone are two atypical antipsychotic drugs which bind, among other receptors, to 5-HT(2C) receptor subtypes. They inhibit the basal inositol phosphate production in mammalian cells expressing rat or human 5-HT(2C) receptors. This biochemical effect is indicative of inverse agonist activity at these receptors. There is evidence that 5-HT(2C) receptors are involved in the control of the activity of central dopaminergic system. Therefore, the effects of clozapine (5 mg/kg ip), risperidone (0.08 mg/kg ip) and of the typical antipsychotic haloperidol (0.1 mg/kg ip) were studied on the extracellular concentration of dopamine (DA) in the nucleus accumbens of chloral hydrate-anesthetized rats, using intracerebral microdialysis. When injected alone, clozapine, risperidone and haloperidol caused only small variations in DA efflux. However, clozapine and risperidone completely prevented the inhibitory action of RO 60-0175 (1 mg/kg ip), a 5-HT(2C) receptor agonist, on DA release. On the other hand, haloperidol did not affect RO 60-0175-induced decrease in DA release. Taken together, these data indicate that clozapine and risperidone, unlike haloperidol, are capable of blocking 5-HT(2C) receptors in the nucleus accumbens. It is concluded that the experimental model presented in this study might represent a simple and useful in vivo biochemical method to test the effect of putative atypical antipsychotic drugs on 5-HT(2C) receptors.
authors.affiliation: Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro, Chieti, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Matteo
authors.forename: Marisa
authors.initials: M
authors.lastname: Cacchio
authors.forename: Camillo
authors.initials: C
authors.lastname: Di Giulio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Giovanni
authors.forename: Ennio
authors.initials: E
authors.lastname: Esposito
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004563:Electrochemistry; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects*; D018967:Risperidone / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone; D004298:Dopamine