Regulation of serotonin 5-HT2C receptors in the rat choroid plexus after acute clozapine treatment.
We studied the effects of acute clozapine and haloperidol treatments on 5-HT2C receptor binding characteristics and 5-HT2C receptor-mediated phosphoinositide hydrolysis in the rat choroid plexus. Scatchard analysis (with [3H]mesulergine) showed that acute clozapine treatment (10 and 25 mg/kg) decreased the density (Bmax) of 5-HT2C receptors by 20-25% with no marked change in the affinity (Kd). Quantitative autoradiography was in accordance with homogenate binding studies showing that acute clozapine treatment, unlike haloperidol (0.5 mg/kg), decreased the number of both agonist ([125I](+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, [125I]DOI) and antagonist ([3H]mesulergine) labeled 5-HT2C receptor binding sites. The decrease was more robust with the higher dose of clozapine. For comparison, both doses of clozapine, unlike haloperidol, decreased equally the density of 5-HT2A receptors in the frontal cortex by about 45%, whereas none of the treatments altered dopamine D2 receptor characteristics in the striatum. The Kd value of 5-HT2A receptors was significantly increased after the dose of 25 mg/kg of clozapine. These clozapine treatments failed to decrease the maximal 5-HT2C receptor-mediated phosphoinositide hydrolysis response. The higher dose of clozapine increased 5-HT-induced phosphoinositide hydrolysis response, but also decreased significantly the basal levels of phosphoinositide hydrolysis. Haloperidol did not significantly affect the 5-HT2C receptor-mediated phosphoinositide hydrolysis. To summarize, the present data show that a single injection of clozapine is able to reduce the density of 5-HT2C receptors but fails to cause functional desensitization of 5-HT2C receptors in the rat choroid plexus.
Kuoppamäki
M
M
Department of Pharmacology, University of Turku, Finland.
Seppälä
T
T
Syvälahti
E
E
Hietala
J
J
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001345:Autoradiography; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002831:Choroid Plexus / Q000187:drug effects / Q000378:metabolism*; D003024:Clozapine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004873:Ergolines / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D007279:Injections, Subcutaneous; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D000662:Amphetamines; D000978:Antiparkinson Agents; D004873:Ergolines; D010716:Phosphatidylinositols; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D003024:Clozapine; D006220:Haloperidol; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; C031649:mesulergine