Regulation of serotonin 5-HT 2C receptors in the rat choroid plexus after acute clozapine treatment

Abstract

We studied the effects of acute clozapine and haloperidol treatments on 5-HT 2C receptor binding characteristics and 5-HT 2C 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 ( B max) of 5-HT 2C receptors by 20–25% with no marked change in the affinity ( K d). 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-HT 2C receptor binding sites. The decrease was more robust with the higher dose of clozapine. For comparison, both doses of clozepine, unlike haloperidol, decreased equally the density of 5-HT 2A receptors in the frontal cortex by about 45%, whereas none of the treatments altered dopamine D 2 receptor characteristics in the striatum. The K d value of 5-HT 2A receptors was significantly increased after the dose of 25 mg/kg of clozapine. These clozapine treatments failed to decrease the maximal 5-HT 2C 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-HT 2C receptor-mediated phosphoinositide hydrolysis. To summarize, the present data show that a single injection of clozapine is able to reduce the density of 5-HT 2C receptors but fails to cause functional desensitization of 5-HT 2C receptors in the rat choroid plexus.