THE EFFECTS OF CLOZAPINE AND HALOPERIDOL ON SEROTONIN-1A, SEROTONIN-2A AND SEROTONIN-2C RECEPTOR GENE-EXPRESSION AND SEROTONIN METABOLISM IN THE RAT FOREBRAIN

The therapeutic and side-effect profiles of clozapine differ from thos e of typical antipsychotic drugs such as haloperidol. Effects on the s erotonin system, especially serotonin-2 receptors, may contribute to c lozapine's atypicality. We injected rats for 14 days with clozapine (2 5 mg/kg/day) or haloperidol (2 mg/kg/day), and measured three aspects of the serotonin system in forebrain regions: abundance of serotonin-2 A, -2C and -1A receptor messenger RNAs by in situ hybridization histoc hemistry; serotonin-2A and -1A binding sites using receptor autoradiog raphy, and levels of serotonin and 5-hydroxyindoleacetic acid with hig h-performance liquid chromatography. Clozapine administration decrease d serotonin-2A receptor messenger RNA and the density of [H-3]ketanser in binding in cingulate and frontal cortex, but not in piriform cortex . Serotonin-1A receptor expression and serotonin-2C receptor messenger RNA were unchanged in all areas. The treatment markedly decreased ser otonin and 5-hydroxyindoleacetic acid concentrations in striatum with similar trends in cortex and hippocampus. Haloperidol administration d id not affect the expression of the three serotonin receptors, but was associated with a modest reduction of striatal and hippocampal 5-hydr oxyindoleacetic acid. The selective reduction of serotonin-2A receptor s confirms earlier findings and supports the view that this receptor m ay have relevance for the actions of clozapine. The fact that the enco ding messenger RNA is decreased shows that the the effect is mediated at the level of gene expression. In contrast, the unchanged serotonin- 2C receptor messenger RNA level indicates that the reported loss of se rotonin-2C receptors after clozapine treatment is due to translational or post translational events. The relationship between the reduction in serotonin-2A receptor expression and the altered serotonin metaboli sm remains unclear. Copyright (C) 1996 IBRO.