5-HT1A AND 5-HT2A RECEPTOR MESSENGER-RNAS AND BINDING-SITE DENSITIES ARE DIFFERENTIALLY ALTERED IN SCHIZOPHRENIA

We have investigated 5-HT1A (serotonin(1A)) and 5-HT2A (serotonin(2A)) receptor mRNA abundance and binding site densities in various neocort ical and hippocampal regions of schizophrenics and control subjects. A ge, agonal state (brain pH), and post mortem interval were included wh ere necessary as covariates in our analyses. In schizophrenics, 5-HT1A binding site densities, determined autoradiographically by [H-3]8-hyd roxy-2,3-(dipropylamino)-tetralin ([H-3]8-OH-DPAT), were significantly increased (+23%) in the dorsolateral prefrontal cortex, with a simila r trend in anterior cingulate gyrus. These increases were not accompan ied by any change in 5-HT1A receptor mRNA. No differences between the groups in [H-3]8-OH-DPAT binding or 5-HT1A receptor mRNA were seen in superior temporal gyrus, striate cortex, or hippocampus. 5-HT2A bindin g sites, determined by [H-3]ketanserin, were decreased in the dorsolat eral prefrontal cortex (-27%) and parahippocampal gyrus (-38%) of schi zophrenics, with a similar trend in cingulate gyrus, but not in superi or temporal gyrus or striate cortex. 5-HT2A receptor mRNA abundance wa s reduced in schizophrenics in the dorsolateral prefrontal (-49%), sup erior temporal (-48%), anterior cingulate (-63%) and striate (-63%) co rtices, brit not in parahippocampal gyrus. Parallel analyses of rat br ain tissue showed no changes in 5-HT1A or 5-HT2A receptor mRNAs or bin ding site densities after chronic administration of haloperidol. These data show that schizophrenia is associated with alterations in the ex pression of central 5-HT1A and 5-HT2A receptors. They confirm reports of increased 5-HT1A and decreased 5-HT2A binning site densities in pre frontal cortex, and reveal more extensive decreases in 5-HT2A receptor gene expression at the mRNA level. The resulting imbalance in the 5-H T1A to 5-HT2A receptor ratio, when considered in terms of the chemoarc hitectural distribution of these receptors, may contribute to an impai rment of corticocortical association pathways. The apparent dissociati on of the normal relationships between the abundance of each 5-HT rece ptor and its mRNA in schizophrenia introduces a separate complexity to the data, which may give clues to the underling molecular mechanisms. (C) 1996 American College of Neuropsychopharmacology