ELEVATION OF D-4 DOPAMINE-RECEPTOR MESSENGER-RNA IN POSTMORTEM SCHIZOPHRENIC BRAIN

The D-4 dopamine (DA) receptor has been proposed to be a target for th e development of a novel antipsychotic drug based on its pharmacologic al and distribution profile. There is much interest in whether D-4 DA receptor levels are altered in schizophrenia, but the lack of an avail able receptor subtype-specific radioligand made this difficult to quan titate. In this study, we examined whether D-4 mRNA levels are altered in different brain regions of schizophrenics compared to controls. Ri bonuclease protection assays were carried out on total RNA samples iso lated postmortem from frontal cortex and caudate brain regions of schi zophrenics and matched controls. P-32-labelled RNA probes to the D-4 D A receptor and to the housekeeping gene, glyceraldehyde-3-phosphate de hydrogenase (G3PDH), were hybridised with the RNA samples, digested wi th ribonucleases to remove unhybridised probe, and separated on 6% seq uencing gels. Densitometer analysis on the subsequent autoradiogams wa s used to calculate the relative optical density of D-4 mRNA compared to G3PDH mRNA. Statistical analysis of the data revealed a 3-fold high er level (P < 0.011) of D-4 mRNA in the frontal cortex of schizophreni cs compared to controls. No increase was seen in caudate. D-4 receptor s could play a role in mediating dopaminergic activity in frontal cort ex, an activity which may be malfunctioning in schizophrenia. (C) 1998 Elsevier Science B.V.