Elevation of D4 dopamine receptor mRNA in postmortem schizophrenic brain

The D-4 dopamine (DA) receptor has been proposed to be a target for the development of a novel antipsychotic drug based on its pharmacological and distribution profile. There is much interest in whether D-4 DA receptor levels are altered in schizophrenia, but the lack of an available receptor subtype-specific radioligand made this difficult to quantitate. In this study, we examined whether D-4 mRNA levels are altered in different brain regions of schizophrenics compared to controls. Ribonuclease protection assays were carried out on total RNA samples isolated postmortem from frontal cortex and caudate brain regions of schizophrenics and matched controls. P-32-labelled RNA probes to the D-4 DA receptor and to the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (G3PDH), were hybridised with the RNA samples, digested with ribonucleases to remove unhybridised probe, and separated on 6% sequencing gels. Densitometer analysis on the subsequent autoradiogams was used to calculate the relative optical density of D-4 mRNA compared to G3PDH mRNA. Statistical analysis of the data revealed a 3-fold higher level (P < 0.011) of D-4 mRNA in the frontal cortex of schizophrenics compared to controls. No increase was seen in caudate. D-4 receptors could play a role in mediating dopaminergic activity in frontal cortex, an activity which may be malfunctioning in schizophrenia. (C) 1998 Elsevier Science B.V.