The D4 dopamine 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 D4 DA receptor levels are altered in schizophrenia, but the lack of an available receptor subtype specific radioligand makes this difficult to quantitate. In this study, we examined the antomical distribution of D4 mRNA in human cortex and adressed the issue whether D4 mRNA levels are altered in different brain regions of schizophrenics compared to controls. Ribonuclease protection assays were carried out on total RNA samples isolated post-mortem from frontal cortex and caudate brain regions of schizophrenics and matched controls. [ 32 P] RNA probes to the D4 dopamine 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 D4 mRNA compared to G3PDH mRNA. The distribution of D4 mRNA was widespread across all 13 anatomical structures of CNS of control brain tissue including areas assosiated with the limbic and basal ganglia. The highest expression was found though in human retina. Regarding the comparison study of D4 gene expression in controll and schizophrenic post-mortem brain, statistical analysis of the data revealed a three-fold higher level (p<0.02) of D4 mRNA in the frontal cortex of schizophrenics compared to controls. No increase was seen in caudate. D4 receptors could play a role in mediating dopaminergic activity in frontal cortex , an activity which may be malfunctioning in schizophrenia.