DOPAMINE D-4 RECEPTORS AND EFFECTS OF GUANINE-NUCLEOTIDES ON [H-3] RACLOPRIDE BINDING IN POSTMORTEM CAUDATE-NUCLEUS OF SUBJECTS WITH SCHIZOPHRENIA OR MAJOR DEPRESSION

The densities of dopamine-D-4 receptors were determined in postmortem samples of caudate nucleus from patients with schizophrenia (n = 9) and age-matched controls (n = 10). D-4 receptor binding was defined as the difference between binding sites labeled by [H-3]YM-09151-2 (D-2 + D-3 + D-4 receptors) and those by [H-3]raclopride, in the presence of 5'-guanylylimidodiphosphate (Gpp(NH)p) (D-2 + D-3 receptors). D-4 receptor binding was measurable in all the subjects with schizophrenia (mean = 3.8 pmol/g tissue) but only in 3/10 controls. To determine the specificity of these findings for schizophrenia, D-4 receptor binding was also measured in the caudate nucleus of suicide victims with major depression (n = 6) and age-matched controls (n = 6). A small amount of D-4 binding was noted in some of the controls + depressed subjects and there was no significant difference between controls and patients with major depression. The addition of 200 mu M Gpp(NH)p to the assay significantly increased the amount of specific binding of [H-3]raclopride in control tissues, but not in tissues from subjects with schizophrenia, suggesting an abnormality in the G-protein component coupled to the D-2 receptor. [H-3]Raclopride binding was also significantly increased by Gpp(NH)p in subjects with major depression. These results confirm a previous report of Seeman et al. (1993) and suggest that measurable D-4 receptor binding in the caudate nucleus is more frequent in patients with schizophrenia as compared with normal controls and subjects with major depression and that guanine nucleotides do not enhance [H-3]raclopride binding in schizophrenia. Further study is needed to determine if D-4 binding is increased and if an abnormality in the G-protein component coupled to the D-2 receptor is present in other brain areas in schizophrenia.