Extrastriatal and striatal D(2) dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia.

BACKGROUND: Both traditional and atypical antipsychotics have been hypothesised to be effective in schizophrenia through limbic and cortical D(2) dopamine receptor blockade. AIMS: To investigate this hypothesis with the D(2)/D(3)-selective positron emission tomography (PET) probe [(76)Br]-FLB457. METHOD: PET scans were performed on 6 controls and 18 patients with schizophrenia treated with haloperidol or with risperidone, clozapine, amisulpride or olanzapine. RESULTS: The D(2) dopamine receptor blockade was high in the temporal cortex with both haloperidol and atypical antipsychotics. The atypicals, however, induced a significantly lower D(2) binding index than haloperidol in the thalamus and in the striatum. CONCLUSIONS: Results suggest that cortical D(2) dopamine receptors are a common target of traditional and atypical antipsychotics for therapeutic action. Higher in vivo binding to the D(2) receptors in the cortex than in the basal ganglia is suggested as an indicator of favourable profile for a putative antipsychotic compound.

In vivo extrastriatal and striatal D2 dopamine receptor blockade by amisulpride in schizophrenia.

Amisulpride, a substituted benzamide with high affinity for dopamine D2 and D3 receptors only, has been reported to have therapeutic effects on both negative and positive schizophrenic symptoms, although at distinct dose ranges (50-300 mg/day vs. 400-1,200 mg/day). The purpose of this study was to investigate the binding of amisulpride to extrastriatal (i.e., thalamus and temporal cortex) and striatal D2 dopamine receptors with respect to plasma amisulpride determinations. Ten patients with schizophrenia treated with amisulpride over a wide range of doses (25-1,200 mg/day) were studied. Positron emission tomography images were acquired by using 76Br-FLB-457, a highly specific antagonist of the D2 and D3 dopamine receptors. Binding indexes (BI) in the regions studied were estimated with reference to values from six healthy subjects. A curvilinear relationship was demonstrated between plasma concentration of amisulpride and the BI in extrastriatal regions. The BI also varied as a function of plasma concentration in striatum. Furthermore, the data provide evidence for different binding profiles: low plasma concentrations (28-92 ng/mL) induced marked extrastriatal binding and low striatal binding, whereas higher plasma concentrations (>153 ng/mL) induced marked binding both in extrastriatal and striatal regions. Dose-dependent differential binding profiles of amisulpride to D2 receptors in extrastriatal and striatal regions were demonstrated, and two therapeutic ranges of plasma concentrations for negative and positive schizophrenic symptoms, respectively, are suggested.