UTILIZATION OF RADIOLIGANDS IN SCHIZOPHRENIA RESEARCH

Interest in the role of monoaminergic mechanisms in schizophrenia has stimulated the development of specific radioligands that allow PET ana lysis of quantitative aspects of monoamine receptor subtypes in the li ving human brain. Clinical studies with such ligands have not consiste ntly demonstrated specific alterations of the total populations of D-1 and D-2 dopamine receptors in the caudate putamen complex of drug-nai ve schizophrenic patients. However, recent studies using [C-11]SCH 233 90, a specific D-1 dopamine receptor ligand, disclosed a highly signif icant reduction of ligand binding in pixel elements of the basal gangl ia that normally contain high activity. This finding may be related to reduced D-1 dopamine regulated transmission in subsets of neuronal pa thways within the basal ganglia. D-3, D-4, and D-5 receptor subtypes c onstitute minor fractions of the total number of dopamine receptors in the human brain. However, efforts to find selective ligands for D-3 a nd Dq subtypes also show promise. Radioligands for monoamine receptors have also been used to follow drug effects on receptor subtypes in sc hizophrenic patients treated with different types of antipsychotic dru gs. Such studies have allowed the analysis of relationships between oc cupancy of dopamine receptor subtypes and some clinical manifestations of drug treatment. Such studies with the selective D-2 antagonist rac lopride indicated quantitative relationships between the degree of D-2 dopamine receptor occupancy in the basal ganglia and the extrapyramid al manifestations, as well as the antipsychotic action. Some of the cu rrently available antipsychotic drugs also induced significant occupan cy of D-1 dopamine receptors. However, the selective D-1 antagonist SC H 39166 in doses inducing a more than 70% occupancy of D-1 dopamine re ceptors in the caudate putamen failed to induce an antipsychotic actio n. This indicates that, in contrast to D-2 blockade, selective antagon ism of D-1-regulated pathways does not mediate antipsychotic action in schizophrenia. Some but not all antipsychotic drugs also induced high occupancy of neocortical 5HT(2A) receptors. Because selective 5HT(2A) antagonism does not appear to be an efficient treatment for schizophr enia, it seems most likely that 5HT(2A) receptors and, perhaps, D-1 re ceptors act in concert to modify aspects of the mandatory D-2 blockade to induce antipsychotic actions. Computer graphic methods for image a nalysis add new dimensions to brain imaging research, allowing three-d imensional visualization of receptor populations computed from molecul ar PET data. This will make possible further exploration of the detail ed molecular compartmentalization of the human brain using radioligand binding. (C) 1995 Wiley-Liss, Inc.