The dopamine (DA) hypothesis of schizophrenia proposed that positive symptoms are associated with hyperactivity of DA transmission. This hypothesis was later refined by the proposition this DA hyperactivity was localized in the ventral striatum (VST) and the limbic regions of the medial temporal lobe. This was supported by the mesolimbic selectivity of atypical antipsychotic drugs, demonstrated in preclinical studies, and by imaging studies suggested that these drugs achieve higher D2 receptor occupancy in temporal limbic regions compared to striatum. On the other hand, brain imaging studies have recently demonstrated that schizophrenia is associated with increased presynaptic DA activity in the striatum. Furthermore, preliminary data obtained with high resolution PET suggest that schizophrenia is associated with excessive DA activity in the associative striatum (AST) rather than in the VST, and that AST DA hyperactivity is predictive of fast treatment response to antipsychotic drugs. These results suggest that D2 receptor blockade in the AST, rather than in the VST, might be critical for antipsychotic action. The general goal of this career development plan is to further evaluate this proposition, by determining D2 receptor occupancy in the VST, AST and sensorimotor striatum of the rat following administration of typical and atypical antipsychotic drugs, and to compare these regional occupancies to the degree of occupancy required to achieve a therapeutic response in patients with schizophrenia.
In specific aim (SA) 1, microPET imaging studies will be combined with ex vivo binding studies to define the dose-occupancy relationship of 8 antipsychotic drugs (2 typical and 6 atypical). In SA2, imaging D2 receptors in striatal subregions and extrastriatal regions with the novel tracer [18F]fallypride will be developed in humans. In SA3, occupancy of D2 receptors achieved in these regions by theses drugs during treatment of schizophrenia will be measured with [18F]fallypride. Together, these data will permit testing the overarching hypothesis that, for both typical and atypical drugs, occupancy in the AST is required to achieve clinical response. The research plan will require the candidate to develop a sophisticated understanding of PET imaging and antipsychotic medication pharmacology, skills that will be essential in the candidate's development toward becoming an independent clinical investigator using PET.
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