Probing dopamine D2 receptor trafficking in schizophrenia

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DESCRIPTION (provided by applicant): A large body of work has focused on excess dopamine within striatum of patients with schizophrenia but we know little about the underlying mechanistic involvement of dopamine D2 receptors (D2R) in the illness. Some imaging and postmortem studies have suggested that D2R density is elevated in patients with schizophrenia compared to healthy controls, however, these findings have not been consistent and it was argued that they may be more related to prior exposure to antipsychotics rather than to the disease process per se. Nevertheless, the alleviation of positive symptoms specifically after blockade of D2R by antipsychotics suggests that homeostatic regulation of D2R signaling is likely to be compromised. One mechanism that may explain this is impaired internalization. D2R internalization is a mechanism that enables the cell to retract the receptors from the cell surface into the cytosol so they are no longer available for dopamine stimulation. Recent research, including genetic, molecular and postmortem studies, suggests that D2R internalization may be impaired in schizophrenia. These findings now call for further clinical studies of the role of D2R trafficking in schizophrenia. PET imaging combined with amphetamine challenge may offer a way to study D2R trafficking in humans. PET imaging has been commonly used to assess dopamine transmission by measuring the change in binding potential ( BPND) of a D2R radiotracer after an amphetamine challenge. BPND is thought to reflect direct displacement of the radiotracer due to increased competition from endogenous dopamine. However, some observations have suggested that the displacement is not only related to increased competition from dopamine, but also to internalization of the D2Rs. This was initially suggested by the observation that BPND remains decreased several hours after the amphetamine induced dopamine surge. This "late phase" decrease (e4 hr after amphetamine) in BPND has been observed across species including rodents, cats, monkeys and humans. Tests of a wide range of D2R radiotracers found on average about two-fold lower affinity for internalized D2R than cell surface bound, a change sufficient to explain the "late phase" decrease in BPND after amphetamine challenge. Consistent with this idea, a PET study in a mouse model deficient in D2R internalization failed to observe the "late phase" effect, suggesting that this imaging paradigm may provide information about D2R internalization. The goal of this proposal is to explore the hypothesis that impaired D2R trafficking plays a critical role in the dopaminergic abnormalities in schizophrenia. We propose to image 15 patients with schizophrenia and 15 healthy controls with PET, [11C]raclopride, at baseline, 3 h, and 8 h after amphetamine challenge (0.5 mg/kg, PO). We hypothesize that the "late phase" decrease in BPND will be blunted in patients with schizophrenia, reflecting impaired D2R trafficking in schizophrenia, most likely related to impaired D2R internalization. If successful, this lin of research may provide novel insight to the pathophysiology of schizophrenia.