Measuring brain dopamine release in sensitization and first episode schizophrenia

Schizophrenia is a frequent and disabling psychiatric disorder with largely unknown pathogenesis. An increase in mesolimbic dopamine (DA) is believed to be a final common pathway mediating the expression of psychotics in schizophrenia. Patients with schizophrenia show enhanced behavioural and neurochemical response towards DA- releasing substances such as d-amphetamine (AMPH). Enhanced release of DA after a small dose of AMPH is also found in the striatum of subjects who had been sensitized by repeated intermittent administration of AMPH. Schizophrenia has thus been conceptualized as a state of `endogenous sensitization`. Since there is a broad array of animal literature on the neurochemical effects of sensitization, exploring parallels between schizophrenia and sensitization might help elucidating neurochemical alterations associated with the disease. In this study, we aim to show that patients with schizophrenia display enhanced AMPH induced DA release when compared to not-sensitized healthy subjects, and that the process of sensitization brings DA release to levels seen in patients with schizophrenia. For this aim, we will perform a `competition paradigm` using positron emission tomography and [ 11C]-(+)-PHNO, a novel DA D2/3 receptor agonist radioligand with enhanced sensitivity towards fluctuations in endogenous DA. Patients (n=12) with first-episode schizophrenia (for avoiding the confounds of antipsychotic medication) will undergo two [ 11C]-(+)-PHNO PET scans, one naive and another one after a small dose of oral AMPH. Healthy volunteers (n=12) will undergo four [ 11C]-(+)-PHNO PET scans. The first scan will be performed without intervention, a second one after administration of AMPH. This AMPH dose also serves as the first sensitizing dose. AMPH intake will then be repeated three and five days after dose one. After a resting period of two weeks, subjects will undergo a third [ 11C]-(+)-PHNO PET scan (naive) and a fourth scan after yet another dose of AMPH. Subjects will be genotyped for genetic polymorphisms known to be associated with schizophrenia and DA neurotransmission. Our specific hypothesis is that changes in [ 11C]-(+)-PHNO non-displaceable binding potential (BPND) values after AMPH in healthy volunteers will be significantly lower than AMPH induced changes in patients with schizophrenia and sensitized healthy volunteers. A recent report has shown that AMPH induced changes in D2/3 receptor binding in the striatum show a negative correlation to receptor binding in the substantia nigra/ventral tegmental area (SN/VTA). We thus hypothesize further, that healthy subjects with low SN/VTA [ 11C]-(+)-PHNO BPND values in naive scans will display greater AMPH-induced changes in the striatal [ 11C]-(+)-PHNO binding than those subjects with high naive [ 11C]-(+)- PHNO binding in SN/VTA. Since this, to our knowledge, has never been studied in schizophrenia, we do not have a specific hypothesis on how this feedback-loop will behave in patients with schizophrenia.