Estimating Endogenous Dopamine at D2 and D3 Receptors in the Human Brain using the Agonist Radiotracer [11C]-(+)-PHNO: Clinical, Cognitive, and Metabolic Correlates

Using positron emission tomography (PET), and reversibly binding radiotracers which label the dopamine (DA) D2/3 receptors (D2/3R), it is possible to estimate endogenous DA levels in the brain of humans in vivo. This thesis has four themes. The first theme is validating the use of an agonist radiotracer for D2/3R to estimate endogenous DA levels. The second theme is applying this method to better understand differences in DA levels between healthy persons and persons with schizophrenia. The third theme is determining other biologically relevant factors which may affect endogenous DA levels in the human brain in vivo, in particular, factors related to metabolic health. The final theme combines those previous – attempting to extend the basic metabolic correlates relating to endogenous DA to better understand how abnormalities in DA levels may arise in persons with schizophrenia. For the first time, an agonist radiotracer for the DA D2/3R was used to provide in vivo estimates of endogenous DA in the brains of healthy humans. Furthermore, it was determined that this radiotracer could be used to estimate endogenous DA in the brains of persons with schizophrenia who were currently taking antipsychotics. Elucidating relevant cognitive and biological factors which may relate to differences in endogenous DA levels is pertinent for better understanding how abnormalities in DA tone may arise in neuropsychiatric diseases. Thus, for the first time it is demonstrated that differences in insulin sensitivity among healthy persons is related to differences in endogenous DA in the ventral striatum. Given that insulin resistance can be comorbid or concurrent in persons with schizophrenia, future studies are proposed.Ph.D