Dopamine D1 -like receptors (D1Rs) influence important neuronal circuits and have been associated with a number of physiological functions and illnesses, including working memory, Parkinson disease and substance abuse. However, they also mediate vascular effects. Consequently, they may disrupt the usual linkage of neuronal function to positron emission tomography (PET) or functional MRI (fMRI) neuroimaging methods. Blood oxygenation level dependent (BOLD) signals, for instance, are sensitive to variations in global cerebral blood flow. These effects are of significant concern for interpreting imaging studies in populations exposed to dopaminergic agonists or stimulants. In this RO1 application we propose to directly measure, using well-validated quantitative PET techniques, whether activation of dopamine D1 receptors in primates alters regional cerebral blood flow (rCBF) through direct vascular effects or, rather, via effects on neuronal work and metabolism We will also test whether the effects on rCBF are mediated specifically by D1 receptors. These results will be compared to pharmacological fMRI (phMRI) responses to the same D1R agonist. Although more sensitive MRI techniques have been used in nonhuman species, using contrast agents and/or high field strength, this application focuses on the physiology of those PET and phMRI techniques that are commonly applied in humans. Our experience with quantitative PET measurements, neuroimaging in nonhuman primates, and phMRI positions us to immediately address these questions. These results will inform interpretation of human neuroimaging studies in which dopamine D I receptors are affected. These results are also necessary for planning D DIR challenge phMRI studies in human disease or animal models. In this laboratory, potential applications would include longitudinal studies of treatment induced side effects *in Parkinson's disease or MPTP models, and pathophysiological studies in dopa-related dystonia or a nonhuman dystonia model.
| Koller, Jonathan M; Vachon, M Jonathan; Bretthorst, G Larry et al. (2016) Rapid Quantitative Pharmacodynamic Imaging with Bayesian Estimation. Front Neurosci 10:144 |
| Miller, Brad; Lim, Audrey N; Heidbreder, Arnold F et al. (2015) An Automated Motion Detection and Reward System for Animal Training. Cureus 7:e397 |
| Black, Kevin J; Koller, Jonathan M; Miller, Brad D (2013) Rapid quantitative pharmacodynamic imaging by a novel method: theory, simulation testing and proof of principle. PeerJ 1:e117 |
