Abstract

The ability to objectively index dopamine (DA) levels in the brain has the potential to revolutionize the field of neuropsychopharmacology, as having a peripheral biomarker of brain DA would enable the objective monitoring of the progression of Parkinson's disease (PD) and other DA-dependent psychiatric states. Of particular relevance to commercialization, it would provide an objective measure of treatment efficacy. We used a DA-depletion approach to determine if peripheral D2Rs are a biomarker for brain DA; mainly, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model and PD subjects, which are well-known models of DA depletion in the midbrain of rodents and humans, respectively. Dopamine depletion in the substantia nigra resulted a significant change to DA and norepinephrine (NE) levels in the plasma. Interestingly, these changes could be tracked as a time course from baseline to 15 days after injection with MPTP. Also, the proportion of D2R expressing leukocytes steadily increased (specifically B cells and T cells) during this same time of DA depletion. These results suggest that changes to the dopamine neuron population in the substantia nigra can be tracked with DA and NE level changes and D2R expression on B and T cells, providing a possible biomarker for nigral DA neuron loss to further investigate. In two cohorts of studies comparing subjects with PD vs controls, we found that Parkinson's subjects displayed significantly decreased D2R expression in all populations except for (natural killer) NK cells, CD16+ monocytes, and cytotoxic T cells. We also found that subjects with PD show increased levels in epinephrine (EPI) and DA as compared to control subjects. We did not, however, find any statistically significant correlations between the recorded leukocytic D2R downregulation in PD patients and their elevated DA and EPI plasma levels. Therefore, the results of this study did not provide a clear indication how brain DA levels are being represented in the periphery. Regardless, the modulation of peripheral D2Rs in PD and MPTP seen in this study do show that substantia nigra DA depletion in humans and rodents do manifest in the periphery. Although our study didn't result in a clear narrative of how nigral and peripheral DA system mirror each other, our result provide more evidence D2Rs may be both biomarkers and important substrates for treatment of DA-dependent disorders. Our results give a foundation from which future studies can investigate this connection further.

Degree

College and Department

Life Sciences

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