Vesicular Monoamine Transporter 2 Imaging in Cocaine Abuse

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

DESCRIPTION (provided by applicant): Previous studies using PET and SPECT endogenous competition binding techniques have shown that chronic cocaine users relative to healthy controls release less dopamine following an acute amphetamine challenge. A likely explanation for a decrease in DA transmission in chronic cocaine users is a loss of DA nerve terminals caused by chronic and persistent exposure to cocaine. Previous PET investigations to study DA terminals have focused primarily on the plasmalemmal dopamine transporter (DAT) and DA synthesis enzymes such as DOPA-decarboxylase. Unfortunately postmortem and imaging studies conducted with these markers have yielded inconsistent results for they are extremely vulnerable to fluctuations in dopamine concentrations caused by chronic cocaine use. In contrast to these markers the vesicular monoamine transporter type 2 (VMAT2) markers such as radiolabeled (+)- dihydrotetrabenazine (DTBZ) have been shown to not be readily regulated by drugs that can affect monoamine neurotransmission. [11C]DTBZ, first radiolabeled and reported as a PET radiotracer by Kilbourn and colleagues binds to the VMAT2, which is located exclusively in the pre-synaptic vesicular membranes. The in vivo binding of [11C]DTBZ as measured with PET in the striatum has been reported to largely (>95%) represent storage vesicles in the dopaminergic nerve terminals. Based on these data we propose to use [11C]DTBZ as a probe to measure the availability of DA terminals in cocaine dependent human subjects. The results of these preliminary studies will further our understanding of the mechanism by which chronic cocaine abuse leads to DA transmission deficits and potentially lead to novel treatments. PUBLIC HEALTH RELEVANCE: In this application, we propose to evaluate in vivo status of VMAT2 in cocaine dependent subjects and matched healthy controls (HC) with [11C]-(+)-DTBZ in PET experiments