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From the Centre for Addiction and Mental Health (Drs. Guttman, Stewart, Wilson, Houle, and Kish, and D. Hussey), Division of Neurology (Dr. Guttman), and Department of Psychiatry (Drs. Guttman, Wilson, Houle, and Kish), University of Toronto, Ontario, Canada.
Address correspondence and reprint requests to Dr. Mark Guttman, 377 Church St. #407, Markham, ON, Canada, L6B 1A1; e-mail: mguttman{at}idirect.com
Background: Animal data indicate that chronic exposure to dopaminergic drugs can alter levels of the dopamine transporter (DAT), which is critically involved in regulation of synaptic dopamine levels. DAT changes could influence the response to therapy in PD. Methods: A randomized, assessor-blinded, placebo-controlled clinical trial was performed in subjects with early PD to determine whether L-dopa or pramipexole might regulate striatal DAT binding as measured by PET with [11C]RTI-32. Thirty clinically asymmetrical patients were randomly assigned to receive 6 weeks of L-dopa (300/75 mg/d), pramipexole (1.5 mg/d), or placebo; PET studies were performed before and after treatment. Results: Mean interval change in DAT binding was significantly reduced by 16% to 22% in all striatal regions (caudate, anterior and posterior putamen) of the L-dopa–treated patients, whereas significant changes in the pramipexole-treated patients were limited to the contralateral caudate (-15%), ipsilateral anterior putamen (-14%), and posterior putamen (-20%). In the placebo group there were significant changes in contralateral caudate (-11%) and ipsilateral anterior putamen (-12%). L-dopa and pramipexole produced similar clinical benefit. Conclusions: Short-term therapy with L-dopa and, to a lesser extent, pramipexole can modestly down-regulate striatal DAT in patients with early PD. Decreased striatal DAT could increase dopaminergic neurotransmission with potential benefit, but might also play a role in the development of dopamine-related response fluctuations in patients with advanced disease. Our data also suggest caution in interpretation of longitudinal imaging studies employing DAT to assess disease progression and the efficacy of neuroprotective agents.
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