Imaging Dopamine and Serotonin Systems on MPTP Monkeys: A Longitudinal PET Investigation of Compensatory Mechanisms

It is now widely accepted that compensatory mechanisms are involved during the early phase of Parkinson's disease (PD) to delay the expression of motor symptoms. However, the neurochemical mechanisms underlying this presymptomatic period are still unclear. Here, we measured in vivo longitudinal changes of both the dopaminergic and serotonergic systems in seven asymptomatic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated monkeys (when motor symptoms are less apparent) using PET. We used the progressively MPTP-intoxicated monkey model that expresses recovery from motor symptoms to study the changes in dopamine synthesis ([F-18] DOPA), dopamine D-2/D-3 receptors ([C-11] raclopride), and serotonin transporter C-11-N, N-dimethyl-2-(-2-amino-4-cyanophenylthio) benzylamine ([C-11] DASB) and serotonin 1A receptor ([F-18] MPPF) levels between four different states (baseline, early symptomatic, full symptomatic and recovered). During the early symptomatic state, we observed increases of [F-18] DOPA uptake in the anterior putamen, [C-11] raclopride binding in the posterior striatum, and 2'-methoxyphenyl-(N-2'-pyridinyl)-p-[F-18] fluoro-benzamidoethylpiperazine [F-18 ] MPPF uptake in the orbitofrontal cortex and dorsal ACC. After recovery from motor symptoms, the results mainly showed decreased [C-11] raclopride binding in the anterior striatum and limbic ACC. In addition, our findings supported the importance of pallidal dopaminergic neurotransmission in both the early compensatory mechanisms and the functional recovery mechanisms, with reduced aromatic L-amino acid decarboxylase (AAAD) activity closely related to the appearance or perseveration of motor symptoms. In parallel, this study provides preliminary evidence of the role of the serotonergic system in compensatory mechanisms. Nonetheless, future studies are needed to determine whether there are changes in SERT availability in the early symptomatic state and if [F-18] MPPF PET imaging might be a promising biomarker of early degenerative changes in PD.