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

Abstract

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 ([ Significance StatementThe present research provides evidence of the potential of combining a multitracer PET imaging technique and a longitudinal protocol applied on a progressively 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated monkey model to further elucidate the nature of the compensatory mechanisms involved in the preclinical period of Parkinson's disease (PD). In particular, by investigating the dopaminergic and serotonergic changes both presynaptically and postsynaptically at four different motor states (baseline, early symptomatic, full symptomatic, and recovered), this study has allowed us to identify putative biomarkers for future therapeutic interventions to prevent and/or delay disease expression. For example, our findings suggest that the external pallidum could be a new target for cell-based therapies to reduce PD symptoms.

Enhancement of Striatal Dopaminergic Function Following Autologous Neural Cell Ecosystems (ANCE) Transplantation in a Non-Human Primate Model of Parkinson’s Disease

“…In absence of production of new dopaminergic neurons derived from the implanted ANCE cells, the significant re-increase of striatal 18F-DOPA uptake may be due to an indirect effect of the transplant, possibly via growth factors (see below), promoting sprouting of the nigrostriatal axons which survived the MPTP intoxication [34,43]. One may speculate that such sprouting of residual dopaminergic projection contributes to functional recovery, in cooperation with non-dopaminergic compensatory mechanisms [44,45]. The observation in monkey Mk-LY of a modest decrease of striatal 18F-DOPA uptake post-MPTP lesion (17%) may possibly be interpreted as a resistance to MPTP [46], at least to some extent.…”

Roles of Multiple Globus Pallidus Territories of Monkeys and Humans in Motivation, Cognition and Action: An Anatomical, Physiological and Pathophysiological Review

“…The GP neurons in MPTP-treated monkeys lose functional selectivity and begin to respond to electrical stimulation in a much wider area of the striatum (Tremblay et al, 1989), which suggests that this dysfunction involves the GP. Additionally, MPTP-treated monkeys exhibit various motor symptoms (Tremblay et al, 2015), and there is a correlation between the level of dopamine in the GP and parkinsonian motor score (Ballanger et al, 2016). Moreover, the GP is involved in compensatory mechanisms (Neumane et al, 2012).…”

Transcriptome responses to reduced dopamine in the Substantia Nigra Pars Compacta reveals a potential protective role for dopamine

“…With this degree of regulation in normal DA physiology, it is not surprising that in pathological conditions that cause loss of DA neurons, brain physiology is altered in a compensatory manner. Both in Parkinson's Disease and in Parkinson's Disease models resulting from agents leading to death of DA neurons, motor symptoms occur only after a majority of DA neurons are lost (Ballanger et al 2016;Golden et al 2013).…”

“…This compensation for DA neuron loss is not well understood (Bezard and Gross 1998;Erwan Bezard et al 2001;Erwan Bezard, Gross, and Brotchie 2003;Blesa et al 2012;Hornykiewicz 1975;Perez et al 2008). Although many of these reports indicate compensatory modulation of the DA system, other transmitter systems may also be involved, including striatal preproenkephalin (Erwan Bezard et al 2001), altered cortical-basal ganglia-thalamocortical circuitry (Erwan Bezard, Gross, and Brotchie 2003;Erica J. Melief et al 2018), alterations of the serotonergic system, in addition to altered DA signaling and altered extracortical circuits (Ballanger et al 2016).…”