Breathing new life into neurotoxic-based monkey models of Parkinson's disease to study the complex biological interplay between serotonin and dopamine.

Numerous clinical studies have shown that the serotonergic system also degenerates in patients with Parkinson's disease. The causal role of this impairment in Parkinson's symptomatology and the response to treatment remains to be refined, in particular thanks to approaches allowing the two components DA and 5-HT to be isolated if possible. We have developed a macaque monkey model of Parkinson's disease exhibiting a double lesion (dopaminergic and serotonergic) thanks to the sequential use of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MDMA (3,4-methylenedioxy-N-methamphetamine) (or MDMA prior MPTP). We characterized this monkey model by multimodal imaging (PET, positron emission tomography with several radiotracers; DTI, diffusion tensor imaging), behavioral assessments (parkinsonism, dyskinesia, neuropsychiatric-like behavior) and post-mortem analysis (with DA and 5-HT markers). When administrated after MPTP, MDMA damaged the 5-HT presynaptic system without affecting the remaining DA neurons. The lesion of 5-HT fibers induced by MDMA altered rigidity and prevented dyskinesia and neuropsychiatric-like symptoms induced by levodopa therapy in MPTP-treated animals. Interestingly also, prior MDMA administration aggravates the parkinsonian deficits and associated DA injury. Dystonic postures, action tremor and global spontaneous activities were significantly affected. All together, these data clearly indicate that late or early lesions of the 5-HT system have a differential impact on parkinsonian symptoms in the macaque model of Parkinson's disease. Whether MDMA has an impact on neuropsychiatric-like symptoms such as apathy, anxiety, depression remains to be addressed. Despite its limitations, this toxin-based double-lesioned monkey model takes on its full meaning and provides material for the experimental study of the heterogeneity of patients.