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Prior MDMA administration aggravates MPTP-induced Parkinsonism in macaque monkeys
Mathilde Millot1, Yosuke Saga1, Sandra Duperrier1
1Univ Lyon, CNRS UMR 5229, Institut des Sciences Cognitives Marc Jeannerod, 67 Boulevard Pinel, Bron F-69675, France.
Abstract:
The aim of this study was to investigate the causal role of an early serotonin injury on parkinsonian-like motor symptomatology. Monkeys were pretreated with 3,4-methylenedioxy-N-methamphetamine (MDMA, or "ecstasy"), known to lesion serotonergic fibers, before being administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We combined behavioural assessment, PET imaging, and immunohistochemistry. Strikingly, prior MDMA administration aggravated MPTP-induced Parkinsonism and associated dopaminergic injury. Monkeys with early MDMA lesions developed parkinsonian deficits more rapidly and more severely. Interestingly, not all symptoms were impacted. Bradykinesia, rigidity and freezing were not affected by early MDMA lesions, whereas spontaneous activities, tremor and abnormal posture were significantly aggravated. Finally, as expected, MDMA induced a decrease of the serotonergic transporter availability. More surprisingly, we found that MDMA evoked also a decreased availability of the dopaminergic transporter to a lesser extent. Altogether, these results show that MDMA administration in non-human primates not only damage serotonergic terminals, but also injure dopaminergic neurons and enhance MPTP neurotoxic action, a completely new result in primates.
Insights
Early serotonin injury from 3,4-methylenedioxy-N-methamphetamine (MDMA) worsened MPTP-induced Parkinsonism in primates. MDMA aggravated motor deficits and dopaminergic injury, revealing a novel neurotoxic interaction.
Area of Science:
- Neuroscience
- Primate Research
- Neurotoxicology
Background:
- Parkinsonism is a neurodegenerative disorder primarily affecting motor function.
- The role of serotonin in Parkinsonism is not fully understood.
- MPTP is a neurotoxin that selectively damages dopaminergic neurons, causing Parkinsonism.
Purpose of the Study:
- To investigate the causal role of early serotonin injury on parkinsonian-like motor symptoms.
- To determine if MDMA pretreatment exacerbates MPTP-induced Parkinsonism and dopaminergic injury in primates.
- To explore the impact of MDMA on specific motor deficits and transporter availability.
Main Methods:
- Non-human primates were pretreated with MDMA to lesion serotonergic fibers.
- Animals were subsequently administered MPTP to induce Parkinsonism.
- Evaluations included behavioral assessment, Positron Emission Tomography (PET) imaging, and immunohistochemistry.
Main Results:
- MDMA pretreatment significantly aggravated MPTP-induced Parkinsonism and dopaminergic injury.
- Parkinsonian deficits developed more rapidly and severely in MDMA-lesioned monkeys.
- While bradykinesia, rigidity, and freezing were unaffected, spontaneous activities, tremor, and abnormal posture were aggravated.
- MDMA decreased both serotonergic and, to a lesser extent, dopaminergic transporter availability.
Conclusions:
- MDMA administration in primates damages serotonergic terminals and injures dopaminergic neurons.
- MDMA enhances the neurotoxic action of MPTP, a novel finding in primates.
- Early serotonin system damage can exacerbate Parkinsonism and associated neurodegeneration.