Behavioural impact of a double dopaminergic and serotonergic lesion in the non-human primate

Serotonergic (5-HT) neurons degenerate in Parkinson’s disease. To determine the role of this 5-HT injury—besides the dopaminergic one in the parkinsonian symptomatology—we developed a new monkey model exhibiting a double dopaminergic/serotonergic lesion by sequentially using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3,4-methylenedioxy- N -methamphetamine (MDMA, better known as ecstasy). By positron emission tomography imaging and immunohistochemistry, we demonstrated that MDMA injured 5-HT nerve terminals in the brain of MPTP monkeys. Unexpectedly, this injury had no impact on tremor or on bradykinesia, but altered rigidity. It abolished the l-DOPA-induced dyskinesia and neuropsychiatric-like behaviours, without altering the anti-parkinsonian response. These data demonstrate that 5-HT fibres play a critical role in the expression of both motor and non-motor symptoms in Parkinson’s disease, and highlight that an imbalance between the 5-HT and dopaminergic innervating systems is involved in specific basal ganglia territories for different symptoms. * Abbreviations : 5-HT : serotonin BPND : non-displaceable binding potential DASB : N , N -dimethyl-2-(-2-amino-4-cyanophenylthio)benzylamine MDMA : 3,4-methylenedioxy- N -methamphetamine MPTP : 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine PE2I : N -(3-iodoprop-2E-enyl)-2beta-carbomethoxy-3beta-(4-methylphenyl)nortropane SERT : serotonergic transporter