Pathophysiology of dyskinesia and behavioral disorders in non-human primates: the role of serotonergic fibers.

The MPTP monkey model of Parkinson's disease (PD) has allowed huge advances regarding the understanding of the pathological mechanisms of PD and L-DOPA-induced adverse effects. Among the main findings were the imbalance between the efferent striatal pathways in opposite directions between the hypokinetic and hyperkinetic states of PD. In both normal and parkinsonian monkeys, the combination of behavioral and anatomical studies has allowed the deciphering of the cortico-basal ganglia circuits involved in both movement and behavioral disorders. A major breakthrough has then been made regarding the hypothesis of the involvement of serotonergic fibers in the conversion of L-DOPA to dopamine when dopaminergic neurons are dying and to release it, in an uncontrolled manner, as serotonergic neurons are deprived from the machinery required for buffering dopamine from the synaptic cleft. The crucial involvement of serotonergic fibers underlying L-DOPA-induced dyskinesia (LID) has been demonstrated in both rodent and monkey models of PD, in which dyskinesia induced by L-DOPA is abolished following lesion of the serotonergic system. Moreover, the role of serotonergic fibers goes well beyond dyskinesia, as lesioning of such serotonergic fibers by MDMA in the monkey also decreased other L-DOPA-induced adverse effects such as impulsive compulsive behaviors and visual hallucinations. The same pathological mechanism, i.e., an imbalance between serotonin and dopamine terminals may, therefore, favor L-DOPA-induced adverse effects according to the basal ganglia territory it inhabits. Further non-human primate studies will be needed to demonstrate the role of such a pathological mechanism in both movement and behavioral disorders driven by L-DOPA therapy but also to determine the causal link between serotonin lesions and the expression of non-motor symptoms like apathy, depression and anxiety, frequently observed in PD patients.