Monoaminergic systems : involvement in the pathophysiology and therapy of Parkinson’s disease

décembre 2014 Directeur(s) de thèse : Abdelhamid BENAZZOUZ Résumé de thèse

Parkinson’s disease is characterized by the manifestation of motor symptoms mostly associated with the degeneration of dopaminergic neurons. While Parkinson’s disease is often focused on motor deficits, the disease is also characterized by non-motor deficits, including anxiety and depression, which are under studied and consequently are not well treated. Whereas some clinical studies suggested that anxiety and depression could be linked to the degeneration of dopaminergic neurons, others suggested the involvement of norepinephrine and serotonin in the observed symptoms and also in the efficacy of Levodopa and deep brain stimulation of the subthalamic nucleus.

In a first time, we investigated the respective role of the neuronal degeneration of dopamine, noradrenaline and serotonin in the manifestation of motor and non-motor parkinsonian-like disorders in the rat. Our results demonstrate that despite the importance of the dopaminergic system, the disturbances in the three-monoaminergic systems play a key role in the manifestation of motor and non-motor deficits.

In a second time, we studied the impact of monoamine depletions on the efficacy of antiparkinsonian treatments, the Levodopa and deep brain stimulation of the subthalamic nucleus. Our results showed that the combined depletions could deteriorate the efficacy of the Levodopa and of the deep brain stimulation on some deficits. Together, these results can explain the lack of efficacy of the antiparkinsonian treatments in some patients and the difficulty to treat all the symptoms.

Finally, we investigated the link between the subthalamic nucleus, which is an excitatory structure of the basal ganglia, and the motor deficits, as well as the involvement of the basolateral amygdala and the lateral habenula in emotional control of the behavior, and non-motor deficits. We showed the parallel between changes in the neuronal activity of the subthalamic nucleus and the motor deficits, of the basolateral amygdala and anxiety and of the lateral habenula and depression.

Results from this thesis provide new evidences on the involvement of the three-monoaminergic systems in the pathophysiology and the therapy of Parkinson’s disease.