Beyond the classical triad of motor symptoms observed in Parkinson's disease (PD), behavioural and cognitive disturbances are also commonly observed, including apathy, defined as a decrease in motivated directed behaviours, and which is often associated with anxiety and depression. Interestingly, these neuropsychiatric symptoms are frequently observed in parkinsonian patients with high frequency stimulation of the subthalamic nucleus. Although the pathophysiological mechanisms behind these troubles are still unknown, a link has been recently suggested between the reduction of dopaminergic drugs (DA) (made possible by the benefits on the motor ability of deep brain stimulation) and the resurgence of the apathetic syndrome in these stimulated patients. In a first set of experiments, we set out to determine the role of the DA system in the emergence of such neuropsychiatric symptoms and which part of the DA ascending pathway is more specifically involved. Our lesion model in rats, by neurotoxic partial, selective and bilateral lesions of different regions of the DA midbrain continuum were performed allowed us to highlight a key role of the nigrostriatal DA pathway in the motivational processes and in regulating depressive- and anxiety-like behaviours, while avoiding motor impairments. In the second part, a pharmacological approach by chronic treatment with L-DOPA or Ropinirole (D2/D3 agonist) allowed us to verify the predictive value of our animal model in regard to treatment classically used in clinic. The administration of different selective agonists of the D1, D2 and D3 DA receptors has allowed us to show the major involvement of the D3 receptors in the efficiency to reverse the phenotype induced by the nigrostriatal pathway lesion, which opens the way for new therapeutic targets. Finally, the data obtained during this doctoral work provides new arguments for an involvement of the nigrostriatal DA pathway in the emergence of the apathetic syndrome in PD. The lesion model developed can lead to a better understanding of the role of DA in the processes underlying these motivational and mood disorders in PD and to identify new therapeutic strategies, more suitable for further treatment.
