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The impact of paraquat/maneb intoxication and the selective depletion of monoamines on the motor and circadian systems: behavioral, biochemical and electrophysiological studies in the context of Parkinson's disease

décembre 2015 Directeur(s) de thèse : Abdelhamid BENAZZOUZ, Nouria LAKHDAR-GHAZAL Résumé de thèse

The present study aimed to investigate the effects of monoaminergic system lesions on the motor and non motor functions , including anxiety, depression and circadian rhythms within the context of Parkinson’s disease. First, we developed appropriate animal models using combined paraquat/maneb (PQ/MB) intoxication or using selective lesions of monoaminergic systems; second, we characterized the models using behavioral, biochemical and electrophysiological approaches.

In the first part of the study, we investigated the relevance of the PQ/MB model by studying the effects of combined PQ/MB on: (1) locomotor activity and motor coordination using the open field and the rotarod test respectively, (2) anxiety and “depressive-like” behaviors using the elevated plus maze and the forced swim test respectively, (4) subthalamic nucleus neuronal activity using extracellular single unit recordings and (5) tissue level of dopamine, noradrenaline and serotonin in the striatum and frontal cortex.

Our data provide evidence that male Sprague Dawley rats are not equally sensitive to PQ/MB and and that the observed motor deficits in vulnerable animals are not only a result of dopamine neuron degeneration, but may also be a consequence of peripheral disabilities. Nevertheless, the parkinsonian-like non-motor impairments may be a direct consequence of the bilateral dopamine depletion.

Based on the results of the first part, we used the 6-OHDA rat model to investigate the effects of DA cell degeneration, alone or combined with the noradrenaline (NA) and/or serotonin (5-HT) depletions, on the electrical activity of suprachiasmatic nucleus (SCN) neurons using extracellular electrophysiological recordings. SCN is a key structure involved in the control of circadian rhythms. Our data provide the first evidence that monoamine depletions are at the origin of changes in the firing activity of SCN neurons, suggesting new insight into the involvement of these electrical changes in the pathophysiology of circadian rhythms disruption in PD.

Keywords: Parkinson disease’s, Paraquat/Maneb, suprachiasmatic nucleus, circadian rhythms, electrophysiology.