Effets de l'amantadine sur la transmission dopaminergique : rôle du récepteur sigma1 = Effects of amantadine on dopaminergic transmission. Implication of the sigma1 receptor
(2003)
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- Parkinson's disease affects approximately one of every 1000 persons over the world. It constitutes the most common neurodegenerative disorder of the elderly after the Alzheimer's disease. Usually associated with loss of dopaminergic nigral neurons and depletion of dopamine levels in both substantia nigra and striatum, Parkinson's disease, unlike most of neurodegenerative diseases, may be accessible to drug therapy. Amantadine, empirically used for more than 30 years to alleviate locomotor symptoms in Parkinson s disease, has recently been found to reduce dyskinesias induced by chronic L-DOPA therapy. This non competitive NMDA glutamate receptor antagonist is proposed to exert its therapeutic effects by increasing the dopaminergic transmission. Nevertheless, less is known about the biochemical mechanisms involved in this modulation of dopaminergic pathway. This work aims to study the effects of repeated administrations of amantadine on dopaminergic transmission, in particular on the expression and on the functional activity of dopamine receptors and transporter. Our results show that a 4-day amantadine treatment enhances the functional coupling between dopamine receptors and G-protein without any changes of dopamine receptor density. These biochemical data correlate with behavioural analyse as a sensitisation of rats behavioural response after the administration of a dopaminergic agonist (apomorphine) was also observed. In order to determine if this response was sustained or not, the effects of a longer treatment (7 days) were studied revealing the development of compensatory mechanisms including a decrease in dopamine receptor density and an enhancement of dopamine transporter activity. The implication of a second molecular target for amantadine, the sigma1 receptor, was then suggested. First, the pharmacological profile of amantadine for the sigma1 receptor was determined. Then, the sensitisation of dopamine transmission induced by repeated amantadine administrations was demonstrated to reflect the interaction of amantadine with the sigma1 receptor. As the activation of this receptor is involved in the regulation of membrane fluidity and cytoskeletal protein activity, this may constitute a relevant explanation for the modulation of G-protein activity observed after amantadine administrations. These works lead to the identification of a new potential molecular target of amantadine which could be involved in the regulation of the functional activity of dopamine receptors. They may also contribute to the development of new therapeutic strategies in the treatment of Parkinson's disease.
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Peeters, M. (2003). Effets de l’amantadine sur la transmission dopaminergique : rôle du récepteur sigma1 = Effects of amantadine on dopaminergic transmission. Implication of the sigma1 receptor. https://hdl.handle.net/2078.5/110815