Implication of nigral dopaminergic lesion and repeated L-dopa exposure in neuropsychiatric symptoms of Parkinson’s disease

Simon Loiodice 1 Harry Wing Young 1 Bertrand Rion 1 Benoît Méot 1 Pierre Montagne 1 Anne-Sophie Denibaud 1 Roselyne Viel 2 Christophe Drieu La Rochelle 1
1 Biotrial
2 H2P2 - H2P2 - Histo Pathologie Hight Precision
UR1 - Université de Rennes 1, Biosit : Biologie - Santé - Innovation Technologique - Structure Fédérative de Recherche en Biologie et Santé de Rennes
Abstract : This study aims to investigate the contribution of nigral dopaminergic (DA) cell loss, repeated exposure to DA medication and the combination of both to the development of neuropsychiatric symptoms observed in Parkinson's disease (PD). A bilateral 6-OHDA lesion of the substantia nigra pars compacta (SNc) was performed in rats. A set of animals was repeatedly administered with L-dopa (20 mg/kg/day) and benserazide (5 mg/kg/day) over 10 days starting from day 11 post-lesion. Behavioural testing was performed in week 3 post-lesion: novel object recognition (NOR), elevated plus maze (EPM) social interaction (SI) tests, and amphetamine-induced hyperlocomotion (AIH). Immunohistochemical analysis revealed a significant partial lesion (48%) in 6-OHDA versus sham rats. This lesion was not associated with motor impairment. However, lesioned rats displayed a significant deficit in the NOR, which was reversed by acute treatment with l-dopa/benserazide (12.5 mg/kg and 15 mg/kg respectively). Lesioned rats also displayed a deficit in the EPM which was not reversed by acute treatment with l-dopa. No difference was observed in the SI test or in the AIH assay. In all assays, no effect of chronic l-dopa exposure was observed. This study provides new insights into the neuropathophysiology associated with neuropsychiatric symptoms of PD. Our data strongly emphasises a not previously clearly identified critical role in cognition for the SNc. The results suggest that DA pathways were less directly involved in lesion-induced anxiety-like behaviour. We did not report any effect of chronic l-dopa exposure in the context of partial nigral cell loss.
Keywords : neuropsychiatric symptoms 6-OHDA L-dopa Parkinson’s disease Parkinson's disease
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Simon Loiodice, Harry Wing Young, Bertrand Rion, Benoît Méot, Pierre Montagne, et al.. Implication of nigral dopaminergic lesion and repeated L-dopa exposure in neuropsychiatric symptoms of Parkinson’s disease. Behavioural Brain Research, Elsevier, 2019, 360, pp.120-127. ⟨10.1016/j.bbr.2018.12.007⟩. ⟨hal-01988160⟩

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