Acute L-DOPA administration reverses changes in firing pattern and low frequency oscillatory activity in the entopeduncular nucleus from long term L-DOPA treated 6-OHDA-lesioned rats

A Aristieta,J.A Ruiz-Ortega,T Morera-Herreras,C Miguelez,L Ugedo

doi:10.1016/j.expneurol.2019.113036

A Aristieta, J.A Ruiz-Ortega + Show 3 more

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https://doi.org/10.1016/j.expneurol.2019.113036

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Journal: Experimental neurology	Publication Date: Aug 16, 2019
Citations: 10	License type: cc-by

Affiliation: University of the Basque Country

Abstract

The pathophysiology of Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID) is associated with aberrant neuronal activity and abnormal high levels of oscillatory activity and synchronization in several basal ganglia nuclei and the cortex. Previously, we have shown that the firing activity of neurons in the substantia nigra pars reticulata (SNr) is relevant in dyskinesia and may be driven by subthalamic nucleus (STN) hyperactivity. Conversely, low frequency oscillatory activity and synchronization in these structures seem to be more important in PD because they are not influenced by prolonged L-DOPA administration. The aim of the present study was to assess (through single-unit extracellular recording techniques under urethane anaesthesia) the neuronal activity of the entopeduncular nucleus (EPN) and its relationship with LID and STN hyperactivity, together with the oscillatory activity and synchronization between these nuclei and the cerebral cortex in 6-OHDA-lesioned rats that received long term L-DOPA treatment (or not). Twenty-four hours after the last L-DOPA injection the firing activity of EPN neurons in long term L-DOPA treated 6-OHDA-lesioned rats was more irregular and bursting compared to sham rats, being those alterations partially reversed by the acute challenge of L-DOPA. No correlation between EPN neurons firing activity and abnormal involuntary movements score was found. However, there was a significant correlation between the firing activity parameters of EPN and STN neurons recorded from long term L-DOPA treated 6-OHDA-lesioned rats. Low frequency oscillatory activity and synchronization both within the EPN and with the cerebral cortex were enhanced in 6-OHDA-lesioned animals. These changes were reversed by the acute L-DOPA challenge only in long term L-DOPA treated 6-OHDA-lesioned rats. Altogether, these results obtained from long term L-DOPA treated 6-OHDA-lesioned rats suggest (1) a likely relationship between STN and EPN firing patterns and spiking phases induced by changes after prolonged L-DOPA administration and (2) that the effect of L-DOPA on the firing pattern, low frequency oscillatory activity and synchronization in the EPN may have a relevant role in LID.

Highlights

Pharmacological replacement of dopamine (DA) with its precursor L-3,4-dihydroxyphenylalanine (L-DOPA) is the gold standard treatment for Parkinson's disease (PD)
In our hands, the acute L-DOPA challenge partially reversed the increment in firing irregularity and in the number of bursting neurons induced by prolonged L-DOPA treatment in the entopeduncular nucleus (EPN) of 6-OHDA-lesioned animals. These results suggest that the EPN may have a direct role in the motor symptomatology associated with LDOPA-induced dyskinesia (LID), we did not observe any correlation between EPN neuron activity and the scored abnormal involuntary movements (AIMs) in 6OHDA-lesioned rats treated with L-DOPA
Cortical information is transmitted to the subthalamic nucleus (STN) and the EPN through several basal ganglia (BG) pathways

Summary

Introduction

Pharmacological replacement of dopamine (DA) with its precursor L-3,4-dihydroxyphenylalanine (L-DOPA) is the gold standard treatment for Parkinson's disease (PD). Long-term administration of LDOPA induces abnormal involuntary movements (AIMs) known as LDOPA-induced dyskinesia (LID). These motor complications are potentially disabling, and affect up to 40% of PD patients within 5 years of treatment (Ahlskog and Muenter, 2001). Altered neural activity and abnormally synchronized oscillatory activity at multiple levels of the cortico-basal ganglia (BG) loop have been linked to motor dysfunction in PD patients with or without LID (Alonso-Frech et al, 2006; Fogelson et al, 2006; Kühn et al, 2006; Lozano et al, 2000; Obeso et al, 2000). In PD patients, abnormal oscillatory activities are found at different

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