Eltoprazine prevents levodopa-induced dyskinesias by reducing causal interactions for theta oscillations in the dorsolateral striatum and substantia nigra pars reticulate

Abstract

Oscillatory activities within basal ganglia (BG) circuitry in L-DOPA induced dyskinesia (LID), a condition that occurs in patients with Parkinson disease (PD), are not well understood. The aims of this study were firstly to investigate oscillations in main BG input and output structures—the dorsolateral striatum (dStr) and substantia nigra pars reticulata (SNr), respectively— including the direction of oscillation information flow, and secondly to investigate the effects of 5-HT1A/B receptor agonism with eltoprazine on oscillatory activities and abnormal involuntary movements (AIMs) characteristic. To this end, we conducted local field potential (LFP) electrophysiology in the dStr and SNr of LID rats simultaneous with AIM scoring. The LFP data were submitted to power spectral density, coherence, and partial Granger causality analyses. AIM data were analyzed relative to simultaneous oscillatory activities, with and without eltoprazine. We obtained four major findings. 1) Theta band (5–8 Hz) oscillations were enhanced in the dStr and SNr of LID rats. 2) Theta power correlated with AIM scores in the 180-min period after the last LID-inducing L-DOPA injection, but not with daily summed AIM scores during LID development. 3) Oscillatory information flowed from the dStr to the SNr. 4) Chronic eltoprazine reduced BG theta activity in LID rats and normalized information flow directionality, relative to that in LID rats not given eltoprazine. These results indicate that dStr activity plays a determinative role in the causal interactions of theta oscillations and that serotonergic inhibition may suppress dyskinesia by reducing dStr-SNr theta activity and restoring theta network information flow.