Context: Parkinson’s disease (PD) is a slowly progressive and disabling neurodegenerative disorder affecting an estimated 7 to 10 million people worldwide. Despite recent advances in drug development, dopaminergic drugs such as L-DOPA remain today’s standard-of-care, despite the side-effects it is inducing in the long-term. To gain in effectiveness, translational research needs clinically relevant animal models of PD that show similar pathophysiological and functional traits than the ones identified in human patients. The widely adopted 6-OHDA rat model is one of them and expresses the same aberrant EEG oscillatory patterns as those characterized in the clinic, making the model highly predictive for drug discovery. 
 
Objectives: State-of-the-art clinical literature shows that motor symptoms of Parkinson’s disease result from a dysfunction of the cortico-basal ganglia circuits. A hyper synchronization of beta rhythms in this circuit, positively correlated to motor symptoms, has been characterized in both parkinsonian patients and animal models. This aberrant excessive beta oscillation is suppressed by dopaminergic treatments, and which improve motor deficits at the same time. A chronic L-DOPA treatment induces abnormal involuntary movements (AIMs) and a prominent resonant gamma oscillation. This project aimed at investigating the effect of an acute injection of the antidyskinetic drug amantadine on L-DOPA low dose-induced gamma oscillations in the 6-OHDA rat. 

Methods: Unilaterally 6-OHDA-lesioned rats were implanted with a bipolar electrode in the motor cortex ipsilateral of the lesion. On one hand the acute effect of dopaminergic drugs was evaluated on the abnormal beta oscillation. On the other hand, 6-OHDA-lesioned rats were treated daily for two weeks with 6mg/kg L-DOPA to induce stable gamma oscillations, which were monitored at day 1, 5, 8, 12 and 15 using EEG recordings. The effects of pre-treatments with either vehicle or amantadine (45 or 90mg/kg) 120 min before L-DOPA injection was then evaluated on gamma oscillations and L-DOPA induced AIMS. 

Results: Acute injections of dopaminergic drugs differentially modulate the abnormal beta and gamma oscillations depending on their mechanism of action. Chronic injection of L-DOPA low dose induces specific gamma oscillations and AIMs which gradually increased along the repeated treatments. The highest dose of amantadine (90mg/kg) reduced L-DOPA low dose-induced gamma oscillations and significantly reduced the AIMs score. 

Conclusions: The analysis of cortical beta and gamma oscillations in the unilateral 6-OHDA model offers an objective and quantifiable endpoint for the assessment of the motor effect of dopaminergic agonists. The antidyskinetic drug amantadine, which is routinely used in the clinic, showed significant impact on L-DOPA low dose-induced gamma oscillations in the 6-OHDA rat. As a reliable hallmark of L-DOPA induced dyskinesias, this EEG biomarker brings a significant added value to drug development as a stable, quantitative, and objective endpoint for the development of new antiparkinsonian and antidyskinetic neurotherapeutics.