Objective: The aim of this study was to assess the use of cortical oscillations as translational biomarkers for drug development for the motor symptoms of Parkinson’s disease.

Background: Most movement disorders with a central origin are associated with pathological cortical oscillations, and Parkinson’s disease (PD) is among the most prevalent of these disorders. Motor symptoms observed in Parkinson’s disease result from a dysfunction of the cortico-basal ganglia circuits mainly due to the death of dopaminergic neurons in the substantia nigra pars compacta. A hypersynchronization of beta frequency oscillatory activity in these circuits has been observed in both Parkinsonian patients and animal models of the disease. In addition, two recent studies have shown an increase of gamma power oscillations in the motor cortex of both hemiParkinsonian rats and patients associated with L-DOPA injection.

Methods: We focused on drugs with different targets to determine whether oscillations are differentially modulated according to the mode of action of the drug. Compounds tested here were SKF-38393 (D1/D5 partial agonist) and ropinirole (D2/D3/D4 agonist).

Results: Using the unilateral 6-OHDA lesioned rat model of PD, we found a prominent beta band (centered at 30Hz) in the motor cortex, which was inexistent in control Sprague-Dawley rats. Acute injections of the D1/D5 partial agonist SKF-38393 at 1 and 2 mg/kg both significantly reduced the beta band (25-45Hz) in the motor cortex, while lower doses (0.25 and 0.5mg/kg) were ineffective. The highest dose of SKF-38393 also induced a prominent 80-100Hz gamma increase that was not observed at lower doses. The D2/D3/D4 agonist Ropinirole at 0.2, 0.4, and 0.8mg/kg also strongly decreased the 25-45Hz Beta band but none of these doses caused any significant gamma band increase. Decrease of the Beta band was systematically associated with behavioral rotations of the animals, contralateral to the 6-OHDA lesion.

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. This study highlights the fact that different targets appear to yield differential patterns of oscillations. Possible correlations between modes of action and spectral effects remain to be investigated.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/improving-drug-discovery-using-brain-oscillations-as-biomarkers-of-parkinsons-disease/