Neurophysiological treatment effects of mesdopetam, pimavanserin and
amantadine in a rodent model of levodopa-induced dyskinesia
Abstract
Levodopa provides effective symptomatic treatment for Parkinson’s
disease. However, non-motor symptoms are often insufficiently relieved,
and its long-term use is complicated by motor fluctuations and
dyskinesia. To clarify mechanisms of levodopa-induced dyskinesia and
pharmacological interventions aimed at reducing dyskinetic symptoms, we
have here characterized the neurophysiological activity patterns in
sensorimotor and cognitive-limbic circuits in dyskinetic rats, comparing
the effects of amantadine, pimavanserin and the novel prospective
antidyskinetic and antipsychotic treatment mesdopetam. Parallel
recordings of local field potentials from eleven cortical and
sub-cortical regions revealed suppression of narrowband gamma
oscillations (NBGs) in sensorimotor structures by amantadine and
mesdopetam in conjunction with alleviation of dyskinetic signs.
Concomitant gamma oscillations in cognitive-limbic circuits were not
directly linked to dyskinesia and were not affected by antidyskinetic
treatments to the same extent, although treatment-induced reductions in
functional coupling was observed in both sensorimotor and
cognitive-limbic circuits, in parallel. In a broad frequency spectrum
(1-200Hz), mesdopetam treatment displayed greater similarities to
pimavanserin than to amantadine. These findings point to reduction of
NBGs as a valuable biomarker for characterization of antidyskinetic
treatment effects and provide systems-level mechanistic insights into
the antidyskinetic efficacy of mesdopetam, with potential additional
benefits for the treatment of Parkinson’s-related psychosis.