Rostral Pedunculopontine Nucleus Infusion of M4 Positive Allosteric Modulator VU0467154 Augments L-DOPA Effects in Hemiparkinsonian Rats

Standard treatment for Parkinson’s disease (PD) is dopamine replacement therapy with L-DOPA. However, chronic treatment often results in abnormal involuntary movements called L-DOPA-induced dyskinesia (LID). Prior evidence indicates that heightened striatal cholinergic tone may contribute to LID. Restoring cholinergic inhibition by targeting the inhibitory M4 muscarinic acetylcholine (ACh) receptor (M4) reduces LID in preclinical models. Although intrinsic striatal sources of ACh have been considered for their role in LID, extrinsic sources of ACh such as the pedunculopontine nucleus (PPN) have not been well investigated for their role in LID. Therefore, the current study employed hemiparkinsonian Long-Evans rats with a PPN-targeted cannula ipsilateral to 6-OHDA lesion. Following chronic treatment with L-DOPA, we examined the effect of local unilateral PPN infusion of M4 PAM VU0467154 on LID, motor performance, and c-fos expression within the PPN. It was expected that PPN infusion of VU0467154 would reduce LID, reduce L-DOPA’s motor benefit, and globally reduce c-fos expression in the PPN. Contrary to our expectations, PPN infusion of M4 PAM did not significantly affect LID severity. Furthermore, the group receiving M4 PAM showed slightly elevated motor improvement compared to L-DOPA, and decreased c-fos expression specifically in PPN cholinergic neurons. These results suggest that local PPN ACh dynamics differ from those of the striatum. Specifically, our results suggest that PPN cholinergic neurons may be a promising therapeutic target for augmenting L-DOPA-mediated motor benefit without increasing LID. ### Competing Interest Statement The authors have declared no competing interest. * 6-OHDA : 6-hydroxydopamine ACh : Acetylcholine AIMs : Abnormal involuntary movements scale ALO : Axial, limb, and orolingual ChAT : Choline acetyltransferase DA : Dopamine D1 : Dopamine D1 receptor FAS : Forepaw adjusting steps GABA : Gamma-aminobutyric acid IHC : Immunohistochemistry IR : Immunoreactivity LID : L-DOPA-induced dyskinesia M4 : M4 muscarinic acetylcholine receptor PBS : Phosphate buffered saline PD : Parkinson’s disease PPN : Pedunculopontine nucleus rPPN : Rostral pedunculopontine nucleus TH : Tyrosine hydroxylase