Striatal and nigral muscarinic type 1 and type 4 receptors modulate levodopa-induced dyskinesia and striato-nigral pathway activation in 6-hydroxydopamine hemilesioned rats

Significance 

Striatal cholinergic interneurons have made recognizable contributions to striatal functions and Parkinsonism. The role of striatal cholinergic interneurons in levodopa-induced dyskinesia (LID) has also emerged in the last decade. Abnormal involuntary movements of dystonic and choreic nature characterize dyskinesia and it occurs as a major side effect from the administration of levodopa in the treatment of Parkinson’s disease. Striatal cholinergic interneurons are involved in the development of LID and previous original findings that stated that the ablation or inhibition of the function of cholinergic interneurons attenuate LID  were recently complemented by an optogenetic study that showed that at low firing rates, cholinergic interneurons facilitate LID and attenuate it at higher ones. Studies have also shown that both acetylcholine muscarinic receptors (mAChRs) and acetylcholine nicotinic receptors (nAChRs) play a role in LID. However, while the role of nAChRs in the prevention of LID has been convincingly demonstrated, the role of mAChRs is still unclear.

In a new study published in the Journal Neurobiology of Disease, scientists from the University of Ferrara in Italy: Dr. Alberto Brugnoli, Dr. Clarissa Anna Pisanò and led by Professor Michele Morari identified the role of striatal and nigral M1 and/or M4 mAChRs in the regulation of dyskinesia and in turn LID and the underlying striato-nigral pathway activation. Their findings showed that M1 mAChRs enable dyskinesia and the activation of striato-nigral pathway. Whereas striatal M4 mAChRs can both enable and inhibit dyskinesia.

The research team observed that LID was alleviated by the striatal perfusion of telenzepine, which also inhibited the release of nigral GABA and striatal glutamate. The expression of LID was found to be associated with an increase in nigral GABA and glutamate, and striatal glutamate. Intrastriatal perfusion with telenzepine inhibited the rise of nigral GABA and striatal glutamate caused by levodopa, but not that of nigral glutamate.

Similarly, striatal perfusion of M4 mAChR preferring antagonists, tropicamide and PD-102807 was found to alleviate LID and inhibit the release of nigral GABA and glutamate, and striatal glutamate. Furthermore, striatal perfusion of VU0152100 also alleviated LID and inhibited the release of nigral GABA and striatal glutamate. However, intrastriatal VU0152100 unlike the M4 mAChR preferential antagonists, had no effect on the LID associated increase of striatal glutamate release.

The antidyskinetic effect of PD102807 was noticed to be blocked by the striatal perfusion of M2 mAChR preferring antagonist, AFDX-116. Consequently, AFDX-116 also blocked the PD-102807-induced inhibition of the LID-associated rise of nigral GABA or glutamate. However, AFDX-116 did not prevent the PD-102807-induced inhibition of the LID-associated rise of striatal glutamate release

The nigral perfusion of VU0152100 was found to alleviate LID and its neurochemical correlates whereas nigral perfusion of PD-102807 was not effective. Consistent with its inability in regulating LID, intranigral PD-102807 had no effect on the LID-associated increase of nigral GABA and glutamate.

In summary, the authors have been able to demonstrate that intrastriatal telenzepine, tropicamide and PD-102807 attenuate LID and the activation of the striato-nigral medium-sized spiny neurons. This finding is consistent with evidence from previous studies that showed that unspecific muscarinic antagonists atropine and dicyclomine inhibited LID expression. It is also an indicator that both M1 and M4 receptors contribute to LID.

This landmark study provides compelling evidence for multilevel and potent M4 mAChR  regulation of striato-nigral medium-sized spiny neurons in vivo, further confirming the view that the M4 mAChR is a potential target in LID therapy.

Reference

Brugnoli A, Pisanò CA, Morari M. Striatal and nigral muscarinic type 1 and type 4 receptors modulate levodopa-induced dyskinesia and striato-nigral pathway activation in 6-hydroxydopamine hemilesioned rats. Neurobiol Dis. 2020;144:105044

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