Conclusive remarks
Previous studies showed that striatal ChIs contribute to LID (Bordia et al. , 2016; Ding et al. , 2011; Won et al. , 2014) and that unspecific muscarinic antagonists dicyclomine and atropine prevented LID expression (Bordia et al. , 2016; Ding et al. , 2011). Consistently, intrastriatal telenzepine, PD-102807 and tropicamide attenuated LID and striato-nigral MSNs activation, further indicating that that M1 and M4 receptors are involved. Moreover, in keeping with the view that muscarinic receptors also mediate an inhibitory action of endogenous ACh on LID (Bordia et al. , 2016), potentiation of cholinergic transmission at striatal M4 receptors resulted in significant LID and striato-nigral MSNs inhibition. This suggest that M4 receptors, possibly located on different neuronal elements, can both facilitate and inhibit LID. During LID, the action of endogenous ACh at postsynaptic M4 receptors seems to prevail. Nonetheless, pharmacological potentiation of striatal M4 transmission during LID favors/unmasks other sets of M4 receptors, located on different neuronal elements, shifting the cholinergic control towards LID inhibition. This adds to a similar control in SNr. In fact, in line with previous evidence that PPN cholinergic inputs to SNr affect basal ganglia functions (Moehle et al. , 2017; Xiao et al. , 2016), the present study shows for the first time that nigral M4 receptor stimulation inhibited LID and nigral output. Altogether, these data reinforce the view that the M4 receptor is a promising target in LID therapy (Moehle et al. , 2019), providing in vivo evidence for powerful M4 receptor modulation of striato-nigral MSNs at both the striatal and nigral levels.