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.