VU0152100 and PD-102807 in SNr
Intranigral reverse dialysis of VU0152100 prevented LID and the accompanying rise of nigral GABA release. This is consistent with the finding that M4 PAM VU0467154 inhibited the D1 agonist-induced GABA release from striato-nigral MSNs terminals in vitro, and CBV in SNr neurons in vivo (Moehle et al. , 2017). The profile of intranigral VU0152111 confirms the role of the cholinergic afferents arising from PPN in the modulation of D1 signaling in SNr (Moehle et al. , 2017) and shows that this modulation shapes LID. Indeed, the neurochemical responses to intranigral VU0152100, also considering the inhibition of striatal Glu, are consistent with the view that M4 receptor stimulation inhibits GABA release from striato-nigral MSN terminals, thus limiting the overinhibition of nigro-thalamic GABAergic neurons (i.e. the nigral output) associated with LID. In vitro electrophysiological experiments in nigral slices showed that the M4 inhibition of nigral D1 signalling and GABA release is tonically active (Moehle et al. , 2017). However, in the present in vivo model, blockade of nigral M4 receptors with tropicamide did not alter nigral LID and nigral GABA and Glu release, suggesting that endogenous ACh acting at nigral M4 receptors does not contribute to LID. Nonetheless, we should consider that LID is already maximal in these animals, thus making it difficult to capture further increase of AIMs.