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.