Telenzepine in striatum
Reverse dialysis of the M1 preferential antagonist telenzepine in
striatum attenuated LID expression and the accompanying rise of GABA in
SNr. Since previous microdialysis studies
(Marti et al. , 2012;
Mela et al. , 2012;
Mela et al. , 2007) demonstrated
that the rise of nigral GABA release which accompanies AIMs appearance
reflects the activation of D1-expressing striato-nigral MSNs, it appears
that M1 receptor stimulation contributes to LID expression and the
underlying striato-nigral pathway activation. Indeed, M1 receptors
increase striato-nigral and striato-pallidal MSNs excitability through
different mechanisms: i) closure of Kir2 and KCNQ (Kv7)
K+ channels (Shenet al. , 2005), particularly in striato-pallidal MSNs
(Shen et al. , 2007); ii)
enhancement of Ca2+-currents through
Cav1 channels, particularly in striato-nigral MSNs
(Hernandez-Flores et al. , 2015;
Hernandez-Lopez et al. , 1997;
Perez-Garci et al. , 2003); iii)
facilitation of NMDA transmission
(Calabresi et al. , 1998) through
persistent sodium currents (Carrillo-Reidet al. , 2009); iv) inactivation of N- and P/Q
Cav channels, leading to reduced GABA release from
striatal interneurons (Perez-Roselloet al. , 2005). Telenzepine was proposed to improve motor
symptoms in parkinsonian mice, acting at striato-pallidal M1 receptors
(Ztaou et al. , 2016). Our study
would point to an inhibitory action of telenzepine at M1 receptors on
striato-nigral MSNs. To possibly confirm this view, telenzepine also
reduced the LID-associated elevation of striatal Glu release
(Brugnoli et al. , 2016;
Gardoni et al. , 2018;
Ostock et al. , 2011;
Paolone et al. , 2015). In fact,
elevation of striatal Glu release might result from striato-nigral MSNs
stimulation leading to activation of cortico-basal
ganglia-thalamo-cortical loop (Market al. , 2004; Marti et al. ,
2005) and cortico-striatal terminals
(Ostock et al. , 2011;
Paolone et al. , 2015). However,
Glu might be also released from striatal ChIs, which express the
vesicular Glu transporter 3 (VGLUT3)
(Kljakic et al. , 2017), thus
contributing to PD symptoms and LID
(Divito et al. , 2015;
Gangarossa et al. , 2016). Finally,
Glu released from thalamo-striatal terminals stimulates striato-pallidal
MSNs, thereby sustaining akinesia in parkinsonian mice
(Tanimura et al. , 2019).
Therefore, the reduction of striatal Glu in our model might not only
reflect cortico-basal ganglia-thalamo-cortical loop inhibition but also
normalization of ChIs activity and cortico/thalamo-striatal
transmission, which might impact behaviors beyond dyskinesia. Indeed,
high frequency stimulation of the subthalamic nucleus normalized the
elevation of cortico-striatal glutamatergic transmission in dyskinetic
rats, which was associated with motor improvement but not LID
attenuation (Gubellini et al. ,
2006). Moreover, inhibition of Glu release from thalamo-striatal Glu
terminals (via nicotinic receptor desensitization) reduced the firing of
striato-pallidal MSNs and improved PD-related motor learning deficits
(Tanimura et al. , 2019). This
might explain why striatal Glu release can sometimes dissociate from
AIMs appearance. In fact, in dyskinetic rats chronically treated with
the MAO-B and NaV channel inhibitor, safinamide
(Gardoni et al. , 2018), or
intrastriatally perfused with AFDX-116 and PD-102807 (present study)
striatal Glu did not rise along with AIMs.