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.