Striatal perfusion with AFDX-116 blocked the antidyskinetic effect of PD-102807
Striatal M4 receptors are predominantly located presynaptically on ChIs (autoreceptors) or postsynaptically on glutamatergic cortico-striatal terminals and striato-nigral MSNs. To investigate whether the behavioral and neurochemical effects induced by striatal perfusion with PD-102807 were due to pre- or post-synaptic mechanisms, we intrastriatally perfused PD-102807 in combination with the M2 preferential antagonist, AFDX-116 (100 nM). Indeed, this concentration of AFDX-116 has been shown to elevate striatal ACh levels (Billardet al. , 1995; Galarraga et al. , 1999) and affect MSNs postsynaptically (Galarraga et al. , 1999). We reasoned that if the effects of PD-102807 were mediated by M4 autoreceptor blockade and elevation of striatal ACh levels, M2 autoreceptor blockade by AFDX-116 would further enhance or, at most, leave unchanged the effects of PD-102807. On the contrary, if the effects of PD-102807 were induced by postsynaptic M4 receptor blockade, an increase of ACh release would reverse them. Striatal perfusion with AFDX-116 did not affect LID expression but prevented the antidyskinetic effect of PD-102807. In fact, in the presence of AFDX-116, PD-102807 failed to attenuate AIMs severity (H=4.29 p= 0.11; Fig. 5A). Consistently, in the presence of AFDX-116, PD-102807 failed to inhibit the LID-associated rise of nigral GABA (F3,30=7.89, p=0.0005; Fig 5B) or Glu (F3,30=5.54, p=0.0038; Fig. 5C). Surprisingly enough, however, AFDX-116 failed to prevent the PD-102807 inhibition of the LID-associated increase of striatal Glu release (Fig. 5D).