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).