CCG-203920 potentiated the AT-403 inhibition of ERK signaling in
striatum
Aberrant D1 receptor transmission in direct pathway MSNs is associated
with LID and leads to alterations in phosphorylating activity of several
downstream kinases, such as PKA and DARPP-32
(Bastide et al. , 2015). A
direct consequence of the hyperactivity of DARPP-32 is the increased
phosphorylation of ERK1/2, a well-accepted correlate of LID in rodents
(Pavon et al. , 2006;
Santini et al. , 2007). In a
previous study we showed that AT-403 (0.1 mg kg-1) was
able to normalize the L-Dopa induced pERK levels in the 6-OHDA lesioned,
DA-depleted striatum (Arcuri et al. ,
2018). In the present study, we investigated whether a lower dose of
AT-403 (0.03 mg kg-1) alone or in combination with
CCG-203920 could normalize L-Dopa-induced increase of pERK in the
striatum of dyskinetic rats (Fig. 6). As expected, LID was associated
with a significant increase of pERK levels in the lesioned striatum
relative to the unlesioned striatum (+47%; t=3.584 df=12), which was
unaffected by pretreatment with AT-403 (+79%; t=2.261, df=10) or
CCG-203920 (+117%; significance just above the threshold value t=1.947,
df=10, p=0.08; Fig. 6A). However, when L-Dopa was combined with
CCG-203920 and AT-403, pERK levels did not rise in the lesioned striatum
(Fig. 6A). Pharmacological treatments did not affect total protein
levels (Fig. 6B), suggesting that the changes observed were due to the
activation of the pathway and not protein expression.