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.