CCG-203920 targets RGS4 in vivo
To confirm the RGS4 selectivity of CCG-20920 in vivo, the
neuroleptic-induced akinesia/catalepsy model was used since we
previously reported that the RGS4 inhibitor CCG-203769 reversed
raclopride-induced akinesia in mice (Blazeret al. , 2015). RGS4-/- mice were slightly
hypokinetic at baseline, showing >2-fold greater immobility
time in the bar test (14.45 ± 1.40 s, n=20) and 40% reduced stepping
activity in the drag test (6.59 ± 0.56 steps, n=20) compared to controls
(5.7 ± 0.48 s and 10.08 ± 0.45 steps, respectively; n=20 each). Two-way
ANOVA revealed that raclopride caused a prolonged and marked increase of
the immobility time (time F3,108=117.3,
p<0.0001; treatment F3,36=11.34,
p<0.0001, time X treatment interaction
F9,108=6.35, p<0.0001) and a reduction of
stepping activity (time F3,95=67.50, p<0.0001;
treatment F3.36=18.95, p<0.0001, time X
treatment interaction F9,108=4.09, p=0.0002) in both
wild-type and RGS4-/- mice (Fig. 4). CCG-203920
administration significantly reversed raclopride-induced hypokinesia in
wild-type animals but was ineffective in RGS4-/- mice,
suggesting RGS4 targeting at this dose.