Regulators of
G-protein signalling (
RGS) proteins are implicated in striatal
G-protein coupled receptor (GPCR) sensitisation in the pathophysiology of
l-DOPA-induced abnormal
involuntary movements (AIMs), also known as
dyskinesia (LID), in
Parkinson's disease (PD). In this study, we investigated RGS
protein subtype 4 in the expression of AIMs in the unilateral
6-hydroxydopamine (6-OHDA)-lesioned rat model of LID. The effects of RGS4 antisense brain infusion on the behavioural and molecular correlates of
l-DOPA priming in 6-OHDA-lesioned rats were assessed. In situ hybridisation revealed that repeated
l-DOPA/
benserazide treatment caused an elevation of RGS4
mRNA levels in the striatum, predominantly in the lateral regions. The increased expression of RGS4
mRNA in the rostral striatum was found to positively correlate with the behavioural (AIM scores) and molecular (
pre-proenkephalin B, PPE-B expression) markers of LID. We found that suppressing the elevation of RGS4
mRNA in the striatum by continuous infusion of RGS4
antisense oligonucleotides, via implanted osmotic mini-pumps, during
l-DOPA priming, reduced the induction of AIMs. Moreover, ex vivo analyses of the rostral dorsolateral striatum showed that RGS4 antisense infusion attenuated
l-DOPA-induced elevations of PPE-B
mRNA and
dopamine-stimulated [(35)S]GTPĪ³S binding, a marker used for measuring
dopamine receptor super-sensitivity. Taken together, these data suggest that (i) RGS4
proteins play an important pathophysiological role in the development and expression of LID and (ii) suppressing the elevation of RGS4
mRNA levels in
l-DOPA priming attenuates the associated pathological changes in LID, dampening its physiological expression. Thus, modulating RGS4
proteins could prove beneficial in the treatment of
dyskinesia in PD.