Cellular and behavioural effects of the adenosine A_2a receptor antagonist KW‐6002 in a rat model of l‐DOPA‐induced dyskinesia

Abstract

We have examined the ability of KW-6002, an adenosine A 2a antagonist, to modulate the dyskinetic effects of L-DOPA in 6-hydroxydopamine-lesioned rats. In animals rendered dyskinetic by a previous course of L-DOPA treatment, KW-6002 did not elicit any abnormal involuntary movements on its own, but failed to reduce the severity of dyskinesia when coadministered with L-DOPA. A second experiment was undertaken in order to study the effects of KW-6002 in L-DOPA-naive rats. Thirty-five animals were allotted to four groups to receive a 21-day treatment with: (i) KW-6002 (10 mg/kg/day); (ii) L-DOPA (6 mg/kg/day) i.p.; (iii) KW-6002 plus L-DOPA (same doses as above) or (iv) vehicle. Chronic treatment with KW-6002-only produced a significant relief of motor disability in the rotarod test in the absence of any abnormal involuntary movements. Combined treatment with L-DOPA and KW-6002 improved rotarod performance to a significantly higher degree than did each of the two drugs alone. However, this combined treatment induced dyskinesia to about the same degree as did L-DOPA alone. In situ hybridization histochemistry showed that KW-6002 treatment alone caused an approximately 20% reduction in the striatal levels of preproenkephalin mRNA, whereas neither the coadministration of KW-6002 and L-DOPA nor L-DOPA alone significantly altered the expression of this transcript in the dopamine-denervated striatum. Either alone or in combination with L-DOPA, KW-6002 did not have any modulatory effect on prodynorphin mRNA expression or FosB/DFosB-like immunoreactivity in the dopamine-denervated striatum. These results show that monotreatment with an adenosine A 2a receptor antagonist can relieve motor disability without inducing behavioural and cellular signs of dyskinesia in rats with 6-hydroxydopamine lesions. Cotreatment with KW-6002 and L-DOPA potentiates the therapeutic effect but not the dyskinesiogenic potential of the latter drug.

Enhanced striatal cholinergic neuronal activity mediatesl-DOPA–induced dyskinesia in parkinsonian mice

“…Thus, repeated L-DOPA treatment in Pitx3 ak/ak mice, which produces LID, correlates with increased ERK phosphorylation in striatal cholinergic interneurons and a decrease in MSN. To further confirm the correlation of ERK phosphorylation in striatal cholinergic neurons with L-DOPA-induced behavioral expression of dyskinesia, we used a selective A2A receptor antagonist, which ameliorates akinesia in human PD patients without producing dyskinesia after repeated treatment (22). The selective A2A antagonist, KW-6002, significantly improved akinesia in Pitx3 ak/ak mice, as evidenced by both open-field test and rearing activity (Fig.…”

A Crucial Role for Forebrain Adenosine A2A Receptors in Amphetamine Sensitization

“…Their use of a different psychostimulant drug and paradigm of sensitization, as well as an A 2A agonist (which may be less relevant to endogenous adenosine actions on CNS A 2A Rs than are A 2A antagonists) could account for the difference in results. Moreover, although Lundblad et al (2003) have confirmed that treatment of 6-OHDA-lesioned rats with an adenosine A 2A antagonist alone did not elicit any abnormal involuntary movements while relieving motor disabilities, they did not observe any effect of KW-6002 on the severity of dyskinesias when it was coadministered with L-dopa. Another study of unilaterally 6-OHDA-lesioned rats found that an A 2A antagonist reversed but did not prevent L-dopa-induced motor alterations (Bove et al, 2002).…”

“…Changes in the expression of presumably postsynaptic A 2A Rs after repeated dopaminergic exposures might also play a functional role in the nucleus accumbens or dorsal striatum (Zeng et al, 2000;Calon et al, 2004;Tomiyama et al, 2004). Potential downstream postsynaptic mediators of sensitization that are also known to be regulated by the A 2A R include cytoplasmic signal transducers (eg dopamineand cAMP-regulated phosphoprotein of 32 kDa or DARPP-32) and nuclear transcriptional targets (eg DFosB, enkephalin, and dynorphin gene expression in striatal neurons; Fienberg et al, 1998;Canals et al, 2003;Lundblad et al, 2003;Hakansson et al, 2004).…”

Unprecedented therapeutic potential with a combination of A2A/NR2B receptor antagonists as observed in the 6-OHDA lesioned rat model of Parkinson's disease

“…without L-Dopa) in preclinical models. A 2A antagonists have been shown to be efficacious against haloperidolinduced catalepsy [16,20,50] and showed positive effects in the forepaw stepping test in unilaterally 6-OHDA lesioned rats [51] and in the rotarod test [52]. However, most studies failed to demonstrate a significant effect of A 2A receptor antagonists on the level of contralateral rotation in lesioned rats in the absence of L-Dopa [14][15][16]53].…”