Cellular and behavioural effects of the adenosine A2a receptor antagonist KW-6002 in a rat model of l-DOPA-induced dyskinesia.
We have examined the ability of KW-6002, an adenosine A2a 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/DeltaFosB-like immunoreactivity in the dopamine-denervated striatum. These results show that monotreatment with an adenosine A2a 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.
Lundblad
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Department of Physiological Sciences, Wallenberg Neuroscience Centre, Neurobiology Division, Lund, Sweden.
Vaudano
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Cenci
M A
MA
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000150:complications / Q000188:drug therapy*; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D005260:Female; D007980:Levodopa / Q000009:adverse effects*; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A; D016896:Treatment Outcome
D004745:Enkephalins; D011498:Protein Precursors; D016760:Proto-Oncogene Proteins c-fos; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; C111599:istradefylline; D007980:Levodopa; D016627:Oxidopamine; C033660:preproenkephalin