Cellular and behavioural effects of the adenosine A2a receptor antagonist KW-6002 in a rat model of l-DOPA-induced dyskinesia.
Författare
Summary, in English
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/ΔFosB-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.
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.
Publiceringsår
2003
Språk
Engelska
Sidor
1398-1410
Publikation/Tidskrift/Serie
Journal of Neurochemistry
Volym
84
Issue
6
Fulltext
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Länkar
Dokumenttyp
Artikel i tidskrift
Förlag
Wiley-Blackwell
Ämne
- Neurosciences
Nyckelord
- Parkinsonian Disorders: chemically induced
- Oxidopamine
- Levodopa: adverse effects
- Motor Activity: drug effects
- Female
- Enkephalins: metabolism
- Enkephalins: genetics
- Disease Models
- Animal
- Behavior
- Drug Therapy
- Combination
- Dyskinesia
- Drug-Induced: complications
- Drug-Induced: drug therapy
- Corpus Striatum: metabolism
- Corpus Striatum: drug effects
- Animal: drug effects
- Parkinsonian Disorders: complications
- Parkinsonian Disorders: drug therapy
- Protein Precursors: genetics
- Protein Precursors: metabolism
- Proto-Oncogene Proteins c-fos: metabolism
- Purines: pharmacology
- RNA
- Messenger: metabolism
- Rats
- Sprague-Dawley
- Receptors
- Purinergic P1: antagonists & inhibitors
- Treatment Outcome
Status
Published
Forskningsgrupp
- Neurobiology
- Neuronano Research Center (NRC)
- Basal Ganglia Pathophysiology
ISBN/ISSN/Övrigt
- ISSN: 1471-4159