Striatal adenosine A(2A) receptor blockade increases extracellular dopamine release following l-DOPA administration in intact and dopamine-denervated rats.
The influence of the selective adenosine A(2A) receptor antagonist ZM 241385 on exogenous l-DOPA-derived dopamine (DA) release in intact and dopamine-denervated rats was studied using an in vivo microdialysis in freely moving animals. Local infusion of l-DOPA (2.5 microM) produced a marked increase in striatal extracellular DA level in intact and malonate-lesioned rats. Intrastriatal perfusion of ZM 241385 (50-100 microM) had no effect on basal extracellular DA level, but enhanced dose-dependently the l-DOPA-induced DA release in intact and malonate-lesioned animals. A non-selective adenosine A(2A) receptor antagonist DMPX (100 microM), similarly to ZM 241385, accelerated conversion of l-DOPA in intact and malonate-denervated rats. This effect was not produced by the adenosine A(1) receptor antagonist, CPX (10-50 microM). However, ZM 241385 did not affect the l-DOPA-induced DA release in rats pretreated with reserpine (5 mg/kg i.p.) and alpha-methyl-p-tyrosine (AMPT, 300 mg/kg i.p.). Obtained results indicate that blockade of striatal adenosine A(2A) receptors increases the l-DOPA-derived DA release possibly by indirect mechanism exerted on DA terminals, an effect dependent on striatal tyrosine hydroxylase activity. Selective antagonists of adenosine A(2A) receptors may exert a beneficial effect at early stages of Parkinson's disease by enhancing the therapeutic efficacy of l-DOPA applied exogenously.
Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31343 Krakow, Poland. nfgolemb@cyf-kr.edu.pl
Krystyna
K
Gołembiowska
Anna
A
Dziubina
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D058917:Adenosine A2 Receptor Antagonists; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D003714:Denervation / Q000379:methods; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005110:Extracellular Space / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D008314:Malonates / Q000494:pharmacology; D008781:Methyltyrosines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D058917:Adenosine A2 Receptor Antagonists; D015259:Dopamine Agents; D008314:Malonates; D008781:Methyltyrosines; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; D014970:Xanthines; C097270:ZM 241385; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; C022260:alpha-methyltyrosine methyl ester; D007980:Levodopa; D006897:Hydroxyindoleacetic Acid; D012110:Reserpine; C030290:malonic acid; C051360:1,3-dipropyl-8-cyclopentylxanthine; D004298:Dopamine; D006719:Homovanillic Acid