Striatal adenosine A2A 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 muM) produced a marked increase in striatal extracellular DA level in intact and malonate-lesioned rats. Intrastriatal perfusion of ZM 241385 (50-100 muM) 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 muM), similarly to ZM 241385, accelerated conversion Of L-DOPA in intact and malonate-denervated rats. This effect was not produced by the adenosine A, receptor antagonist, CPX (10-50 muM). 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. (C) 2004 Elsevier Ltd. All rights reserved.