Adenosine A2A receptor antagonists improve deficits in initiation of movement and sensory motor integration in the unilateral 6-hydroxydopamine rat model of Parkinson's disease

Evidence obtained in rodent and primate models of Parkinson's disease (PD) and preliminary clinical trials, indicates that adenosine A(2A) receptor antagonists might represent a promising nondopaminergic therapeutic tool for the treatment of PD. Those studies demonstrated the ability of adenosine A2A receptor antagonists to potentiate L-dopa-mediated motor improvement, whereas very little is known about counteraction of specific motor deficits and on the effects of these compounds when administered alone. To this aim we evaluated the effects of different adenosine A2A receptor antagonists on initiation of movement deficits, gait impairment and sensory-motor deficits, induced in rats by a unilateral 6-hydroxydopamine lesion of dopaminergic nigrostriatal neurons. The following tests were used: (1) initiation time of stepping; (2) adjusting step (stepping with forelimb was measured as the forelimb was dragged laterally); (3) vibrissae-elicited forelimb placing (as index of sensory-motor integration deficits). Acute administration of the A2A receptor antagonists SCH 58261 (5 mg/kg i.p.) and ST 1535 (20 mg/kg i.p.) similarly to L-dopa (6 mg/kg i.p.) counteracted the impairments in the initiation time of stepping test, in the adjusting step and in the vibrissae-elicited forelimb placing induced by the lesion. The intensity of the effect was L-dopa > SCH 58261 > ST 1535. The results provide the first evidence that blockade of A2A receptors is effective in antagonizing specific motor deficit induced by DA neuron degeneration, such as initiation of movement and sensory-motor integration deficits, even without L-dopa combined administration.