Modulation by adenosine A2A receptors of dopamine-mediated motor behavior as a basis for antiparkinson's disease drugs

Several studies have evidenced the opposite role played by dopamine and adenosine receptors in the control of motor behavior. In line with those studies, we have previously shown that the acute administration of the A2A receptor antagonist SCH 58261 potentiated the turning behavior induced by L-DOPA in the unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson’s disease (PD), suggesting that selective adenosine A2A receptor antagonists might be useful as adjuncts to L-DOPA therapy. One of the most important problems in the treatment of PD is to find a drug regimen effective after chronic administration and devoid of dyskinesia-like side effects. Previous studies have shown that the sensitized turning response, developed in 6-OHDA-lesioned rats after chronic intermittent L-DOPA, is a useful model of dyskinesia. In the present study, we evaluated the effect of a chronic administration of SCH 58261 alone or in combination with L-DOPA in 6-OHDA lesioned rats in order to verify the effectiveness of SCH 58261 after repeated administration and its dyskinetic potential. Repeated administration of SCH 58261 (5 mg/kg) did not produce tolerance to its ability to potentiate L-DOPA-turning behavior. Moreover, chronic intermittent SCH 58261 (5 mg/kg) plus L-DOPA produced a stable turning behavior response during the course of the treatment, whereas L-DOPA alone produced a progressive increase in turning behavior intensity and duration (sensitization). These results suggest that SCH 58261 is effective in potentiating L-DOPA-induced turning behavior even after a chronic treatment and it does not produce, in combination with L-DOPA, motor response alterations. A2A receptor antagonists could be a new and useful tool for the treatment of PD