Modulation by adenosine A(2A) 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 ade nosine receptors in the control of motor behavior. In line with those studi es, we have previously shown that the acute administration of the A(2A) rec eptor antagonist SCH 58261 potentiated the turning behavior induced by L-DO PA in the unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson's di sease (PD) suggesting that selective adenosine A(2A) receptor antagonists m ight be useful as adjuncts to L-DOPA therapy One of the most important prob lems in the treatment of PD is to find a drug regimen effective after chron ic administration and devoid of dyskinesia-like side effects. Previous stud ies have shown that the sensitized turning response, developed in 6-OHDA-le sioned rats after chronic intermittent L-DOPA, isa useful model of dyskines ia. in the present study, we evaluated the effect of a chronic administrati on 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 administr ation and its dyskinetic potential. Repeated administration of SCH 58261 (5 mg/kg) did not produce tolerance to its ability to potentiate L-DOPA-turni ng behavior. Moreover, chronic intermittent SCH 58261 (5 mg/kg) plus L-DOPA produced a stable turning behavior response during the course of the treat ment, whereas L-DOPA alone produced a progressive increase in turning behav ior intensity and duration (sensitization). These results suggest that SCH 58261 is effective in potentiating L-DOPA-induced turning behavior even aft er a chronic treatment and it does not produce, in combination with L-DOPA, motor response alterations. A(2A) receptor antagonists could be a new and useful tool for the treatment of PD. Drug Dev. Res. 52:387-393, 2001. (C) 2 001 Wiley-Liss, Inc.