The effects of systemic, intrastriatal, and intrapallidal injections of caffeine and systemic injections of A2A and A1 antagonists on forepaw stepping in the unilateral 6-OHDA-lesioned rat

Abstract

Given that adenosine A2A antagonists appear to be therapeutic in several animal models of Parkinson's disease (PD), we examined the extent to which caffeine and selective A2A and A1 antagonists could enhance contralateral forepaw stepping in the unilateral 6-OHDA-lesioned rat. Following unilateral injections of 12 microg 6-OHDA into the medial forebrain bundle (MFB), frequency of stepping with both front paws was counted separately as the paws were dragged anteriorally and laterally by a treadmill. The MFB lesions decreased contralateral stepping by 74-83%, and 8 mg/kg 3,4-dihydroxy-L-phenylalanine (L-DOPA) increased contralateral stepping by 25-26%. Caffeine given systemically (15 mg/kg) or into the dorsal striatum or external globus pallidus (GPE; 20-40 microg) increased contralateral forepaw stepping by 14%, 27%, and 26%, respectively, and enhanced the effect of 8 mg/kg L-DOPA on stepping. The selective A(2A) antagonist SCH-58261 (2 mg/kg) also increased stepping by 13% and enhanced the therapeutic effect of L-DOPA, whereas the selective A(1) [corrected] antagonist 8-cyclopentyltheophylline (3-7 mg/kg) and A(1) agonist N(6)-cyclopentyladenosine (0.03-0.2 mg/kg) had no effect. None of these drugs appeared to produce dyskinesic effects. In this well-validated animal model of the akinesic effects of PD, caffeine and a selective A2A, but not an A1, antagonist were able to provide both monotherapeutic and adjunctive therapeutic effects. These data are consistent with the hypothesis that A2A antagonists may be therapeutic in human PD patients and indicate that the dorsal striatum and GPE are critical sites of therapeutic action.