Parkinson's disease (PD) is characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Adenosine is a neuromodulator that inhibit the release of dopamine via a disinhibitory mechanism. In this study, we investigated the neuroprotective effect of 8-cyclopentyl-1,3-dipropylxanthine and ZM241385 (respectively, A1 and A2A receptors antagonists), on nigrostriatal dopamine neurons degradation reduction in a rotenone-induced PD model using histopathological and immunohistochemical methods. 32 male rats were randomly divided into 4 groups, 8 in each one: vehicle control (1 ml/kg/48 h), rotenone (1.5 mg/kg/48 h, s.c.), ZM241385 (3.3 mg/kg/day, i.p) and 8-cyclopentyl-1,3-dipropylxanthine (5 mg/kg/day, i.p). 24 h after the last rotenone injection, animals were sacrificed and their brains were sectioned and prepared for histopathological staining with hematoxylin and eosin, cresyl violet for Nissl-staining, Mallory's phosphotungestic acid haematoxylin staining as well as for immunohistochemical staining for tyrosine hydroxylase. Our study showed that A2A-receptor blockade by ZM241385, but not A1 receptor blocking by 8-cyclopentyl-1,3-dipropylxanthine, decreased histopathological degeneration in SNpc neurons and hindered the reduction in dopamine levels caused by rotenone application. These results indicate that the selective A2A, but not A1 receptor blocking, has a neuroprotective effect, and may provide a more selective pharmacological strategy for the treatment of PD symptoms.