A dual role of adenosine A2A receptors in 3-nitropropionic acid-induced striatal lesions:: Implications for the neuroprotective potential of A2A antagonists

Reduction of A(2A) receptor expression is one of the earliest events occurring in both Huntington's disease (HD) patients and mice overexpressing the N-terminal part of mutated huntingtin. Interestingly, increased activity of A(2A) receptors has been found in striatal cells prone to degenerate in experimental models of this neurodegenerative disease. However, the role of A(2A) receptors in the pathogenesis of HD remains obscure. In the present study, using A(2A)(-/-) mice and pharmacological compounds in rat, we demonstrate that striatal neurodegeneration induced by the mitochondrial toxin 3-nitropropionic acid (3NP) is regulated by A(2A) receptors. Our results show that the striatal outcome induced by 3NP depends on a balance between the deleterious activity of presynaptic A(2A) receptors and the protective activity of postsynaptic A(2A) receptors. Moreover, microdialysis data demonstrate that this balance is anatomically determined, because the A(2A) presynaptic control on striatal glutamate release is absent within the posterior striatum. Therefore, because blockade of A(2A) receptors has differential effects on striatal cell death in vivo depending on its ability to modulate presynaptic over postsynaptic receptor activity, therapeutic use of A(2A) antagonists in Huntington's as well as in other neurodegenerative diseases could exhibit undesirable biphasic neuroprotective-neurotoxic effects.