A Dual Role of Adenosine A2AReceptors in 3-Nitropropionic Acid-Induced Striatal Lesions: Implications for the Neuroprotective Potential of A2AAntagonists

Abstract

Reduction of A_2Areceptor 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_2Areceptors has been found in striatal cells prone to degenerate in experimental models of this neurodegenerative disease. However, the role of A_2Areceptors 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_2Areceptors. Our results show that the striatal outcome induced by 3NP depends on a balance between the deleterious activity of presynaptic A_2Areceptors and the protective activity of postsynaptic A_2Areceptors. Moreover, microdialysis data demonstrate that this balance is anatomically determined, because the A_2Apresynaptic control on striatal glutamate release is absent within the posterior striatum. Therefore, because blockade of A_2Areceptors has differential effects on striatal cell deathin vivodepending on its ability to modulate presynaptic over postsynaptic receptor activity, therapeutic use of A_2Aantagonists in Huntington's as well as in other neurodegenerative diseases could exhibit undesirable biphasic neuroprotective—neurotoxic effects.