Gene knockout approach to adenosine A2A receptors in Parkinson's disease

Abstract

AbstractRecently, the adenosine A2A receptor (A2AR) has emerged as an attractive target for Parkinson's disease (PD) treatment by virtue of its coexpression with the dopamine D2 receptor (D2R) in the striatum and its modulation of dopamine receptor‐mediated functions. Moreover, the adenosine antagonist, caffeine, has recently been linked to a reduced risk of developing PD in large prospective epidemiological studies, raising the possibility that caffeine and more specific adenosine antagonists may protect against dopaminergic neuron death. Recently, we and others have developed a series of A2AR and D2R knockout (KO) mouse models. These mutant mouse models with complete, specific genetic inactivation of A2ARs and D2Rs overcome some of the intrinsic limitations of A2A antagonists and provide an opportunity to investigate A2AR's role in the development and treatment of PD. First, we used D2 as well as A2AR KO mice to dissect the molecular mechanism of the A2AR's action by determining the dependence of A2AR function on D2 receptors. The A2A antagonist (CSC) and the nonspecific antagonist caffeine induced motor stimulation in naive and reserpinized mice deficient in D2 receptor. These results suggest that A2AR antagonists enhance motor function at least partially independent of D2 receptors. Second, we explored the role of A2ARs in the development of L‐dopa‐induced behavioral sensitization in unilaterally 6‐hydroxydopamine‐lesioned mice, an animal model of the behavioral and neurochemical features of dyskinesia in PD. Genetic inactivation of A2ARs markedly attenuated the development and persistence of L‐dopa‐induced rotational behavioral sensitization and attenuated induction of dynorphin mRNA in the striatum. The results suggest that A2AR plays a critical role in the development of persistent maladaptive dyskinetic responses to chronic L‐dopa treatment in PD. Finally, we showed that genetic inactivation of A2ARs attenuates MPTP‐induced depletion of dopamine and dopamine transporter (DAT) in the striatum and loss of dopaminergic neurons in the substantia nigra. Together, these results obtained with genetic approaches demonstrate that A2AR inactivation may have multiple therapeutic benefits for PD: motor enhancement through a partial D2‐independent mechanism, prevention of L‐dopa‐induced behavioral sensitization, and attenuation of dopaminergic neurodegeneration. The generation of tissue‐specific and inducible A2A KO mouse models will further refine our understanding of the A2A receptor's role in the development and treatment of PD. Drug Dev. Res. 58:354–367, 2003. © 2003 Wiley‐Liss, Inc.