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

Recently, the adenosine A(2A) receptor (A(2A)R) has emerged as an attractive target for Parkinson's disease (PD) treatment by virtue of its coexpression with the dopamine D-2 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 A(2A)R and D2R knockout (KO) mouse models. These mutant mouse models with complete, specific genetic inactivation of A(2A)Rs and D(2)Rs overcome some of the intrinsic limitations of A(2A) antagonists and provide an opportunity to investigate A(2A)R's role in the development and treatment of PD. First, we used D-2 as well as A(2A)R KO mice to dissect the molecular mechanism of the A(2A)R's action by determining the dependence of A(2A)R function on D-2 receptors. The A(2A) antagonist (CSC) and the nonspecific antagonist caffeine induced motor stimulation in naive and reserpinized mice deficient in D-2 receptor. These results suggest that A(2A)R antagonists enhance motor function at least partially independent of D-2 receptors. Second, we explored the role of A(2A)Rs in the development of L-clopa-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 A(2A)Rs 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 A(2A)R 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 A(2A)Rs 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 A(2A)R inactivation may have multiple therapeutic benefits for PD: motor enhancement through a partial D-2-independent mechanism, prevention of L-dopa-induced behavioral sensitization, and attenuation of dopaminergic neurodegeneration. The generation of tissue-specific and inducible A(2A) KO mouse models will further refine our understanding of the A(2A) receptor's role in the development and treatment of PD. (C) 2003 Wiley-Liss, Inc.