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A_2A receptor and striatal cellular functions

Regulation of gene expression, currents, and synaptic transmission

From the Laboratory of Neurophysiology (Drs. Schiffmann, Dassesse, and d’Alcantara), IRIBHM, and School of Medicine (Drs. d’Alcantara, Ledent, and Swillens), Université Libre de Bruxelles, Belgium; and Dipartimento di Scienze Biomediche, sezione di Fisiologia (Dr. Zoli), Universitá di Modena e Reggio Emilia, Italy.

Address correspondence and reprint requests to Dr. S.N. Schiffmann, Laboratory of Neurophysiology, Université Libre de Bruxelles, Campus Erasme, CP 601, 808 route de Lennik, 1070 Brussels, Belgium; e-mail: sschiffm{at}ulb.ac.be

A_2A receptor is highly coexpressed with enkephalin and D₂ receptor in striatopallidal neurons. A_2A antagonists acutely enhance motor behavior in animal models of Parkinson’s disease (PD) and are therefore considered potential PD therapeutic agents. Analysis of gene expression regulation using pharmacologic tools or A_2A receptor-deficient mice (A_2A^-/-) shows that the A_2A receptor positively and tonically controls the expression of enkephalin and immediate early genes in striatopallidal neurons. Because this regulation strictly mirrors the effect of D₂ receptor, these data strongly support the hypothesis that A_2A antagonists reduce the activity of striatopallidal neurons in models of PD. However, analysis of A_2A^-/- mice suggests additional effects of A_2A receptor in the control of striatal physiology. Unexpectedly, these animals exhibited a reduction in exploratory activity and a 50% reduction in substance P expression. This was associated with a 45% decrease in the striatal extracellular dopamine concentration, suggesting that chronic absence of A_2A receptor results in a functional hypodopaminergic state in the striatum. The A_2A receptor controls inhibitory synaptic transmission negatively in the striatum and positively in the globus pallidus; this further supports the efficacy of A_2A antagonists in reducing the activity of striatopallidal neurons in PD. The A_2A receptor does not modulate basal -amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)-mediated excitatory corticoaccumbal synaptic transmission during normal physiologic conditions. However, genetic inactivation or pharmacologic blockade of the A_2A receptor significantly reduced long-term potentiation (LTP) at this synapse. Therefore, this receptor is implicated in the induction of corticoaccumbal LTP, an effect that could be related to its involvement in long-term behavioral sensitization to repeated dopaminergic treatment.

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