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Volume 9, Pages 1321-1344
Research Article

Key Modulatory Role of Presynaptic Adenosine A2A Receptors in Cortical Neurotransmission to the Striatal Direct Pathway

1National Institute on Drug Abuse, IR , NIH, DHHS, Baltimore, MD, USA
2Departamento de Ciencias Médicas, Facultad de Medicina, Universidad de Castilla-La Mancha, Albacete, Spain
3Department of Anatomy, Hokkaido University School of Medicine, Sapporo, Japan
4Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
5Gladstone Institute of Neurological Disease, Department of Physiology, University of California, San Francisco, USA
6Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Charlestown, USA
7Department of Pharmacology, University of Virginia Health Sciences Center, Charlottesville, USA

Received 18 September 2009; Revised 19 October 2009; Accepted 22 October 2009

Academic Editor: Gianluigi Tanda

Copyright © 2009 César Quiroz et al.


Basal ganglia processing results from a balanced activation of direct and indirect striatal efferent pathways, which are controlled by dopamine D1 and D2 receptors, respectively. Adenosine A2A receptors are considered novel antiparkinsonian targets, based on their selective postsynaptic localization in the indirect pathway, where they modulate D2 receptor function. The present study provides evidence for the existence of an additional, functionally significant, segregation of A2A receptors at the presynaptic level. Using integrated anatomical, electrophysiological, and biochemical approaches, we demonstrate that presynaptic A2A receptors are preferentially localized in cortical glutamatergic terminals that contact striatal neurons of the direct pathway, where they exert a selective modulation of corticostriatal neurotransmission. Presynaptic striatal A2A receptors could provide a new target for the treatment of neuropsychiatric disorders.