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Letters to Nature

Nature 388, 674-678 (14 August 1997) | ; Received 21 April 1997; Accepted 5 June 1997

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Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor

Catherine Ledent1, Jean-Marie Vaugeois2, Serge N. Schiffmann3, Thierry Pedrazzini4, Malika El Yacoubi2, Jean-Jacques Vanderhaeghen3, Jean Costentin2, John K. Heath5, Gilbert Vassart1,6 & Marc Parmentier1

  1. IRIBHN, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Bruxelles, Belgium
  2. Laboratoire de Recherche sur les Neuropeptides, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Bruxelles, Belgium
  3. Service de Génétique Médicale, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Bruxelles, Belgium
  4. IFRMP, Unité de Neuropsychopharmacologie Expérimentale, CNRS UPRESA 6036, Faculté de Médecine et de Pharmacie, Avenue de l'Université, 76803 Saint Etienne du Rouvray, France
  5. Division of Hypertension, Lausanne University Medical School, CH-1011 Lausanne, Switzerland
  6. CRC Growth Factors, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK

Correspondence to: Marc Parmentier1 Correspondence and request for materials should be addressed to M.P. (e-mail: Email: mparment@ulb.ac.be). The EMBL/Genbank accession numbers for the mouse A2aR gene sequences are Y13344, Y13345 and Y13346.

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Adenosine is released from metabolically active cells by facilitated diffusion, and is generated extracellularly by degradation of released ATP. It is a potent biological mediator that modulates the activity of numerous cell types, including various neuronal populations, platelets, neutrophils and mast cells, and smooth muscle cells in bronchi and vasculature. Most of these effects help to protect cells and tissues during stress conditions such as ischaemia. Adenosine mediates its effects through four receptor subtypes: the A1, A2a, A2b and A3 receptors1. The A2a receptor (A2aR)2,3 is abundant in basal ganglia, vasculature and platelets, and stimulates adenylyl cyclase. It is a major target of caffeine, the most widely used psychoactive drug4. Here we investigate the role of the A2a receptor by disrupting the gene in mice. We found that A2aR-knockout (A2aR-/-) mice were viable and bred normally. Their exploratory activity was reduced, whereas caffeine, which normally stimulates exploratory behaviour, became a depressant of exploratory activity. Knockout animals scored higher in anxiety tests, and male mice were much more aggressive towards intruders. The response of A2aR-/-mice to acute pain stimuli was slower. Blood pressure and heart rate were increased, as well as platelet aggregation. The specific A2a agonist CGS 21680 lost its biological activity in all systems tested.