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

Abstract

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.

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Figure 1: Organization of the mouse A2aR gene, the targeting construct, and the allele resulting from homologous recombination.
Figure 2: a, In situhybridization of brain sections from A2aR+/+and A2aR−/−mice, using oligonucleotide probes corresponding to the first (A2aR-5′) and second (A2aR-3′) exons of the mouse A2aR gene, the protachykinin (substance-P precursor) cDNA (SP) and the proenkephalin cDNA (Enk).
Figure 3: a, Exploratory behaviour.
Figure 4: Aggressive behaviour as measured by the resident–intruder test.
Figure 5: Behavioural response to acute thermal stimuli.
Figure 6: Platelet aggregation in A2aR+/+and A2aR−/−mice.
Figure 7: Basal mean blood pressure and heart rate were measured on anaesthetized A2aR+/+(n= 9/f>) and A2aR−/−(n= 11) mice by carotid artery catheterization.

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Acknowledgements

The R1 ES and STP cell lines were provided by A. Nagy and B. Colledge, respectively. We thank J.-F. Aubert for his help with the determination ofthe haemodynamic parameters; O. Le Moine, H. Louis, D. Penninck and C. Kucharzewski for discussion; and E. Bressy, M. J. Simons, E. Quertainmont and M. Verslype for technical assistance. This work was supported by the Belgian programme on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Federal Service for Science, Technology and Culture. It was also supported by the Fonds de la Recherche Scientifique Médicale of Belgium, the BIOMED2 programme, and the Foundation Médicale Reine Elisabeth. Scientific responsiblity belongs to the authors. C.L. and S.N.S. are Chercheurs Qualifiés of the Fonds National de la Recherche Scientifique.

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Correspondence to Marc Parmentier.

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Ledent, C., Vaugeois, JM., Schiffmann, S. et al. Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature 388, 674–678 (1997). https://doi.org/10.1038/41771

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