Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine a2a receptor

Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine a2a receptor

Play all audios:

Loading...

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. Access through your institution Buy or subscribe This is a preview of


subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 51 print issues and online access $199.00 per year only


$3.90 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout


ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS NEUROINFLAMMATORY ALTERATIONS


IN TRAIT ANXIETY: MODULATORY EFFECTS OF MINOCYCLINE Article Open access 30 July 2020 UNIQUE BRAIN ENDOTHELIAL PROFILES ACTIVATED BY SOCIAL STRESS PROMOTE CELL ADHESION, PROSTAGLANDIN E2


SIGNALING, HYPOTHALAMIC–PITUITARY–ADRENAL AXIS MODULATION, AND ANXIETY Article 14 September 2022 HEMOKININ-1 IS A MEDIATOR OF CHRONIC RESTRAINT STRESS-INDUCED PAIN Article Open access 16


November 2023 REFERENCES * Olah, M. E. & Stiles, G. L. Adenosine receptor subtypes: characterization and therapeutic regulation. _Annu. Rev. Pharmacol. Toxicol._ 35, 581–606 (1995).


Article  CAS  Google Scholar  * Libert, F. et al. Selective amplification and cloning of four new members of the G protein-coupled recptor family. _Science_ 244, 569–572 (1989). Article  ADS


  CAS  Google Scholar  * Maenhaut, C. et al. RDC8 codes for an adenosine A2receptor with physiological constitutive activity. _Biochem. Biophys. Res. Commun._ 173, 1169–1178 (1990). Article


  CAS  Google Scholar  * Fredholm, B. B. Adenosine, adenosine receptors and the actions of caffeine. _Pharmacol. Toxicol._ 76, 93–101 (1995). Article  CAS  Google Scholar  * Fink, J. S. et


al. Molecular cloning of the rat A2adenosine receptor: selective co-expression with D2dopamine receptors in rat striatum. _Mol. Brain. Res._ 14, 186–195 (1992). Article  CAS  Google Scholar


  * Furlong, T. J., Pierce, K. D., Selbie, L. A. & Shine, J. Molecular characterization of a human brain adenosine A2receptor. _Mol. Brain Res._ 15, 62–66 (1992). Article  CAS  Google


Scholar  * Weaver, D. R. A2aadenosine receptor gene expression in developing rat brain. _Mol. Brain Res._ 20, 313–327 (1993). Article  CAS  Google Scholar  * Höpker, V. H., Saffrey, M. J.


& Burnstock, G. The neuritogenic effect of myenteric plexus on striatal neurones in co-culture involves nitric oxide. _Neuroreport_ 6, 1153–1156 (1995). Article  Google Scholar  *


Schiffmann, S. N. & Vanderhaegheen, J. J. Adenosine A2receptors regulate the gene expression of striatopallidal and striatonigral neurons. _J. Neurosci._ 13, 1080–1087 (1993). Article 


CAS  Google Scholar  * Balk, J. H. et al. Parkinsonian-like locomotor impairment in mice lacking dopamine D2receptors. _Nature_ 377, 424–428 (1995). Article  ADS  CAS  Google Scholar  *


Grace, A. A. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. _Neuroscience_ 41, 1–24 (1991). Article


  CAS  Google Scholar  * Nikodijeviç, O., Jacobson, K. A. & Daly, J. W. Locomotor activity in mice during chronic treatment with caffeine and withdrawal. _Pharmacol. Biochem. Behav._ 44,


199–216 (1993). Article  Google Scholar  * File, S. E., Baldwin, H. A., Johnston, A. L. & Wilks, L. J. Behavioral effects of acute and chronic administration of caffeine in the rat.


_Pharmacol. Biochem. Behav._ 30, 809–815 (1988). Article  CAS  Google Scholar  * Jain, N., Kemp, N., Adeyemo, O., Buchanan, P. & Stone, T. W. Anxiolytic activity of adenosine receptor


activation in mice. _Br. J. Pharmacol._ 116, 2127–2133 (1995). Article  CAS  Google Scholar  * Saudou, F. et al. Enhanced aggressive behavior in mice lacking 5-HT1Breceptor. _Science_ 265,


1875–1878 (1994). Article  ADS  CAS  Google Scholar  * Palmour, R. M., Lipowski, C. J., Simon, C. K. & Ervin, F. R. Adenosine analogs inhibit fighting in isolated male mice. _Life Sci._


44, 1293–1301 (1989). Article  CAS  Google Scholar  * Sawynok, J. & Yaksh, T. L. Caffeine as an analgesic adjuvant: a review of pharmacology and mechanisms of action. _Pharmacol. Rev._


45, 43–85 (1993). CAS  PubMed  Google Scholar  * Sweeney, M. I., White, T. D., Jhamandas, K. H. & Sawynok, J. Morphine releases endogenous adenosine from the spinal cord _in vivo_. _Eur.


J. Pharmacol._ 141, 169–170 (1987). Article  CAS  Google Scholar  * De Lander, G. E. & Keil, G. J. Antinociception induced by intrathecal coadministration of selective adenosine


receptor and selective opioid receptor agonists in mice. _J. Pharmacol. Exp. Ther._ 268, 943–951 (1994). CAS  PubMed  Google Scholar  * McQueen, D. S. & Ribeiro, J. A. Pharmacological


characterization of the receptor involved in chemoexcitation induced by adenosine. _Br. J. Pharmacol._ 88, 615–620 (1986). Article  CAS  Google Scholar  * Cristalli, G. et al. Inhibition of


platelet aggregation by adenosine receptor agonists. _Naunyn. Schmiedebergs Arch. Pharmacol._ 349, 644–650 (1994). Article  CAS  Google Scholar  * Dionisotti, S., Zocchi, C., Varani, K.,


Borea, P. A. & Ongini, E. Effects of adenosine derivatives on human and rabbit platelet aggregation. Correlation of adenosine receptor affinities and antiaggregatory activity. _Naunyn.


Schmiedebergs Arch. Pharmacol._ 346, 673–676 (1994). Google Scholar  * Varani, K., Gessi, S., Dalpiaz, A. & Borea, P. A. Pharmacological and biochemical characterization of purified


A2aadenosine receptors in human platelet membranes by [3H]-CGS 21680 binding. _Br. J. Pharmacol._ 117, 1693–1701 (1996). Article  CAS  Google Scholar  * Ongini, E. & Fredholm, B. B.


Pharmacology of adenosine A2Areceptors. _Trends Pharmacol. Sci._ 17, 364–372 (1996). Article  CAS  Google Scholar  * Nagy, A., Rossant, J., Nagy, R., Abramow-Neverly, W. & Roder, J. C.


Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. _Proc. Natl Acad. Sci. USA_ 90, 8424–8428 (1993). Article  ADS  CAS  Google Scholar  * Worst, W.


& Joyner, A. L. in _Gene Targeting, a Practical Approach_ (ed. Joyner, A. L.) 33–61 (Oxford University Press, Oxford, 1993). Google Scholar  * Schiffmann, S. N. & Vanderhaegheen, J.


J. Ontogeny of gene expression of adenosine A2receptor in the striatum: early localization in the patch compartment. _J. Comp. Neurol._ 317, 117–128 (1992). Article  CAS  Google Scholar  *


Costentin, J. et al. Dissociated effects of inhibitors of enkephalin-metabolising peptidases or naloxone on various nociceptive responses. _Eur. J. Pharmacol._ 123, 37–44 (1986). Article 


CAS  Google Scholar  Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS *


IRIBHN, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070, Bruxelles, Belgium Catherine Ledent, Gilbert Vassart & Marc Parmentier * Laboratoire de Recherche sur


les Neuropeptides, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070, Bruxelles, Belgium Serge N. Schiffmann & Jean-Jacques Vanderhaeghen * Service de Génétique


Médicale, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070, Bruxelles, Belgium Gilbert Vassart * IFRMP, Unité de Neuropsychopharmacologie Expérimentale, CNRS UPRESA


6036, Faculté de Médecine et de Pharmacie, Avenue de l'Université, 76803 Saint Etienne du Rouvray, France Jean-Marie Vaugeois, Malika El Yacoubi & Jean Costentin * Division of


Hypertension, Lausanne University Medical School, CH-1011 Lausanne, Switzerland Thierry Pedrazzini * Department of Biochemistry, CRC Growth Factors, University of Oxford, South Parks Road,


OX1 3QU, Oxford, UK John K. Heath Authors * Catherine Ledent View author publications You can also search for this author inPubMed Google Scholar * Jean-Marie Vaugeois View author


publications You can also search for this author inPubMed Google Scholar * Serge N. Schiffmann View author publications You can also search for this author inPubMed Google Scholar * Thierry


Pedrazzini View author publications You can also search for this author inPubMed Google Scholar * Malika El Yacoubi View author publications You can also search for this author inPubMed 


Google Scholar * Jean-Jacques Vanderhaeghen View author publications You can also search for this author inPubMed Google Scholar * Jean Costentin View author publications You can also search


for this author inPubMed Google Scholar * John K. Heath View author publications You can also search for this author inPubMed Google Scholar * Gilbert Vassart View author publications You


can also search for this author inPubMed Google Scholar * Marc Parmentier View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR


Correspondence to Marc Parmentier. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 21 April 1997 *


Accepted: 05 June 1997 * Issue Date: 14 August 1997 * DOI: https://doi.org/10.1038/41771 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get


shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative