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Absence of quasi-morphine withdrawal syndrome in adenosine A2A receptor knockout mice

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Abstract

Rationale

Caffeine and other methylxanthines induce behavioral activation and anxiety responses in mice via antagonist action at A2A adenosine receptors. When combined with the opioid antagonist naloxone, methylxanthines produce a characteristic quasi-morphine withdrawal syndrome (QMWS) in opiate-naive animals.

Objectives

The aim of this study was to establish the role of A2A receptors in the quasi-morphine withdrawal syndrome induced by co-administration of caffeine and naloxone and in the behavioral effects of caffeine.

Methods

We have used A2A receptor knockout (A2AR−/−) mice in comparison with their wild-type and heterozygous littermates to measure locomotor activity in the open field and withdrawal symptoms induced by caffeine and naloxone. Naïve wild-type and knockout mice were also examined for enkephalin and dynorphin mRNA expression by in situ hybridization and for μ-opiate receptor by ligand binding autoradiography to check for possible opiate receptor changes induced by A2A receptor inactivation.

Results

Caffeine increases locomotion and anxiety in wild-type animals, but it has no psychomotor effects in A2AR−/− mice. Co-administration of caffeine (20 mg/kg) and naloxone (2 mg/kg) resulted in a severe quasi-morphine withdrawal syndrome in wild-type mice that was almost completely abolished in A2AR−/− mice. Heterozygous animals exhibited a 40% reduction in withdrawal symptoms, suggesting that there is no genetic/developmental compensation for the inactivation of one of the A2AR alleles. A2AR−/− and wild-type mice have similar levels of striatal μ-opioid receptors, thus the effect is not due to altered opioid receptor expression.

Conclusions

Our results demonstrate that A2A receptors are required for the induction of quasi-morphine withdrawal syndrome by co-administration of caffeine and naloxone and implicate striatal A2A receptors and μ-opiate receptors in tonic inhibition of motor activity in the striatum.

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Acknowledgements

This work has been supported by Plan Nacional Sobre Drogas and FIS (Red RTA, G03/05, and Red CIEN, C03/06) to R.M; M.N. and F.R.F and by the Spanish Ministerio de Educación y Ciencia, SAF2003-4864 and GEN2003-20651-C06-02 to RM and to F.R.F. The authors acknowledge the technical assistance of Luis Franco, Ana Isabel Tena, Coco Castuera and Oskar Ortiz. R. Moratalla, M. Navarro, and F. Rodríguez de Fonseca contributed equally for this work.

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Authors and Affiliations

  1. Departamento de Psicobiología, Instituto Universitario de Drogodependencias, Universidad Complutense, Madrid, 28223, Spain

    Ainhoa Bilbao, Andrea Cippitelli, Miguel Navarro & Fernando Rodríguez de Fonseca

  2. Consejo Superior de Investigaciones Científicas, Instituto Cajal, C/Doctor Arce, 37, Madrid, 28002, Spain

    Ana Belén Martín, Noelia Granado, Oscar Ortiz & R Moratalla

  3. Fundación IMABIS, Hospital Regional Universitario Carlos Haya, Málaga, 29010, Spain

    Ainhoa Bilbao, Andrea Cippitelli & Fernando Rodríguez de Fonseca

  4. Physiologie et Physiopathologie de la Signalization celullaire, UMR-CNRS 5543, Universite Victor Segalen Bordeaux2, 33076, Bordeaux, France

    Erwan Bezard

  5. Department of Neurology, Boston University School of Medicine, Boston, MA, 02218, USA

    Jiang-Fan Chen

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  1. Ainhoa Bilbao
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  2. Andrea Cippitelli
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  7. Jiang-Fan Chen
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  8. Miguel Navarro
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  9. Fernando Rodríguez de Fonseca
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Correspondence to R Moratalla.

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Bilbao, A., Cippitelli, A., Martín, A.B. et al. Absence of quasi-morphine withdrawal syndrome in adenosine A2A receptor knockout mice. Psychopharmacology 185, 160–168 (2006). https://doi.org/10.1007/s00213-005-0284-0

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