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

Ainhoa Bilbao, Andrea Cippitelli, Ana Belén Martín, Noelia Granado, Oscar Ortiz, Erwan Bezard, Jiang-Fan Chen, Miguel Navarro, Fernando Rodríguez de Fonseca, R Moratalla
Psychopharmacology. 2006-02-10; 185(2): 160-168
DOI: 10.1007/s00213-005-0284-0

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1. Psychopharmacology (Berl). 2006 Apr;185(2):160-8. Epub 2006 Feb 10.

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

Bilbao A(1), Cippitelli A, Martín AB, Granado N, Ortiz O, Bezard E, Chen JF,
Navarro M, Rodríguez de Fonseca F, Moratalla R.

Author information:
(1)Departamento de Psicobiología, Instituto Universitario de Drogodependencias,
Universidad Complutense, Madrid 28223, Spain.

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 (A(2A)R(-/-)) 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 mu-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 A(2A)R(-/-) 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 A(2A)R(-/-)
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 A(2A)R alleles. A(2A)R(-/-) and wild-type mice have
similar levels of striatal mu-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 mu-opiate receptors in
tonic inhibition of motor activity in the striatum.

DOI: 10.1007/s00213-005-0284-0
PMID: 16470403 [Indexed for MEDLINE]

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