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

Rationale: Caffeine and other methylxanthines induce behavioral activation and anxiety responses in mice via antagonist action at A(2A) adenosine receptors. When combined with the opioid antagonist naloxone, methylxanthines produce a characteristic quasi-morphine withdrawal syndrome (QMWS) in opiate-naive animals. Objective: The aim of this study was to establish the role of A(2A) 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 A(2A) 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. Naive 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 A(2A) 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 A(2A) receptors are required for the induction of quasi-morphine withdrawal syndrome by co-administration of caffeine and naloxone and implicate striatal A(2A) receptors and mu-opiate receptors in tonic inhibition of motor activity in the striatum.