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


OBJECTIVE
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.
Bilbao
Ainhoa
A
Departamento de Psicobiología, Instituto Universitario de Drogodependencias, Universidad Complutense, Madrid 28223, Spain.
Cippitelli
Andrea
A
Martín
Ana Belén
AB
Granado
Noelia
N
Ortiz
Oscar
O
Bezard
Erwan
E
Chen
Jiang-Fan
JF
Navarro
Miguel
M
Rodríguez de Fonseca
Fernando
F
Moratalla
R
R
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000096:biosynthesis; D004745:Enkephalins / Q000096:biosynthesis; D005106:Exploratory Behavior / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000009:adverse effects*; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000096:biosynthesis; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology
D058917:Adenosine A2 Receptor Antagonists; D000697:Central Nervous System Stimulants; D004745:Enkephalins; D009292:Narcotic Antagonists; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D017450:Receptors, Opioid, mu; D009270:Naloxone; D002110:Caffeine; D004399:Dynorphins; D009020:Morphine