Bilbao Ainhoa, Cippitelli Andrea, Martín Ana Belén, Granado Noelia, Ortiz Oscar, Bezard Erwan, Chen Jiang-Fan, Navarro Miguel, Rodríguez de Fonseca Fernando, Moratalla R
Departamento de Psicobiología, Instituto Universitario de Drogodependencias, Universidad Complutense, Madrid 28223, Spain.
Psychopharmacology (Berl). 2006 Apr;185(2):160-8. doi: 10.1007/s00213-005-0284-0. Epub 2006 Feb 10.
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.
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.
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.
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.
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.
咖啡因和其他甲基黄嘌呤通过对A2A腺苷受体的拮抗作用，在小鼠中诱导行为激活和焦虑反应。当与阿片类拮抗剂纳洛酮联合使用时，甲基黄嘌呤在未接触过阿片类药物的动物中产生一种特征性的准吗啡戒断综合征（QMWS）。
本研究的目的是确定A2A受体在咖啡因和纳洛酮联合给药诱导的准吗啡戒断综合征以及咖啡因的行为效应中的作用。
我们使用A2A受体敲除（A(2A)R(-/-)）小鼠与其野生型和杂合子同窝小鼠进行比较，以测量旷场中的运动活动以及咖啡因和纳洛酮诱导的戒断症状。还通过原位杂交检测未接触过药物的野生型和敲除小鼠脑啡肽和强啡肽mRNA的表达，并通过配体结合放射自显影检测μ-阿片受体，以检查A2A受体失活是否会引起阿片受体的变化。
咖啡因可增加野生型动物的运动和焦虑，但对A(2A)R(-/-)小鼠没有精神运动效应。咖啡因（20mg/kg）和纳洛酮（2mg/kg）联合给药会在野生型小鼠中导致严重的准吗啡戒断综合征，而在A(2A)R(-/-)小鼠中几乎完全消除。杂合子动物的戒断症状减少了40%，这表明对于A(2A)R等位基因之一的失活不存在基因/发育补偿。A(2A)R(-/-)小鼠和野生型小鼠的纹状体μ-阿片受体水平相似，因此该效应不是由于阿片受体表达改变所致。
我们的结果表明，A2A受体是咖啡因和纳洛酮联合给药诱导准吗啡戒断综合征所必需的，并表明纹状体A2A受体和μ-阿片受体参与纹状体运动活动的紧张性抑制。
