Behavioural and biochemical responses to morphine associated with its motivational properties are altered in adenosine A2A receptor knockout mice
Behavioural and biochemical responses to morphine associated with its motivational properties are altered in adenosine A2A receptor knockout mice
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DOI：
10.1038/bjp.2008.299
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发表时间：
2008-11-01
影响因子：
7.3
通讯作者：
Valverde, O.
中科院分区：
文献类型：
--
作者：
Castane, A.;Wells, L.;Valverde, O.
背景与目的：嘌呤能系统通过A（2A）腺苷受体调节不同药物滥用诱导的成瘾。本研究的目的是探讨A（2A）腺苷受体（A（2A）Rs）在吗啡诱导的行为和神经化学反应中的特殊作用及其动机特性。实验方法：用A（2A）Rs缺失小鼠（A（2A）敲除（KO）小鼠）和野生型同窝小鼠评价吗啡诱导的行为反应。抗伤害性使用尾部浸泡和热板测试进行评估。采用位置条件化范式评价吗啡的奖赏效应和吗啡戒断的焦虑反应。微透析研究进行了评估在细胞外多巴胺水平的变化后，吗啡administration.Key结果：急性管理的吗啡诱导的自发活动和抗伤害性反应在两种基因型的增强A（2A）KO小鼠的延髓核。而吗啡诱导的奖赏效应在A（2A）KO小鼠中被完全阻断。此外，纳洛酮没有诱导的地方厌恶缺乏A（2A）Rs的动物。结论和影响：我们的研究结果表明，奖励和厌恶的影响与吗啡戒断被废除在A（2A）KO小鼠，支持的差异作用的A（2A）腺苷受体的躯体和动机的吗啡成瘾的影响。本研究为A（2A）Rs作为滥用药物的动机特性的一般调节剂的作用提供了证据。这些受体的药理学操作可能是药物成瘾管理的新靶点。
Background and purpose: The purinergic system through the A(2A) adenosine receptor regulates addiction induced by different drugs of abuse. The aim of the present study was to investigate the specific role of A(2A) adenosine receptors (A(2A)Rs) in the behavioural and neurochemical responses to morphine associated with its motivational properties.Experimental approach: Mice lacking A(2A)Rs (A(2A) knockout (KO) mice) and wild-type littermates were used to evaluate behavioural responses induced by morphine. Antinociception was assessed using the tail-immersion and the hot-plate tests. Place-conditioning paradigms were used to evaluate the rewarding effects of morphine and the dysphoric responses of morphine withdrawal. Microdialysis studies were carried out to evaluate changes in the extracellular levels of dopamine in the nucleus accumbens of A(2A) KO mice after morphine administration.Key results: The acute administration of morphine induced a similar enhancement of locomotor activity and antinociceptive responses in both genotypes. However, the rewarding effects induced by morphine were completely blocked in A(2A) KO mice. Also, naloxone did not induce place aversion in animals lacking the A(2A)Rs.Conclusions and implications: Our findings demonstrate that the rewarding and aversive effects associated with morphine abstinence were abolished in A(2A) KO mice, supporting a differential role of the A(2A) adenosine receptor in the somatic and motivational effects of morphine addiction. This study provides evidence for the role of A(2A)Rs as general modulators of the motivational properties of drugs of abuse. Pharmacological manipulation of these receptors may represent a new target in the management of drug addiction.