Adenosine transporter ENT1 regulates the acquisition of goal-directed behavior and ethanol drinking through A2A receptor in the dorsomedial striatum.
Adenosine transporter ENT1 regulates the acquisition of goal-directed behavior and ethanol drinking through A2A receptor in the dorsomedial striatum.
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DOI：
10.1523/jneurosci.3094-12.2013
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发表时间：
2013-03-06
期刊：
影响因子：
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通讯作者：
Choi DS
中科院分区：
文献类型：
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作者：
Nam HW;Hinton DJ;Kang NY;Kim T;Lee MR;Oliveros A;Adams C;Ruby CL;Choi DS
腺苷信号传导与包括酗酒在内的许多精神疾病的病理生理学有关。纹状体腺苷A2 A受体（A2 AR）在饮酒和从目标导向行为到习惯行为的转变中起着重要作用。然而，纹状体A2 AR信号在乙醇饮用和习惯发展中的作用的直接证据尚未建立。在这里，我们发现，减少A2 AR介导的CREB活性在背内侧纹状体（DMS）增强目标导向行为的初始行为获得和脆弱性的进展过度饮酒乙醇在缺乏乙醇敏感性腺苷转运蛋白ENT 1（ENT 1 −/−）的小鼠在操作性条件反射。利用在两种基因型（CRE-lacZ/ENT 1 +/+小鼠和CRE-lacZ/ENT 1 −/−小鼠）以及dnCREB（CREB的显性负性形式）中的7个重复CRE位点控制下表达β-半乳糖苷酶（lacZ）的小鼠，我们发现DMS中CREB活性的降低与A2 AR信号传导的降低和目标导向的乙醇饮用增加有因果关系。最后，我们证明了A2 AR拮抗剂（ZM 241385）抑制了DMS中PKA活性介导的信号传导，并促进了ENT 1 +/+小鼠的过度饮酒，但在ENT 1 −/−小鼠中没有。综上所述，我们的研究表明，A2 AR介导的CREB信号在DMS是一个关键的决定因素，以提高发展目标导向的酒精饮用小鼠。
Adenosine signaling has been implicated in the pathophysiology of many psychiatric disorders including alcoholism. Striatal adenosine A2A receptors (A2AR) play an essential role in both ethanol drinking and the shift from goal-directed action to habitual behavior. However, direct evidence for a role of striatal A2AR signaling in ethanol drinking and habit development has not been established. Here, we identified that decreased A2AR-mediated CREB activity in the dorsomedial striatum (DMS) enhanced initial behavioral acquisition of goal-directed behaviors and the vulnerability to progress to excessive ethanol drinking during operant conditioning in mice lacking ethanol-sensitive adenosine transporter ENT1 (ENT1−/−). Utilizing mice expressing β-galactosidase (lacZ) under the control of seven-repeated CRE sites in both genotypes (CRE-lacZ/ENT1+/+ mice and CRE-lacZ/ENT1−/− mice) as well as dnCREB (dominant negative form of CREB), we found that reduced CREB activity in the DMS is causally associated with decreased A2AR signaling and increased goal-directed ethanol drinking. Finally, we demonstrated that A2AR antagonist (ZM241385) dampened PKA-activity mediated signaling in the DMS and promoted excessive ethanol drinking in ENT1+/+ mice, but not in ENT1−/− mice. Taken together, our studies indicate that A2AR-mediated CREB signaling in the DMS is a key determinant to enhance the development of goal-directed ethanol drinking in mice.