Gene expression is altered in the lateral hypothalamus upon activation of the mu opioid receptor
Gene expression is altered in the lateral hypothalamus upon activation of the mu opioid receptor
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DOI：
10.1196/annals.1417.028
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发表时间：
2008-01-01
期刊：
影响因子：
--
通讯作者：
Kieffer, B. L.
中科院分区：
文献类型：
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作者：
Befort, K.;Filliol, D.;Kieffer, B. L.
下丘脑外侧核是一种大脑结构，它控制着自然奖赏和滥用药物的享乐属性。已知MU阿片受体介导药物奖赏，但过度刺激这些受体是否影响促黄体生成素功能还没有研究。在这里，我们使用全基因组微阵列的方法，在转录水平上识别黄体生成素对慢性MU阿片受体激活的反应。我们让野生型和mu型阿片受体基因敲除小鼠接受不断升级的吗啡疗法，这会在野生型动物中产生严重的身体依赖，但不会产生突变动物。我们使用430A.2 Affymetrix阵列分析了黄体生成素样本中的基因图谱，并确定了一组仅在野生型小鼠中被吗啡改变表达的25个基因。通过对来自独立治疗的样本进行实时定量聚合酶链式反应，证实了这些基因中的一部分存在这种调节。水通道蛋白4、载脂蛋白D和前列腺素合成酶的表达改变预示着黄体生成素生理学的改变。两个信号基因(血清糖皮质激素激酶和G蛋白信号转导调节器4)的调节表明，神经传递在黄体生成素回路中发生了改变。最后，apelin的下调可能表明这种神经肽在阿片信号转导和享乐动态平衡中的潜在作用。总之，我们的研究表明，慢性u阿片受体刺激诱导了促黄体生成素基因表达的可塑性，并提供了一组独特的u阿片受体依赖基因，这些基因可能有助于改变成瘾性疾病的奖赏过程。
The lateral hypothalamus (LH) is a brain structure that controls hedonic properties of both natural rewards and drugs of abuse. Mu opioid receptors are known to mediate drug reward, but whether overstimulation of these receptors impacts on LH function has not been studied. Here we have used a genome-wide microarray approach to identify LH responses to chronic mu opioid receptor activation at the transcriptional level. We have subjected wild-type and mu opioid receptor knockout mice to an escalating morphine regimen, which produces severe physical dependence in wild-type but not mutant animals. We have analyzed gene profiles in LH samples using the 430A.2 Affymetrix array and identified a set of 25 genes whose expression is altered by morphine in wild-type mice only. The regulation was confirmed for a subset of these genes using real-time quantitative PCR on samples from independent treatments. Altered expression of aquaporin 4, apolipoprotein D, and prostaglandin synthase is indicative of modified LH physiology. The regulation of two signaling genes (the serum glucocorticoid kinase and the regulator of G protein signaling 4) suggests that neurotransmission is altered in LH circuitry. Finally, the downregulation of apelin may indicate a potential role for this neuropeptide in opioid signaling and hedonic homeostasis. Altogether, our study shows that chronic mu opioid receptor stimulation induces gene expression plasticity in the LH and provides a unique collection of mu opioid receptor-dependent genes that potentially contribute to alter reward processes in addictive diseases.