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Neuropsychopharmacology:揭示胃饥饿素导致酗酒成瘾的分子机理

  1. Neuropsychopharmacology
  2. 分子机理
  3. 胃饥饿素
  4. 酗酒成瘾

来源:生物谷 2012-09-17 12:35

2012年9月17日 讯 /生物谷BIOON/ --近日,来自斯克里普斯研究所的研究者通过研究发现了,控制食欲的蛋白质和涉及酗酒成瘾的脑细胞之间的联系,这项研究发现或许为开发治疗酗酒或者其它成瘾疾病的疗法提供新的思路。相关研究成果刊登在了国际杂志Neuropsychopharmacology上。

2012年9月17日 讯 /生物谷BIOON/ --近日,来自斯克里普斯研究所的研究者通过研究发现了,控制食欲的蛋白质和涉及酗酒成瘾的脑细胞之间的联系,这项研究发现或许为开发治疗酗酒或者其它成瘾疾病的疗法提供新的思路。相关研究成果刊登在了国际杂志Neuropsychopharmacology上。

研究者Marisa Roberto表示,这是首次揭示葛瑞林(胃饥饿素,一种胃肠道激素)对大脑神经元的效应的研究,这种大脑神经元名为杏仁核的中央核。每年由于过度的酒精使用和酗酒在全球范围内会促使40%的该类人群死亡,在美国每年会死亡79,000人。

杏仁核的中央核区域被认为是转换酒精依赖性的大脑关键区域,研究者试图检测葛瑞林对该区域是否有某种影响。葛瑞林可以通过激活大脑下丘脑区域的GHSR1A受体来激发人的食欲,但是研究者近日在动物模型研究中发现,葛瑞林和GHSR1A受体中基因的缺失和严重的酒精中毒明显相关。另外,酗酒病人在血液中存在高水平的葛瑞林循环,而且葛瑞林水平越高,病人越渴望得到酒精。

本项研究中,研究者首次揭示了GHSR1A受体在中央核的神经元细胞中存在。使用细胞内记录技术,研究小组测定了,当给予葛瑞林时,γ氨基丁酸突触的改变情况。γ氨基丁酸突触是神经元传递抑制性神经递质γ的区域。研究者发现葛瑞林可以促使中央杏仁核神经元中γ氨基丁酸的转移。下一步研究者希望通过化学抑制剂阻碍GHSR1A受体功能,同时测定神经递质γ水平的降低。

研究者Roberto表示,我们的研究结果揭示了葛瑞林以及酒精在杏仁核中央核区域的效应,重要的是,葛瑞林信号可以和急慢性的酒精激活途径进行相互作用。或许我们可以找到一种阻碍杏仁核区域的抑制葛瑞林的活性,这样就可以减弱甚至去除酗酒患者的成瘾效应。相关研究由美国国家酒精中毒研究所等机构提供支持。(生物谷Bioon.com)

编译自:Protein Linked to Hunger Also Implicated in Alcoholism

Ghrelin Increases GABAergic Transmission and Interacts with Ethanol Actions in the Rat Central Nucleus of the Amygdala

Maureen T Cruz, Melissa A Herman, Dawn M Cote, Andrey E Ryabinin and Marisa Roberto

The neural circuitry that processes natural rewards converges with that engaged by addictive drugs. Because of this common neurocircuitry, drugs of abuse have been able to engage the hedonic mechanisms normally associated with the processing of natural rewards. Ghrelin is an orexigenic peptide that stimulates food intake by activating GHS-R1A receptors in the hypothalamus. However, ghrelin also activates GHS-R1A receptors on extrahypothalamic targets that mediate alcohol reward. The central nucleus of the amygdala (CeA) has a critical role in regulating ethanol consumption and the response to ethanol withdrawal. We previously demonstrated that rat CeA GABAergic transmission is enhanced by acute and chronic ethanol treatment. Here, we used quantitative RT-PCR (qRT-PCR) to detect Ghsr mRNA in the CeA and performed electrophysiological recordings to measure ghrelin effects on GABA transmission in this brain region. Furthermore, we examined whether acute or chronic ethanol treatment would alter these electrophysiological effects. Our qRT-PCR studies show the presence of Ghsr mRNA in the CeA. In naive animals, superfusion of ghrelin increased the amplitude of evoked inhibitory postsynaptic potentials (IPSPs) and the frequency of miniature inhibitory postsynaptic currents (mIPSCs). Coapplication of ethanol further increased the ghrelin-induced enhancement of IPSP amplitude, but to a lesser extent than ethanol alone. When applied alone, ethanol significantly increased IPSP amplitude, but this effect was attenuated by the application of ghrelin. In neurons from chronic ethanol-treated (CET) animals, the magnitude of ghrelin-induced increases in IPSP amplitude was not significantly different from that in naive animals, but the ethanol-induced increase in amplitude was abolished. Superfusion of the GHS-R1A antagonists D-Lys3-GHRP-6 and JMV 3002 decreased evoked IPSP and mIPSC frequency, revealing tonic ghrelin activity in the CeA. D-Lys3-GHRP-6 and JMV 3002 also blocked ghrelin-induced increases in GABAergic responses. Furthermore, D-Lys3-GHRP-6 did not affect ethanol-induced increases in IPSP amplitude. These studies implicate a potential role for the ghrelin system in regulating GABAergic transmission and a complex interaction with ethanol at CeA GABAergic synapses.

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