Dysregulation of nociceptin/orphanin FQ activity in the amygdala is linked to excessive alcohol drinking in the rat
Dysregulation of nociceptin/orphanin FQ activity in the amygdala is linked to excessive alcohol drinking in the rat
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DOI：
10.1016/j.biopsych.2008.02.004
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发表时间：
2008-08-01
影响因子：
10.6
通讯作者：
Heilig, Markus
中科院分区：
文献类型：
--
作者：
Economidou, Daina;Hansson, Anita C.;Heilig, Markus
背景：酗酒是一种复杂的行为障碍，生活压力事件与遗传易感因素之间的相互作用导致疾病的发生和进展。这些相互作用的神经基质在很大程度上仍然未知。在这里，我们利用动物模型研究了伤害感受肽/孤啡肽 FQ (N/OFQ) 系统的作用，在该动物模型中，对高度酒精偏好的遗传选择导致了对压力行为敏感性升高的共分离（马尔基吉亚撒丁岛酒精偏好 [msP]）。 方法：训练自我饮酒的 msP 和 Wistar 大鼠接受中央注射 N/OFQ。还进行了原位杂交和受体结合测定，以评估初始 msP 和 Wistar 大鼠中的 N/OFQ 受体 (NOP) 功能。结果：脑室内 (ICV) 注射 N/OFQ 显着抑制 msP 中的酒精自我给药，但在未选择的 Wistar 大鼠中则不然。与 Wistar 大鼠相比，msP 大鼠大部分脑区的 NOP 受体信使 RNA 表达和结合均上调。然而，在 msP 大鼠中，[(35)S]GTP gamma S 结合揭示了中央杏仁核 (CeA) 中 NOP 受体信号传导的选择性损伤。将 N/OFQ 显微注射到 CeA 后，msP 大鼠的自我给药受到抑制，但未注射到终纹床核或基底外侧杏仁核中。 结论：这些发现表明，CeA 中 N/OFQ-NOP 受体信号的失调导致了 msP 大鼠的过量酒精摄入，并且这种表型可以通过局部给予药理剂量的外源性 N/OFQ 来挽救。根据 N/OFQ 的抗促肾上腺皮质激素释放因子 (CRF) 作用以及 CRF 系统在促进 mP 大鼠过度饮酒中的重要性来解释数据。
Background: Alcoholism is a complex behavioral disorder in which interactions between stressful life events and heritable susceptibility factors contribute to the initiation and progression of disease. Neural substrates of these interactions remain largely unknown. Here, we examined the role of the nociceptin/orphanin FQ (N/OFQ) system, with an animal model in which genetic selection for high alcohol preference has led to co-segregation of elevated behavioral sensitivity to stress (Marchigian Sardinian alcohol-preferring [msP]).Methods: The msP and Wistar rats trained to self-administer alcohol received central injections of N/OFQ. In situ hybridization and receptor binding assays were also performed to evaluate N/OFQ receptor (NOP) function in naive msP and Wistar rats.Results: Intracerebroventricular (ICV) injection of N/OFQ significantly inhibited alcohol self-ad ministration in msP but not in nonselected Wistar rats. The NOP receptor messenger RNA expression and binding was upregulated across most brain regions in msP compared with Wistar rats. However, in msP rats [(35)S]GTP gamma S binding revealed a selective impairment of NOP receptor signaling in the central amygdala (CeA). Ethanol self-administration in msP rats was suppressed after N/OFQ microinjection into the CeA but not into the bed nucleus of the stria terminalis or the basolateral amygdala.Conclusions: These findings indicate that dysregulation of N/OFQ-NOP receptor signaling in the CeA contributes to excessive alcohol intake in msP rats and that this phenotype can be rescued by local administration of pharmacological doses of exogenous N/OFQ. Data are interpreted on the basis of the anti-corticotropin releasing factor (CRF) actions of N/OFQ and the significance of the CRF system in promoting excessive alcohol drinking in msP rats.