Glutamate Receptors in the Central Nucleus of the Amygdala Mediate Cisplatin-Induced Malaise and Energy Balance Dysregulation through Direct Hindbrain Projections
Glutamate Receptors in the Central Nucleus of the Amygdala Mediate Cisplatin-Induced Malaise and Energy Balance Dysregulation through Direct Hindbrain Projections
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DOI：
10.1523/jneurosci.0440-15.2015
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发表时间：
2015-08-05
影响因子：
5.3
通讯作者：
De Jonghe, Bart C.
中科院分区：
文献类型：
--
作者：
Alhadeff, Amber L.;Holland, Ruby A.;De Jonghe, Bart C.
顺铂化疗通常用于治疗多种癌症，尽管其会产生恶心、呕吐和厌食等严重副作用，影响生活质量并限制治疗依从性。尽管已经临床使用了数十年，但介导这些副作用的神经机制仍然难以捉摸。最近的数据强调背侧迷走神经复合体（DVC）、外侧臂旁核（lPBN）和杏仁核中央核（CeA）是介导顺铂副作用的潜在作用位点。在这里，大鼠免疫组织化学研究的结果确定了一组投射到 lPBN 的顺铂激活的 DVC 神经元和投射到 CeA 的一组顺铂激活的 lPBN 降钙素基因相关肽（CGRP，lPBN 中谷氨酸能神经元的标记）神经元，概述了顺铂激活的神经解剖回路。顺铂治疗后，CeA基因的AMPA和NMDA谷氨酸受体亚基表达显着增加，表明CeA谷氨酸受体信号在介导顺铂副作用中发挥作用。与基因表达结果一致，行为/药理学数据表明，CeA AMPA/红藻氨酸受体阻断可减轻顺铂诱导的异食癖（无呕吐实验室啮齿类动物恶心/行为不适的代表），并且除了异食癖外，CeA NMDA受体阻断还可减轻顺铂诱导的厌食和体重减轻，表明CeA中的谷氨酸受体信号传导对于异食癖引起的能量平衡失调至关重要。顺铂治疗。总之，这些数据强调了一种新的回路和 CGRP/谷氨酸能机制，通过该机制介导顺铂引起的不适和能量平衡失调。
Cisplatin chemotherapy is used commonly to treat a variety of cancers despite severe side effects such as nausea, vomiting, and anorexia that compromise quality of life and limit treatment adherence. The neural mechanisms mediating these side effects remain elusive despite decades of clinical use. Recent data highlight the dorsal vagal complex (DVC), lateral parabrachial nucleus (lPBN), and central nucleus of the amygdala (CeA) as potential sites of action in mediating the side effects of cisplatin. Here, results from immunohistochemical studies in rats identified a population of cisplatin-activated DVC neurons that project to the lPBN and a population of cisplatin-activated lPBN calcitonin gene-related peptide (CGRP, a marker for glutamatergic neurons in the lPBN) neurons that project to the CeA, outlining a neuroanatomical circuit that is activated by cisplatin. CeA gene expressions of AMPA and NMDA glutamate receptor subunits were markedly increased after cisplatin treatment, suggesting that CeA glutamate receptor signaling plays a role in mediating cisplatin side effects. Consistent with gene expression results, behavioral/pharmacological data showed that CeA AMPA/kainate receptor blockade attenuates cisplatin-induced pica (a proxy for nausea/behavioral malaise in nonvomiting laboratory rodents) and that CeA NMDA receptor blockade attenuates cisplatin-induced anorexia and body weight loss in addition to pica, demonstrating that glutamate receptor signaling in the CeA is critical for the energy balance dysregulation caused by cisplatin treatment. Together, these data highlight a novel circuit and CGRP/glutamatergic mechanism through which cisplatin-induced malaise and energy balance dysregulation are mediated.