The melanin-concentrating hormone (MCH) system modulates behaviors associated with psychiatric disorders.
The melanin-concentrating hormone (MCH) system modulates behaviors associated with psychiatric disorders.
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DOI：
10.1371/journal.pone.0019286
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Civelli O
中科院分区：
文献类型：
--
作者：
Chung S;Verheij MM;Hesseling P;van Vugt RW;Buell M;Belluzzi JD;Geyer MA;Martens GJ;Civelli O
通过惊吓的前脉冲抑制（PPI）测量的感觉运动门控缺陷已被认为是精神分裂症和相关神经精神疾病患者的特征。 PPI 破坏被认为依赖于中皮质边缘多巴胺能系统的活动，并且被大多数抗精神病药物抑制。然而，这些药物也作用于黑质纹状体多巴胺能途径并产生不利的运动反应。因此，寻找一种抑制中皮质边缘而不影响黑质纹状体多巴胺能通路的方法可能有利于抗精神病治疗。黑色素浓缩激素 (MCH) 系统已被证明可以调节多巴胺相关反应。其受体 (MCH1R) 在中皮质边缘中高水平表达，而不是在黑质纹状体多巴胺能通路中表达。有趣的是，基因组连锁研究揭示了精神分裂症与 MCH1R 基因位点标记之间的显着关联。我们假设 MCH 系统可以选择性地调节与中皮质边缘多巴胺通路相关的行为。使用小鼠，我们发现 MCH 的中枢给药会增强阿朴吗啡诱导的 PPI 缺陷。使用对 PPI 反应不同的同类大鼠系，我们发现对阿扑吗啡敏感且表现出 PPI 缺陷的大鼠在下丘脑外侧区域表现出较高的 MCH mRNA 表达，并且阻断 MCH 系统可以逆转其 PPI 缺陷。另一方面，在小鼠和大鼠中，MCH 系统的激活或失活不会影响刻板行为，即依赖于黑质纹状体通路活动的多巴胺相关反应。此外，MCH 不会影响地佐西平诱导的 PPI 缺乏（一种谷氨酸相关反应）。因此，我们的数据表明 MCH 系统作为感觉运动门控的调节器，并为理解精神分裂症和相关精神疾病的病因提供了新的原理。
Deficits in sensorimotor gating measured by prepulse inhibition (PPI) of the startle have been known as characteristics of patients with schizophrenia and related neuropsychiatric disorders. PPI disruption is thought to rely on the activity of the mesocorticolimbic dopaminergic system and is inhibited by most antipsychotic drugs. These drugs however act also at the nigrostriatal dopaminergic pathway and exert adverse locomotor responses. Finding a way to inhibit the mesocorticolimbic- without affecting the nigrostriatal-dopaminergic pathway may thus be beneficial to antipsychotic therapies. The melanin-concentrating hormone (MCH) system has been shown to modulate dopamine-related responses. Its receptor (MCH1R) is expressed at high levels in the mesocorticolimbic and not in the nigrostriatal dopaminergic pathways. Interestingly a genomic linkage study revealed significant associations between schizophrenia and markers located in the MCH1R gene locus. We hypothesize that the MCH system can selectively modulate the behavior associated with the mesocorticolimbic dopamine pathway. Using mice, we found that central administration of MCH potentiates apomorphine-induced PPI deficits. Using congenic rat lines that differ in their responses to PPI, we found that the rats that are susceptible to apomorphine (APO-SUS rats) and exhibit PPI deficits display higher MCH mRNA expression in the lateral hypothalamic region and that blocking the MCH system reverses their PPI deficits. On the other hand, in mice and rats, activation or inactivation of the MCH system does not affect stereotyped behaviors, dopamine-related responses that depend on the activity of the nigrostriatal pathway. Furthermore MCH does not affect dizocilpine-induced PPI deficit, a glutamate related response. Thus, our data present the MCH system as a regulator of sensorimotor gating, and provide a new rationale to understand the etiologies of schizophrenia and related psychiatric disorders.
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影响因子：
10.6
作者：
KEITH, VA;MANSBACH, RS;GEYER, MA
通讯作者：
GEYER, MA
影响因子：
7.6
作者：
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DOI：
10.1124/jpet.106.109678
发表时间：
2007-04-01
影响因子：
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作者：
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5.3
作者：
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影响因子：
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作者：
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