Neurokinin-1 Antagonism Distinguishes the Role of Norepinephrine Transporter from Dopamine Transporter in Mediating Amphetamine Behaviors.
Neurokinin-1 Antagonism Distinguishes the Role of Norepinephrine Transporter from Dopamine Transporter in Mediating Amphetamine Behaviors.
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DOI：
10.1159/000518033
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发表时间：
2021
期刊：
影响因子：
3.1
通讯作者：
Jayanthi LD
中科院分区：
文献类型：
--
作者：
Mannangatti P;Ragu Varman D;Ramamoorthy S;Jayanthi LD
安非他明和其他精神兴奋剂作用于去甲肾上腺素（NE）转运体（NET）和多巴胺（DA）转运体（DAT），并增强NE和DA信号传导。NET和DAT都具有相同的解剖学和功能特征，并受到精神兴奋剂和受体相关信号通路的类似调节。我们和其他人已经证明，安非他明（AMPH）和P物质/神经激肽-1受体（NK 1 R）介导的蛋白激酶C途径下调NET和DAT。由于NET和DAT都被AMPH和NK 1 R激活下调，并且具有很高的序列同源性，因此本研究的目的是确定NK 1 R对AMPH诱导的行为的调节中的儿茶酚胺转运蛋白特异性。使用NET和DAT敲除小鼠（NET-KO和DAT-KO）沿着其野生型同窝仔，检查NK 1 R拮抗作用对AMPH诱导的条件性位置偏爱（CPP）以及AMPH诱导的NET和DAT下调的影响。阿瑞匹坦（5 mg/kg i. p.）显著减弱AMPH（2 mg/kg i. p.）在野生型和DAT-KO中诱导CPP，但在NET-KO中不诱导CPP。在后调节测试（在不存在AMPH的情况下）期间测量的运动活性显示与野生型或NET-KO相比，DAT-KO中的运动活性更高。然而，所有三种基因型的自发活动在阿瑞匹坦后保持不变。此外，在野生型腹侧纹状体（VST）中，AMPH诱导的NET功能和表面表达下调，而不是DAT的下调被阿瑞匹坦减弱。当前研究的结果表明，阿瑞匹坦减弱了DAT-KO小鼠中AMPH诱导的CPP表达，但在NET-KO小鼠中没有，表明NK 1 R介导的NET调节在AMPH诱导的行为中发挥作用。
Amphetamine and other psychostimulants act on norepinephrine (NE) transporter (NET) and dopamine (DA) transporter (DAT) and enhance NE and DA signaling. Both NET and DAT share anatomical and functional characteristics and are regulated similarly by psychostimulants and receptor-linked signaling pathways. We and others have demonstrated that NET and DAT are downregulated by amphetamine (AMPH) and substance P/neurokinin-1 receptor (NK1R)-mediated protein kinase C pathway. Since both NET and DAT are downregulated by AMPH and NK1R activation and share high sequence homology, the objective of the study was to determine the catecholamine transporter specificity in NK1R modulation of AMPH-induced behaviors. The effect of NK1R antagonism on AMPH-induced conditioned place preference (CPP) as well as AMPH-induced NET and DAT downregulation were examined using NET and DAT knockout mice (NET-KO and DAT-KO) along with their wild-type littermates. Aprepitant (5 mg/kg i.p.) significantly attenuated AMPH (2 mg/kg i.p.) induced CPP in the wild-type and DAT-KO, but not in the NET-KO. Locomotor activity measured during post-conditioning test (in the absence of AMPH) showed higher locomotor activity in DAT-KO compared to wild-type or NET-KO. However, the locomotor activity of all three genotypes remained unchanged following aprepitant. Additionally, in the ventral striatum (VST) of wild-type, the AMPH-induced downregulation of NET function and surface expression but not that of DAT was attenuated by aprepitant. The results from the current study demonstrates that aprepitant attenuates the expression of AMPH-induced CPP in DAT-KO mice, but not in NET-KO mice suggesting a role for NK1R-mediated NET regulation in AMPH-induced behaviors.
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影响因子：
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