Maryland Psychiatric Research Center, University of Maryland School of Medicine, Maple and Locust streets, Baltimore, MD 21228, USA.
Neuroscience. 2012 Feb 17;203:27-38. doi: 10.1016/j.neuroscience.2011.12.018. Epub 2011 Dec 22.
Mammalian neurokinin-3 (NK(3)) receptors of the tachykinin family of neuropeptides have been shown to activate dopaminergic neurons of the ventral tegmental area (VTA), a midbrain area displaying dopaminergic dysfunctional activity in schizophrenia. The recent finding of NK(3) receptors in VTA neuronal nucleus highlights a new level of neuromodulation, in addition to the traditional tachykinin-induced NK(3) receptor internalization and activation of second messenger signaling pathways. The function of nuclear NK(3) receptors is still unknown. It is also unclear how dopaminergic activation is affecting the NK(3) receptor distribution in the VTA. In the present study, trafficking of the NK(3) receptor in somatodendritic profiles of dopaminergic and non-dopaminergic neurons of the rat VTA was investigated following acute systemic administration of the dopamine D(1)/D(2) receptor agonist apomorphine. VTA sections were dual immunolabeled for the NK(3) receptor (immunogold) and the dopamine synthesizing enzyme tyrosine hydroxylase (TH, immunoperoxidase). Electron microscopic quantifications of somatic and dendritic densities of NK(3) immunogold particles with or without TH immunolabeling were compared in vehicle-injected or apomorphine-injected rats. In dopaminergic (TH) neurons, apomorphine evoked a significant increase in NK(3) receptor densities in cytoplasmic and nuclear portions of the soma. These changes were accompanied by a respective decrease and increase in plasmalemmal and cytoplamic NK(3) receptor densities in dopaminergic dendrites. In non-TH neurons, presumably GABAergic neurons of the VTA, the NK(3) receptor densities in somata and dendrites were not significantly altered by apomorphine. The results suggest that dopaminergic receptor activation is inducing a rapid mobilization of NK(3) receptors in VTA dopaminergic neurons. The apomorphine-evoked NK(3) receptors plasticity might reflect dendritic internalization and translocation of NK(3) receptors toward the soma and nucleus. This trafficking is not observed in non-dopaminergic neurons of the VTA. The selective apomorphine-evoked redistribution of VTA NK(3) receptors might have important implications in normal or pathological conditions such as schizophrenia.
哺乳动物神经激肽-3 (NK(3)) 受体属于速激肽家族神经肽,现已证实其可激活腹侧被盖区 (VTA) 的多巴胺能神经元,而 VTA 中的多巴胺能神经元在精神分裂症中表现出功能障碍。最近在 VTA 神经元核中发现 NK(3) 受体,突显了除传统速激肽诱导的 NK(3) 受体内化和第二信使信号通路激活之外的新的神经调制水平。核 NK(3) 受体的功能仍然未知。多巴胺能激活如何影响 VTA 中 NK(3) 受体的分布也不清楚。在本研究中,通过急性全身给予多巴胺 D(1)/D(2) 受体激动剂阿朴吗啡,研究了 NK(3) 受体在大鼠 VTA 中多巴胺能和非多巴胺能神经元的体树突突中的运输。VTA 切片用 NK(3) 受体(免疫金)和多巴胺合成酶酪氨酸羟化酶(TH,免疫过氧化物酶)双重免疫标记。在载体或阿朴吗啡注射的大鼠中,比较了 NK(3) 免疫金颗粒的体和树突密度的电子显微镜定量,有无 TH 免疫标记。在多巴胺能(TH)神经元中,阿朴吗啡引起 NK(3) 受体在胞体的细胞质和核部分的密度显著增加。这些变化伴随着多巴胺能树突突的质膜和细胞质 NK(3) 受体密度的相应减少和增加。在非 TH 神经元中,可能是 VTA 的 GABA 能神经元,阿朴吗啡对 NK(3) 受体在胞体和树突中的密度没有显著影响。结果表明,多巴胺能受体的激活诱导 VTA 多巴胺能神经元中 NK(3) 受体的快速动员。阿朴吗啡诱导的 NK(3) 受体可塑性可能反映了 NK(3) 受体向胞体和核的树突内化和易位。这种运输在 VTA 的非多巴胺能神经元中观察不到。VTA NK(3) 受体的选择性阿朴吗啡诱导再分布可能对正常或病理条件(如精神分裂症)具有重要意义。