Histamine excites rat superior vestibular nuclear neurons via postsynaptic H1 and H2 receptors in vitro【推荐论文】 .doc
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1、精品论文Histamine excites rat superior vestibular nuclear neurons via postsynaptic H1 and H2 receptors in vitroZHUANG Qianxing, WU Yonghui, WU Guanyi, ZHU Jingning, WANG Jianjun5(School of Life Sciences, Nanjing University, NanJing 210093)Abstract: The superior vestibular nucleus (SVN), which holds a ke
2、y position in vestibulo-ocular reflexes and nystagmus, receives direct hypothalamic histaminergic innervations. By using rat brainstem slice preparations and extracellular unitary recordings, we investigated the effect of histamine on SVN neurons and the underlying receptor mechanisms. Bath applicat
3、ion of histamine10evoked an excitatory response of the SVN neurons, which was not blocked by the low-Ca2+/high-Mg2+medium, indicating a direct postsynaptic effect of the amine. Selective histamine H1 receptor agonist2-pyridylethylamine (2-PyEA) and H2 receptor agonist dimaprit, rather than VUF8430,
4、a selective H4 receptor agonist, mimicked the excitation of histamine on SVN neurons. In addition, selective H1 receptor antagonist mepyramine and H2 receptor antagonist ranitidine, but not JNJ7777120, a selective15H4 receptor antagonist, partially blocked the excitatory response of SVN neurons to h
5、istamine.Moreover, mepyramine together with ranitidine nearly totally blocked the histamine-induced excitation.Immunostainings further showed that histamine H1 and H2 instead of H4 receptors existed in the SVN. These results demonstrate that histamine excites the SVN neurons via post-synaptic histam
6、ine H1 and H2 receptors, and suggest that the central histaminergic innervation from the hypothalamus may20actively bias the SVN neuronal activity and subsequently modulate the SVN-mediated vestibularfunctions and gaze control.Keywords: Histamine; Superior vestibular nucleus; Histamine receptors; Ve
7、stibular reflexes0Introduction25Among the vestibular disorders, pathologic nystagmus is a symptom which often accompanies vertigo and motion sickness. Interestingly, a recent investigation reported an efficacy of the histaminergic drug, betahistine dihydrochloride, in not only antivertigo and anti-m
8、otion sickness but also improving oculomotor activity, including increased gain during pursuit movements and faster and more accurate saccades 1. In fact, anti-histaminergic drugs have been30used for clinical treatment of vestibular related diseases, including vertigo, emesis and motion sickness, fo
9、r almost a century. The therapeutic mechanisms are involved not only in peripheral vestibular system, such as labyrinth in the inner ear 2-3, but also in central vestibular nuclear complex, including at least the medial (MVN) and lateral (LVN) vestibular nucleus 4-6.Immunohistochemical studies have
10、already revealed a moderately dense direct histaminergic35projection from the tuberomammillary nucleus of the hypothalamus to the vestibular nuclei in many species including rat, cat and pigeons 7-9. Nevertheless, histaminergic fiber distribution in the vestibular nuclei shows spatial variations, wi
11、th significantly heavier labelling in the superior vestibular nucleus (SVN) and MVN than in the LVN and descending vestibular nucleus 9. On the other hand, molecular, autoradiographic and pharmacological studies have also demonstrated40that the LVN and MVN are both endowed with histamine H1, H2 and/
12、or H3 receptors 10-11.Among the four nuclei in the central vestibular nuclear complex, the SVN, together with the MVN, receives fibers predominantly from the semicircular canals and sends fibers through the mediallongitudinal fasciculus rostrally to oculomotor centers and caudally to the spinal cord
13、 12-13.Foundations: This work was supported by grants 31070959, 31071021, 31171050, J1103512 and NSFC/RGC JointResearch Scheme 30931160433 from the National Natural Science Foundation of China; RFDP grant20100091110016, NCET Program, and Fundamental Research Funds for the Central Universities 109402
14、0806 and1095020821 from the State Educational Ministry of China; grant BK2011014 from the Natural Science Foundation of Jiangsu Province, China. This work was also supported by a grant 9112020802 ofBrief author introduction:ZHUANG Qianxing (1980-), male, PhD, NeuroscienceCorrespondance author: WANG
15、Jianjun, male, PhD, Neuroscience. E-mail: - 14 -Both of these two nuclei actually hold a key position in vestibulo-ocular reflexes and gaze control4512, 14-16 and are closely related to nystagmus 17-18.In recent years, role of histamine/hypothalamic histaminergic innervation in the MVN neuronal acti
16、vity and the MVN-mediated vestibular compensation has been received increasing attention 4, 19-20, however, the action of histamine on the SVN, another key vestibular nucleus primarily involved in reflexes controlling gaze, still remains enigmatic. Thus, by using50extracellular recordings and immuno
17、stainings, this work was designed to investigate the effect of histamine on neurons in the SVN and the underlying receptor mechanism. The results demonstrated that histamine excited the SVN neurons via activation of both postsynaptic H1 and H2 receptors.1Material and methods551.1 Slice preparations
18、and incubationsSagittal brain slices (400 M thickness) containing the SVN were prepared from Sprague-Dawley rats (120-250 g) of either sex. Under sodium pentobarbital (40 mg/kg) anesthesia, rats were decapitated. After carefully removing the skull, the brain extending from obex to the superior colli
19、culi was rapidly removed into ice-cold artificial cerebrospinal fluid (ACSF,60composition in mM: 124 NaCl, 5 KCl, 1.2 NaH2PO4, 1.3 MgSO4, 26 NaHCO3, 2 CaCl2 and 10D-glucose) equilibrated with 95% O2/5% CO2. According to the rat brain atlas of Paxinos and Watson 21, the sagittal slices 22 containing
20、the SVN, cerebellum and part of midbrain (including colliculi) were cut (Fig. 1A) with a vibroslicer (VT 1200S, Leica, Germany) at 4 C. The slices were subsequently transferred into a recording chamber, which was continuously65perfused with 95% O2/5% CO2 oxygenated ACSF (pH 7.4, 33 0.2 C, flow rate
21、1.5-2 ml/min).All slices were incubated for at least 40 min before neuronal electrophysiological recordings. All experiments completely conformed to the U.S. National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications 80-23, revised 1996). All efforts were made t
22、o minimize the number of animals used and their suffering.701.2 Electrophysiological recordings, data acquisition and statistical analysisThe SVN was visually identified with the aid of a stereomicroscope (SD-3045F, Olympus, Japan) and spontaneous unitary activity of the SVN neurons was recorded ext
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