Grassi Silvarosa, Frondaroli Adele, Dieni Cristina, Dutia Mayank B, Pettorossi Vito E
Department of Internal Medicine, Section of Human Physiology, University of Perugia, Via del Giochetto, I-06126 Perugia, Italy.
Eur J Neurosci. 2007 Jul;26(1):23-32. doi: 10.1111/j.1460-9568.2007.05645.x. Epub 2007 Jun 26.
In rat brainstem slices, we investigated the influence of the neurosteroids tetrahydrodeoxycorticosterone (THDOC) and allopregnanolone (ALLO) on the synaptically driven and spontaneous activity of vestibular neurons, by analysing their effects on the amplitude of the field potentials evoked in the medial vestibular nuclei (MVN) by vestibular afferent stimulation and on the spontaneous firing rate of MVN neurons. Furthermore, the interaction with gamma-aminobutyric acid (GABA) and glutamate receptors was analysed by using specific antagonists for GABA(A) (bicuculline), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/ kainate [2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulphonamide disodium salt (NBQX)], N-methyl-D-aspartate (NMDA) [D-(-)-2-amino-5-phosphonopentanoic acid (AP-5)] and group I metabotropic glutamate receptors (mGlu-I) [(R,S)-1-aminoindan-1,5-dicarboxylic acid (AIDA)] receptors. THDOC and ALLO evoked two opposite long-lasting effects, consisting of either a potentiation or a reduction of field potential and firing rate, which showed early and late components, occurring in conjunction or separately after neurosteroid application. The depressions depended on GABA(A) receptors, as they were abolished by bicuculline, while early potentiation involved glutamate AMPA/kainate receptors, as NBQX markedly reduced the incidence of early firing rate enhancement and, in the case of ALLO, even provoked depression. This suggests that THDOC and ALLO enhance the GABA(A) inhibitory influence on the MVN neurons and facilitate the AMPA/kainate facilitatory one. Conversely, a late potentiation effect, which was still induced after glutamate and GABA(A) receptor blockade, might involve a different mechanism. We conclude that the modulation of neuronal activity in the MVN by THDOC and ALLO, through their actions on GABA(A) and AMPA/kainate receptors, may have a physiological role in regulating the vestibular system function under normal conditions and during the stress response that accompanies many forms of vestibular dysfunction.
在大鼠脑干切片中，我们通过分析神经甾体四氢脱氧皮质酮（THDOC）和别孕烯醇酮（ALLO）对前庭传入刺激在内侧前庭核（MVN）诱发的场电位幅度以及MVN神经元自发放电率的影响，研究了它们对前庭神经元突触驱动活动和自发活动的影响。此外，通过使用GABA(A)（荷包牡丹碱）、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）/ 海人藻酸[2,3-二氧代-6-硝基-1,2,3,4-四氢苯并(f)喹喔啉-7-磺酰胺二钠盐（NBQX）]、N-甲基-D-天冬氨酸（NMDA）[D-(-)-2-氨基-5-膦酰基戊酸（AP-5）]和I组代谢型谷氨酸受体（mGlu-I）[(R,S)-1-氨基茚满-1,5-二羧酸（AIDA）]受体的特异性拮抗剂，分析了它们与γ-氨基丁酸（GABA）和谷氨酸受体的相互作用。THDOC和ALLO诱发了两种相反的长效效应，包括场电位和放电率的增强或降低，这些效应表现为早期和晚期成分，在应用神经甾体后同时或分别出现。抑制作用依赖于GABA(A)受体，因为荷包牡丹碱可消除这种抑制作用，而早期增强作用涉及谷氨酸AMPA/海人藻酸受体，因为NBQX显著降低了早期放电率增强的发生率，并且在ALLO的情况下，甚至引发了抑制作用。这表明THDOC和ALLO增强了GABA(A)对MVN神经元的抑制作用，并促进了AMPA/海人藻酸的促进作用。相反，在谷氨酸和GABA(A)受体阻断后仍能诱导的晚期增强效应可能涉及不同的机制。我们得出结论，THDOC和ALLO通过对GABA(A)和AMPA/海人藻酸受体的作用来调节MVN中的神经元活动，这可能在正常条件下以及伴随多种形式前庭功能障碍的应激反应期间调节前庭系统功能方面具有生理作用。
