Yamanaka Akihiro, Muraki Yo, Ichiki Kanako, Tsujino Natsuko, Kilduff Thomas S, Goto Katsutoshi, Sakurai Takeshi
Department of Molecular Pharmacology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
J Neurophysiol. 2006 Jul;96(1):284-98. doi: 10.1152/jn.01361.2005. Epub 2006 Apr 12.
We reported elsewhere that orexin neurons are directly hyperpolarized by noradrenaline (NA) and dopamine. In the present study, we show that NA, dopamine, and adrenaline all directly hyperpolarized orexin neurons. This response was inhibited by the alpha2 adrenergic receptor (alpha2-AR) antagonist, idazoxan or BRL44408, and was mimicked by the alpha2-AR-selective agonist, UK14304. A low concentration of Ba2+ inhibited NA-induced hyperpolarization, which suggests that activation of G protein coupled inward rectifier potassium channels is involved in the response. In the presence of a high concentration of idazoxan, NA induced depolarization or inward current. This response was inhibited by alpha1-AR antagonist, prazosin, which suggests the existence of alpha1-ARs on the orexin neurons along with alpha2-AR. We also examined the effects of NA on glutamatergic and GABAergic synaptic transmission. NA application dramatically increased the frequency and amplitude of spontaneous inhibitory synaptic currents (sIPSCs) and inhibited excitatory synaptic currents (sEPSCs) in orexin neurons; however, NA decreased the frequency of miniature EPSCs (mEPSCs) and IPSCs and the amplitude of evoked EPSCs and IPSCs through the alpha2-AR, because the NA response on mPSCs was inhibited by idazoxan. These results suggest that the NA-induced increase in sIPSC frequency and amplitude is mediated via alpha1-ARs on the somata of GABAergic neurons that innervate the orexin neurons. Calcium imaging using orexin/YC2.1 transgenic mouse brain revealed that NA-induced inhibition of orexin neurons is not altered by sleep deprivation or circadian time in mice. The evidence presented here revealed that orexin neurons are regulated by catecholamines in a complex manner.
我们曾在其他地方报道过，食欲素神经元会被去甲肾上腺素（NA）和多巴胺直接超极化。在本研究中，我们发现NA、多巴胺和肾上腺素均能直接使食欲素神经元超极化。这种反应被α2肾上腺素能受体（α2-AR）拮抗剂咪唑克生或BRL44408抑制，且被α2-AR选择性激动剂UK14304模拟。低浓度的Ba2+抑制了NA诱导的超极化，这表明G蛋白偶联内向整流钾通道的激活参与了该反应。在高浓度咪唑克生存在的情况下，NA诱导去极化或内向电流。这种反应被α1-AR拮抗剂哌唑嗪抑制，这表明食欲素神经元上除了α2-AR外还存在α1-AR。我们还研究了NA对谷氨酸能和γ-氨基丁酸能突触传递的影响。应用NA显著增加了食欲素神经元中自发抑制性突触电流（sIPSCs）的频率和幅度，并抑制了兴奋性突触电流（sEPSCs）；然而，NA通过α2-AR降低了微小兴奋性突触后电流（mEPSCs）和抑制性突触后电流（IPSCs）的频率以及诱发的兴奋性突触后电流和抑制性突触后电流的幅度，因为咪唑克生抑制了NA对微小突触后电流的反应。这些结果表明，NA诱导的sIPSC频率和幅度增加是通过支配食欲素神经元的γ-氨基丁酸能神经元胞体上的α1-AR介导的。使用食欲素/YC2.1转基因小鼠脑进行的钙成像显示，NA诱导的食欲素神经元抑制不受小鼠睡眠剥夺或昼夜节律时间的影响。此处提供的证据表明，食欲素神经元受到儿茶酚胺的复杂调节。
