Tose Ryuji, Kushikata Tetsuya, Yoshida Hitoshi, Kudo Mihoko, Furukawa Kenichi, Ueno Shinya, Hirota Kazuyoshi
Department of Anesthesiology, University of Hirosaki Postgraduate School of Medicine, Hirosaki 036-8562, Japan.
Brain Res. 2009 Jan 23;1250:81-7. doi: 10.1016/j.brainres.2008.10.041. Epub 2008 Oct 31.
Several studies suggest that NMDA glutamate receptors may play an important role in the activation of a number of brain regions by orexin (OX). We hypothesized that OX and NMDA receptors may interact with cerebrocortical noradrenergic neuron originating from the locus coeruleus (LC). To test this hypothesis, using rats as experimental animals, we examined (i) in vitro effects of MK801 on OXA-evoked norepinephrine release from rat cerebrocortical slices, (ii) in vivo interaction between OXA and the NMDA receptor antagonist, MK801 on norepinephrine release from the prefrontal cortex assessed using microdialysis and (iii) MK801 and OXA-modulation of the electroencephalogram (EEG). We have found that MK801 produced a concentration-dependent inhibition of OXA-evoked norepinephrine release from rat cerebrocortical slices with the IC(50) of 0.9 microM. Moreover, we have also found that icv OXA dose-dependently stimulated norepinephrine release from the rat prefrontal cortex saturating at 213% of baseline. In addition, ip MK801 0.1 mg/kg also significantly increased norepinephrine release in prefrontal cortex to 213%. However, these increases in norepinephrine release were significantly reduced by approximately 70% by simultaneous administration of icv OXA 1 nmol and ip MK801 0.1 mg/kg. Both OXA and MK801 decreased sleep and increased wakefulness, but co-administration caused a return to base-line sleep state. These findings strongly indicate that there is a significant interaction between orexinergic neurons and NMDA receptors in the control of LC-cerebrocortical noradrenergic activity.
多项研究表明，N-甲基-D-天冬氨酸（NMDA）谷氨酸受体可能在食欲素（OX）对多个脑区的激活中发挥重要作用。我们推测，OX和NMDA受体可能与源自蓝斑（LC）的脑皮质去甲肾上腺素能神经元相互作用。为了验证这一假设，我们以大鼠为实验动物，研究了：（i）MK801对OX-A诱发的大鼠脑皮质切片去甲肾上腺素释放的体外作用；（ii）OX-A与NMDA受体拮抗剂MK801在体内对通过微透析评估的前额叶皮质去甲肾上腺素释放的相互作用；以及（iii）MK801和OX对脑电图（EEG）的调节作用。我们发现，MK801对OX-A诱发的大鼠脑皮质切片去甲肾上腺素释放产生浓度依赖性抑制，半数抑制浓度（IC50）为0.9微摩尔。此外，我们还发现，脑室内注射OX-A能剂量依赖性地刺激大鼠前额叶皮质去甲肾上腺素释放，最高可达基线的213%。另外，腹腔注射0.1毫克/千克的MK801也能使前额叶皮质去甲肾上腺素释放显著增加至213%。然而，同时给予1纳摩尔脑室内注射的OX-A和0.1毫克/千克腹腔注射的MK801时，这些去甲肾上腺素释放的增加显著减少了约70%。OX-A和MK801均减少睡眠并增加觉醒，但联合给药会使睡眠状态恢复到基线。这些发现有力地表明，在控制LC-脑皮质去甲肾上腺素能活动方面，食欲素能神经元与NMDA受体之间存在显著的相互作用。
