Department of Anesthesiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103-2714, USA.
J Physiol. 2010 Nov 1;588(Pt 21):4103-16. doi: 10.1113/jphysiol.2010.193904. Epub 2010 Aug 19.
The neurons responsible for the onset of sleep are thought to be located in the ventrolateral preoptic nucleus (VLPO), which receives a dense histaminergic innervation from the tuberomammillary nucleus (TMN). Yet, the role of histamine in the VLPO remains unclear. Here we report that microinjection of histamine into the VLPO increases the motor activity of rats. Moreover, a bath application of histamine to acute brain slices inhibits the majority of VLPO neurons, which are also inhibited by noradrenaline. Histamine hyperpolarizes the membrane potential and lowers the firing rate. These effects are associated with an increase in the frequency but not in the amplitude of spontaneous GABA(A) receptor-mediated inhibitory postsynaptic currents, and are blocked by gabazine or tetrodotoxin, indicating an indirect action. Conversely, on the noradrenaline-excited VLPO neurons, histamine depolarizes the membrane potential and increases the firing rate via activation of H(1) and H(2) subtype histamine receptors. Moreover, histamine-induced depolarization persists in the presence of gabazine or tetrodotoxin, indicating a direct action. Based on these findings, we propose that in the VLPO, noradrenaline-inhibited neurons may normally be under the inhibitory control of noradrenaline-excited neurons. By facilitating the inhibitory control of the noradrenaline-excited neurons, histamine may inhibit the noradrenaline-inhibited neurons, resulting in excitation of histamine-releasing neurons in the TMN through disinhibition. This effect of histamine in the VLPO may contribute to the maintenance of wakefulness.
被认为负责睡眠起始的神经元位于腹外侧视前核（VLPO），该核接受来自结节乳头核（TMN）的密集组胺能神经支配。然而，组胺在 VLPO 中的作用尚不清楚。在这里，我们报告说，向 VLPO 中注射组胺会增加大鼠的运动活动。此外，组胺对急性脑切片的浴应用抑制了大多数 VLPO 神经元，这些神经元也被去甲肾上腺素抑制。组胺使膜电位超极化并降低发射率。这些作用与自发性 GABA(A) 受体介导的抑制性突触后电流频率增加但幅度不变有关，并且被加巴喷丁或河豚毒素阻断，表明这是一种间接作用。相反，在去甲肾上腺素兴奋的 VLPO 神经元上，组胺通过激活 H(1)和 H(2)亚型组胺受体使膜电位去极化并增加发射率。此外，在加巴喷丁或河豚毒素存在的情况下，组胺诱导的去极化仍然存在，表明这是一种直接作用。基于这些发现，我们提出在 VLPO 中，去甲肾上腺素抑制神经元可能通常受到去甲肾上腺素兴奋神经元的抑制控制。通过促进去甲肾上腺素兴奋神经元的抑制控制，组胺可能抑制去甲肾上腺素抑制神经元，从而通过去抑制导致 TMN 中释放组胺的神经元兴奋。组胺在 VLPO 中的这种作用可能有助于维持清醒。
