Studies on the role of histaminergic system in orexin-induced wakefulness in rats.

食欲素A和B是参与调节摄食和觉醒状态的新型神经肽。增食欲素神经元定位于下丘脑外侧区，密集投射到蓝斑、腹侧被盖区、中缝背核和结节乳头核。在此之前，我们曾报道将食欲素A和食欲素B同时注入第三脑室可引起大鼠的觉醒效应。最近，我们在OX2R大量表达的TMN中发现了增食欲素神经末梢与组胺能神经元之间的直接突触连接。因此，食欲素诱导的觉醒状态似乎是通过TMN中的组胺能神经元来调节的。在这项研究中，我们研究了冰冻注射Hi受体拮抗剂吡拉明对增食欲素诱导的大鼠觉醒的影响。连续三天监测皮质FEG和颈部肌电，以10d/h的速率持续输注冰盐水。昼夜期间，食欲素A(1n…更多的摩尔/20ul生理盐水)和吡拉明(25或75ug/25ul生理盐水)代替冰冻的生理盐水输注。在注射食欲素A前30 mm开始给予吡拉明。冰冻注射食欲素A 2小时后，醒觉次数显著增加340.0%(p&lt；0.05)。在25ug/2.5h和75ug/2.5h时，吡拉明使增食欲素A诱导的觉醒分别减少85%(p&lt；0.05)和58%(p&lt；0.05)。吡喃胺对食欲素A诱导的唤醒效应有剂量依赖性的抑制作用。食欲素A对非快速眼动睡眠的抑制可被吡喃胺剂量依赖性地逆转。尽管单独使用吡拉明(75微克)会轻微减少REM睡眠，但没有观察到显著差异。Hi受体拮抗剂吡里拉明可显著抑制增食欲素A诱导的觉醒。由于增食欲素神经元密集分布于高表达OX_2R的TMN，因此增食欲素神经元可能通过调节TMN中组胺能神经元的活动来调节觉醒状态。较少

Orexins A and B are novel neuropeptides involved in the regulation of feeding and arousal state. Orexin-containing neurons are localized in the lateral hypothalamic area and densely project to the locus coeruleus, ventral tegmental area, dorsal raphe nuclei and tuberomammillary nucleus (TMN). Previously, we reported that intracerebroventricular (icy) infusion into the third ventricle of both orexins A and B induced arousal effect in the rats. Recently, we found direct synaptic connectivity between orexin nerve terminals and histaminergic neurons in the TMN where the OX2R is abundantly expressed. Hence, orexin-induced arousal state seems to be regulated via histaminergic neurons in the TMN. In this study, we investigate the effects of icy infusion of pyrilamine (an Hi receptor antagonist) on orexin-induced wakefulness in rats. Cortical FEG and neck EMG were monitored for three consecutive days, during continuous icy saline infusion at a rate of 10 rd/h. For diurnal period, orexin A (1 n … More mol/20 ul saline) and pyrilamine (25 or 75 ug/25 ul saline) replaced the icy infusion of saline. Pyrilamine administration was started 30 mm before orexin A infusion. The icy infusion of orexin A for a 2-h period markedly increased the amount of wakefulness by 340.0 % (p<0.05) over the baseline value. Pyrilamine decreased orexin A-induced wakefulness by 85 % (p<0.05) and 58 % (p<0.05), at 25 and 75 ug/2.5-h period, respectively. Pyrilamine caused a dose-dependent decrease in the orexin A-induced arousal effect. Orexin A-induced suppression of non-REM sleep was dose-dependently reversed by pyrilamine treatment. Although pyrilamine treatment alone (75 ug) slightly decreased REM sleep, no significant difference was observed. Pyrilamine, an Hi receptor antagonist, significantly inhibited the effects of orexin A-induced wakefulness. Since orexin neurons densely innervate TMN where OX_2R is highly expressed, orexin neurons might regulate the arousal state through modulating the activity of histaminergic neurons in the TMN. Less