Hou R H, Langley R W, Szabadi E, Bradshaw C M
Psychopharmacology Section, Division of Psychiatry, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.
J Psychopharmacol. 2007 Aug;21(6):567-78. doi: 10.1177/0269881106071022. Epub 2006 Nov 8.
Arousal is regulated by the interplay between wakefulness- and sleep-promoting nuclei. Major wakefulness-promoting nuclei are the histaminergic tuberomamillary nucleus (TMN) of the hypothalamus and the noradrenergic locus coeruleus (LC) of the pons, which also play a role in autonomic regulation. First generation antihistamines, such as diphenhydramine, are likely to cause sedation by blocking excitatory H1 histamine receptors in the cerebral cortex, and the anti-narcolepsy drug modafinil may promote wakefulness by activating the locus coeruleus. We compared the effects of single doses of diphenhydramine (75 mg) and modafinil (200 mg) on arousal and autonomic functions in 16 healthy male volunteers, using a placebo-controlled, balanced, double-blind design. Arousal was assessed by critical flicker fusion frequency (CFFF), visual analogue scales (VAS) and pupillary fatigue waves (Pupillographic Sleepiness Test (PST)). Autonomic functions measured included resting pupil diameter, light and darkness reflex responses, blood pressure, heart rate and salivation. Data were analysed with ANOVA, with multiple comparisons. Diphenhydramine had sedative effects as shown by reductions in CFFF, VAS alertness ratings and increases of the indices of pupillary fatigue. Modafinil had alerting effects as indicated by reductions in the measures of pupillary fatigue. Comparison of pre-post medication changes in pupil diameter showed a decrease after diphenhydramine and an increase after modafinil. Diphenhydramine reduced salivation, and modafinil increased systolic blood pressure. In conclusion, diphenhydramine and modafinil evoked opposite effects on arousal and sympathetic functions, which are likely to reflect their interaction with the central histaminergic and noradrenergic systems. Hyposalivation by diphenhydramine is likely to be due to its additional anticholinergic property.
觉醒由促进觉醒和促进睡眠的核团之间的相互作用调节。主要的促进觉醒核团是下丘脑的组胺能结节乳头体核（TMN）和脑桥的去甲肾上腺素能蓝斑核（LC），它们在自主神经调节中也发挥作用。第一代抗组胺药，如苯海拉明，可能通过阻断大脑皮层中的兴奋性H1组胺受体而导致镇静，而抗发作性睡病药物莫达非尼可能通过激活蓝斑核来促进觉醒。我们采用安慰剂对照、平衡、双盲设计，比较了单剂量苯海拉明（75毫克）和莫达非尼（200毫克）对16名健康男性志愿者觉醒和自主神经功能的影响。通过临界闪烁融合频率（CFFF）、视觉模拟量表（VAS）和瞳孔疲劳波（瞳孔描记法嗜睡测试（PST））评估觉醒。测量的自主神经功能包括静息瞳孔直径、光反射和暗反射反应、血压、心率和唾液分泌。数据采用方差分析进行分析，并进行多重比较。苯海拉明具有镇静作用，表现为CFFF降低、VAS警觉评分降低以及瞳孔疲劳指数增加。莫达非尼具有警觉作用，表现为瞳孔疲劳测量值降低。用药前后瞳孔直径变化的比较显示，苯海拉明用药后瞳孔直径减小，莫达非尼用药后瞳孔直径增加。苯海拉明减少唾液分泌，莫达非尼增加收缩压。总之，苯海拉明和莫达非尼对觉醒和交感神经功能产生相反的影响，这可能反映了它们与中枢组胺能和去甲肾上腺素能系统的相互作用。苯海拉明导致唾液分泌减少可能是由于其额外的抗胆碱能特性。
