The histaminergic system of the brain: its roles in arousal and autonomic regulation.

Introduction. Histaminergic neurones are located in the tuberomammillary nucleus (TMN) of the posterior hypothalamus and project to most areas of the cerebral cortex, cerebellum, hypothalamus, and many brain stem nuclei (1,2). The central histaminergic neurones have important roles in the regulation of arousal, endrocrine and autonomic functions. The ascending histaminergic projection exerts a powerful alerting effect on the neocortex, via the activation of H1 histamine receptors (1,2,3). Recently it has been shown that the ascending histaminergic system is one of the most important alerting systems of the brain, mediating the sedative effects of GABAergic (e.g, muscimol, propofol and pentobarbitone) (4) and of noradrenergic (e.g, dexmedetomidine) (5) anaesthetics. It has been proposed that the activity of the TMN is essential to the maintenance of wakefulness. In sleep, the activity of the TMN is switched off by a GABAergic input originating from the ventrolateral preoptic nucleus (VLPO) of the hypothalamus. In fact, in order to maintain wakefulness, it is important to switch off the activity of the VLPO: this is accomplished by the activation of a noradrenergic inhibitory input from the locus coeruleus (5). GABAergic anaesthetics act by activating inhibitory GABA receptors in the TMN, whereas noradrenergic anaesthetics act by switching off the locus coeruleus via the activation of inhibitory alpha-2 adrenoceptors (autoreceptors) on locus coeruleus neurones (6). The orexinergic neurones of the lateral hypothalamic area (LHA) play an important role in the maintenance of wakefulness, possibly by activating the TMN either directly (7), or indirectly via the locus coeruleus (8). The activation of the locus coeruleus would enhance the noradrenergic inhibition of the VLPO, which in turn would lead to the disinhibition of the TMN by the VLPO. The importance of the TMN in the maintenance of arousal is demonstrated by clinical observations: the hypersomnia observed in encephalitis lethargica by von Economo in the 1920s could be related to a discrete lesion of the posterior hypothalamus involving the TMN (1,3). Furthermore, the blockade of excitatory H1 receptors in the cerebral cortex may underlie the sedative effects of a number of drugs with affinity for H1 histamine receptors (e.g, first generation antihistamines, phenothiazine antipsychotics, tricyclic antidepressants). The central histaminergic system also plays a role in autonomic regulation: it has been shown that the activation of central H1 and H2 histamine receptors results in an increase in sympathetic outflow (2,9). Although the first generation antihistamines have well-documented sedative properties in humans, their effects on autonomic functions have not been studied in detail. In particular, it was of interest to examine how pupillary function is affected by these drugs, since the pupil is under a well-mapped-out dual sympathetic/parasympathetic regulation (6). Therefore, we have examined the pupillary effects of one such drug, diphenhydramine, and compared them with those of diazepam, a sedative drug with little effect on autonomic functions. It should be noted that diphenhydramine, like most first generation antihistamines, also block muscarinic cholinoceptors, an effect that may modify pupillary function. Methods. Fifteen healthy male volunteers participated in three experimental sessions at weekly intervals in which they received (i) diphenhydramine 75 mg, (ii) diazepam 10 mg, (iii) placebo. The three treatments were administered in a balanced order according to a double-blind protocol. Pupil diameter was measured with a binocular pupillometer (Procyon, UK) under four light intensities (darkness, 6, 91, 360 Cd m). Light reflex responses were evoked by green (peak wavelength 565 nm) light flashes (200 ms, 0.43 mW cm); recordings were made with a binocular infrared television pupillometer (TVP 1015B, Applied Science Laboratories Waltham, MA. USA). The level of