Research report
Wakefulness-inducing effects of histamine in the basal forebrain of freely moving rats

https://doi.org/10.1016/j.bbr.2003.10.031Get rights and content

Abstract

Histamine-containing neurons of the tuberomammillary nucleus (TMN) are implicated in facilitating wakefulness. They project to many brain areas, including the cholinergic basal forebrain (BF). The cholinergic magnocellular regions of the BF are important in the regulation of cortical arousal and wakefulness, and a role for histamine in this activity is suggested by in vitro data indicating histamine excites BF cholinergic and non-cholinergic neurons. To test the hypothesis that histamine induces wakefulness via actions in the BF, we performed microdialysis perfusion of different concentrations of histamine (100, 500 and 1000 μM) in the BF of Sprague-Dawley rats. A MANOVA analysis showed that histamine produced a highly statistically significant and dose-dependent increase in wakefulness and decrease in non-rapid eye movement (NREM) sleep compared with artificial cerebrospinal fluid perfusion. From a wakefulness baseline percentage time of about 12% with artificial cerebrospinal fluid, histamine perfusion increased this value to 26% (100 μM), 36% (500 μM), or 47% (1000 μM). There was no statistically significant change in rapid eye movement (REM) sleep. Histamine perfusion (500 μM) in a control site, the centromedian thalamic nucleus, did not produce any change in behavioral state. The results indicate a prominent role of histamine in wakefulness regulation via the BF and further support the hypothesis that the BF has an important role in EEG activation and wakefulness.

Introduction

Several lines of evidence implicate histamine-containing neurons of the tuberomammillary nucleus (TMN) in the posterior hypothalamus in the regulation of sleep-wakefulness [20], [21], [26], [35]. Histaminergic neurons, located almost exclusively in the TMN, project widely to various brain areas including sites that regulate sleep-wakefulness, such as the cholinergic basal forebrain (BF), the pontine reticular formation, the locus coeruleus, the cortex, the preoptic anterior hypothalamic area (POAH) and the thalamus [1], [12], [19], [22], [30], [47]. Surgical destruction of the posterior hypothalamic area [28] and lesions of the TMN region [35], [42] have been shown to induce hypersomnolence, whereas lesions of the POAH produced insomnia [2], [15], [16], [24], [44].

Systemic injections of histamine-induced prolonged wakefulness with cortical activation [4]. Intracerebroventricular injections of a histamine H1 receptor agonist increased wakefulness dose-dependently and decreased both non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, whereas intraperitoneal injection of H1 receptor antagonists decreased wakefulness and increased NREM sleep [27]. Thus, physiological manipulations which enhance histamine neurotransmission produce arousal, whereas reduction or inhibition of the histaminergic tone reduces wakefulness [17], [21], [22], [25].

Moreover, the in vivo discharge activity of TMN neurons is highest during wakefulness, slows during NREM sleep, and virtually ceases during REM sleep [34], [39]. Further support for this behavioral state selectivity of histamine release has recently come from microdialysis studies done in our laboratory indicating that levels of extracellular histamine are high during waking and low during NREM sleep and REM sleep in the POAH [41].

One of the projection targets of histaminergic neurons, the cholinergic magnocellular regions of the BF, has been shown also to be important in the regulation of cortical arousal and wakefulness (for reviews, see [13], [14], [36], [38], [40], [43]). Single unit recordings in unanesthetized, naturally sleeping animals demonstrated that the majority of the neurons in this region showed highest discharge activity during active waking, with activity decreasing progressively as the animal becomes drowsy and goes to sleep, leading to the hypothesis that these wakefulness-active neurons are crucial in EEG activation and waking state maintenance [6]. Furthermore, in vitro studies have shown that histamine excites both the cholinergic [18] and non-cholinergic [7] neurons of the BF.

However, despite the TMN to BF projections and the wakefulness-active discharge pattern of both regions, the possibility that histamine enhances wakefulness and arousal by its excitatory effects on the wake-active neurons in the cholinergic zone of the BF has not been tested. We thus examined the effect of microdialysis perfusion of histamine in the cholinergic BF and here report a dose-dependent enhancement of wakefulness and reduction of NREM sleep, in contrast to no effect of perfusion in the control region of centromedian thalamus.

Section snippets

Animals

This study used twelve adult male Sprague-Dawley rats (Charles River Breeding Laboratories, MA) that weighed between 250 and 350 g; they were housed under constant temperature (23±1 °C), had a 12 h light:12 h dark cycle (light-on period from 07:00 h to 19:00 h) and had ad libitum access to food and water. All animals were treated in accordance with the American Association for Accreditation of Laboratory Animal Care’s policy on care and use of laboratory animals. Every effort was made to minimize

Histology

All the microdialysis probe tips in experimental animals were located in the cholinergic zone of the BF between the AP levels −0.30 and −0.92 [31], as shown in Fig. 1. In rats the cholinergic zone includes the horizontal limb of the diagonal band (HDB), the magnocellular preoptic nucleus, and the substantia innominata. All of the probe locations were in or near the HDB surrounding the ChAT-positive neurons (Fig. 2). The microdialysis probe tips in the centromedian site control animals were

Discussion

Data in this report demonstrate that histamine, applied locally by microdialysis perfusion in the cholinergic zone of the rat BF, increased wakefulness and decreased NREM sleep. Moreover the effect on wakefulness and NREM sleep was dose-dependent, with the largest effect seen with perfusion of 1000 μM, followed by 500 and 100 μM histamine perfusion. The effect of histamine perfusion on wakefulness and NREM sleep was selective to the BF when compared with thalamus. The trend-level decrease

Acknowledgments

This work was supported by the National Institute of Mental Health (Grants NIMH39683 to RWM and KO1MH01798 to MMT) and the Department of Veterans Affairs Medical Research Service Awards to RES and RWM. We thank Dr. Margaret Niznikiewicz for helpful statistical consultation. We would also like to thank Mr. Michael Gray and Mr. John Franco for providing care for the animals.

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