Research reportHistamine H1 receptors in rat dorsal raphe nucleus: pharmacological characterisation and linking to increased neuronal activity
Introduction
Histamine is a modulator in the mammalian central nervous system where it regulates, through both pre- and postsynaptic mechanisms, a variety of central responses and functions such as wakefulness, feeding, drinking, the neuroendocrine system, body temperature, analgesia and motor activity [31], [37], [42]. Histaminergic neurones are located in the hypothalamus from where they send diffuse projections to almost all brain regions [42]. The actions of histamine are mediated by three well-defined receptors (H1, H2 and H3), characterised by their pharmacology and signal transduction mechanisms [13], although the molecular cloning of a fourth histamine receptor was recently reported [24], [27], [29], [44].
Both neurochemical and electrophysiological studies indicate that the activity of histaminergic neurones is maximal during periods of wakefulness and in rats the intracerebroventricular administration of H1-receptor agonists increases wakefulness at the expense of slow-wave and paradoxical sleep, an effect that can be blocked by H1 antagonists. Inhibition of histamine synthesis increases deep slow-wave sleep and decreases wakefulness in cats and a similar effect is observed in rats. Conversely, inhibition of histamine degradation increases wakefulness [37]. These results support the idea that endogenous histamine, mainly through the activation of H1 receptors, is critically involved in wakefulness.
On the other hand, the activity of serotonergic neurones located in the raphe nuclei is highest during periods of waking arousal and absent during rapid-eye-movement (REM) sleep [7]. With the use of antibodies against histamine, moderate to dense networks of histaminergic fibres have been detected in guinea-pig and rat raphe nuclei [37], and [3H]-mepyramine binding has been showed by autoradiography in guinea-pig raphe nuclei [32]. A possible mechanism, among others, for histamine to regulate wakefulness would be thus the modulation of the activity of raphe serotonergic neurones. We report herein that the dorsal raphe nucleus (DRN) expresses histamine H1 receptors coupled to phosphoinositide hydrolysis, whose activation results in increased activity of presumed serotonergic neurones.
Section snippets
Animals
Rats (male, Wistar strain, 150–200 g), bred in Cinvestav facilities, were used throughout. Animals were maintained under constant room temperature (23 °C) and light–dark cycle (12:12 h); with food and water ad libitum. All procedures were in accordance to the Guide for the Care and Use of Laboratory Animals of the Mexican Council for Animal Care as approved by the Cinvestav’s Animal Care and Use Committee. All efforts were made to minimise animal suffering, to use only as many animals as were
[3H]-Mepyramine binding
The specific binding of [3H]-mepyramine to membranes from the DRN (Fig. 1) did not differ significantly from binding to a single site (Hill coefficient, nH, 1.1±0.1). The best-fit values for the equilibrium dissociation constant (Kd) and maximum binding (Bmax) were 1.2±0.4 nM and 107±13 fmol/mg protein, respectively (means±S.E.M. from the combined data from four experiments).
Histamine-induced [3H]-inositol phosphate ([3H]-IPs) accumulation
To allow for differences in the size of the slices, [3H]-IPs accumulation was expressed as the ratio {[3H]-IPs /[3H]-IPs+[
Discussion
The rat brain contains ∼20 000 serotonergic neurones, most of which (∼60%) are located in the DRN, from where they send projections to numerous parts of the diencephalon, basal ganglia, limbic system and cortex [7], [15]. The tegmental pedunculopontine, tegmental laterodorsal, locus coeruleus and parabrachial nuclei of the upper brain stem conform the so-called REM-on cholinergic–cholinoceptive neuronal system implicated in the generation of REM sleep and phasic related events such as
Acknowledgements
Supported by Cinvestav and CONACyT (grant 37354-N to J.-A.A.-M.). We are grateful to A. Nuñez and A. Sierra for technical assistance, Dr. J. Quevedo for helpful discussions and CONACyT for a predoctoral scholarship to AB.
References (44)
- et al.
Carbachol-induced phosphoinositide metabolism in slices of rat substantia nigra pars reticulata
Mol. Brain Res.
(1993) Homologous and heterologous regulation of receptor-stimulated phosphoinositide hydrolysis
Eur. J. Pharmacol.
(1995)- et al.
Histamine H3 receptor activation selectively inhibits dopamine D1 receptor-dependent [3H]GABA release from depolarisation-stimulated slices of rat substantia nigra pars reticulata
Neuroscience
(1997) Neurophysiological support of consciousness during waking and sleep
Progr. Neurobiol.
(1999)- et al.
Neurotensin and the serotonergic system
Progr. Neurobiol.
(1997) Paradoxical sleep and its chemical/structural substrates in the brain
Neuroscience
(1991)- et al.
Acetylcholine releases of mesopontine PGO-on cells in the lateral geniculate nucleus in sleep–waking cycle and serotonergic regulation
Prog. Neuropsychopharmacol. Biol. Psychiatry
(1996) - et al.
Neurotensin excitation of serotonergic neurons in the rat nucleus raphe magnus: ionic and molecular mechanisms
Neuropharmacology
(2001) Neurotransmitter actions in the thalamus and cerebral cortex and their role in neuromodulation of thalamocortical activity
Prog. Neurobiol.
(1992)- et al.
Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes
J. Biol. Chem.
(2000)
Neuropharmacology of the histaminergic neuron system in the brain and its relationship with behavioral disorders
Progr. Neurobiol.
The distribution of histamine H1-receptors in the rat brain: an autoradiographic study
Neuroscience
Differentiation of presumed serotonergic dorsal raphe neurons in relation to behaviour and wake–sleep states
Neuroscience
Role of epinephrine in regulating the activity of serotonin-containing dorsal raphe neurons
Life Sci.
Electrophysiological and pharmacological characterization of serotonergic dorsal raphe neurons recorded extracellularly and intracellularly in rat brain slices
Brain Res.
Detailed mapping of histamine H2-receptor and its gene transcripts in guinea-pig brain
Neuroscience
Is the histaminergic neuron system a regulatory center for whole-brain activity?
Trends Neurosci.
The measurement of cyclic AMP levels in biological preparations
Histamine H3 receptor-mediated inhibition of depolarisation-induced, dopamine D1 receptor-dependent release of [3H]-γ-aminobutyric acid in rat striatum
Br. J. Pharmacol.
Inositol triphosphate and calcium signalling
Nature
Pacemaker potentials of serotonergic dorsal raphe neurons: contribution of a low-threshold Ca2+ conductance
Synapse
Nomenclature of adrenoceptors
Pharmacol. Rev.
Cited by (26)
Coregulation of sleep-pain physiological interplay by orexin system: An unprecedented review
2020, Behavioural Brain ResearchReview of the histamine system and the clinical effects of H<inf>1</inf> antagonists: Basis for a new model for understanding the effects of insomnia medications
2013, Sleep Medicine ReviewsCitation Excerpt :Thus, H1 receptors are prevalent in key areas of the brain that must be activated for wakefulness to occur. Through the H1 receptor, histamine exerts excitatory effects on multiple neurotransmitter systems, including serotonergic, noradrenergic, and cholinergic.33–35 Blockade of H1 receptors has repeatedly been shown to decrease wakefulness, thus implicating the H1 receptor as an important mediator of histamine's arousal effects.33,34,36
Acute and subchronic treatments with selective serotonin reuptake inhibitors increase Nociceptin/Orphanin FQ (NOP) receptor density in the rat dorsal raphe nucleus; Interactions between nociceptin/NOP system and serotonin
2013, Brain ResearchCitation Excerpt :Haddjeri et al. (2004) indeed showed that administration of atropine in the rat DRN prevented the effect of the antidepressant paroxetine on 5-HT neuron firing. On the other hand, histamine modulates the firing of DRN presumed serotonergic neurons through the activation of H1 receptors coupled to phosphoinositide hydrolysis (Barbara et al., 2002). Thus, the antimuscarinic and antihistaminic side effects of tricyclic antidepressants could interfere with and prevent the effect of 5-HT reuptake inhibition on NOP receptors, which only appeared with SSRIs in the current study.
Effects of simvastatin and 6-hydroxydopamine on histaminergic H1 receptor binding density in rat brains
2010, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Furthermore, since a single concentration of [3H] pyrilamine was used in this study, we were not able to determine whether the changes observed were due to changes in Kd or Bmax. However, consistent with previous reports (Barbara et al., 2002; Tran et al., 1978), our pre-experiment showed that 10 nM [3H] pyrilamine was a saturation concentration in our preparation. Therefore, [3H] pyrilamine binding density should reflect the binding density of H1 receptors.
The role of dorsal raphe nucleus serotonergic and non-serotonergic neurons, and of their receptors, in regulating waking and rapid eye movement (REM) sleep
2010, Sleep Medicine ReviewsCitation Excerpt :Moreover, extracellular single-unit recordings in rat brain stem slices have shown that perfusion of HA results in a significant increase of the firing rate of presumed 5-HT neurons. The stimulatory effect of HA was blocked by mepyramine but not by tiotidine, thus indicating that the effect was mediated by the activation of H1 receptor.61 Furthermore, the suppression of the firing rate of DRN 5-HT cells during REMS in cats was prevented by the iontophoretic administration of HA, and this effect was antagonized by mepyramine.62
Dual projections of tuberomammillary neurons to whisker-related, sensory and motor regions of the rat
2010, Brain ResearchCitation Excerpt :The support for this hypothesis derives from the electrophysiological observation that TMN communicates with DR and LC during various sleep–waking states (Lakoski and Aghajanian, 1983; Lin et al., 1996). Further support derives from the morphological observation that histamine-like immunoreactive fibers as well as histamine receptors exist in the DR and the LC (Panula et al., 1989; Iwase et al., 1993; Barbara et al., 2002) and the TMN, in return, receives noradrenergic and serotonergic inputs from the brainstem regions (Ericson et al., 1989). The input–output circuitry of TMN neurons associated with vibrissal, sensorimotor integration needs to be determined in future studies.