Sleep and Sedative States Induced by Targeting the Histamine and Noradrenergic Systems

Abstract

Sedatives target just a handful of receptors and ion channels. But we have no satisfying explanation for how activating these receptors produces sedation. In particular, do sedatives act at restricted brain locations and circuitries or more widely? Two prominent sedative drugs in clinical use are zolpidem, a GABA_A receptor positive allosteric modulator, and dexmedetomidine (DEX), a selective α2 adrenergic receptor agonist. By targeting hypothalamic neuromodulatory systems both drugs induce a sleep-like state, but in different ways: zolpidem primarily reduces the latency to NREM sleep, and is a controlled substance taken by many people to help them sleep; DEX produces prominent slow wave activity in the electroencephalogram (EEG) resembling stage 2 NREM sleep, but with complications of hypothermia and lowered blood pressure-it is used for long term sedation in hospital intensive care units-under DEX-induced sedation patients are arousable and responsive, and this drug reduces the risk of delirium. DEX, and another α2 adrenergic agonist xylazine, are also widely used in veterinary clinics to sedate animals. Here we review how these two different classes of sedatives, zolpidem and dexmedetomideine, can selectively interact with some nodal points of the circuitry that promote wakefulness allowing the transition to NREM sleep. Zolpidem enhances GABAergic transmission onto histamine neurons in the hypothalamic tuberomammillary nucleus (TMN) to hasten the transition to NREM sleep, and DEX interacts with neurons in the preoptic hypothalamic area that induce sleep and body cooling. This knowledge may aid the design of more precise acting sedatives, and at the same time, reveal more about the natural sleep-wake circuitry.

Keywords: GABAA receptor; NREM sleep; dexmedetomidine; histamine; sedation; xylazine; zolpidem; α2 adrenergic agonists.

Figure 1

Histamine-GABA neurons in the tuberomammillary nucleus (TMN) area project widely to produce wakefulness and are silenced during NREM sleep by preoptic GABAergic neurons or by zolpidem. (A) Simplified view of how histamine/GABA neurons in the tuberomamillary area (TMN) of the posterior hypothalamus promote wakefulness. During the wake state, histamine/GABA neurons are active and their ascending histamine/GABA fibers release histamine (red) and GABA (green) into the prefrontal cortex (PFC), neocortex (Ctx) and striatum (Str, caudate-putamen). Glutamatergic pyramidal neurons in the PFC send excitatory projections to the histamine neurons in the TMN, reinforcing wakefulness. Histamine-only projections from the TMN also excite cholinergic neurons in the basal forebrain, and the axons of these excited cholinergic neurons release acetylcholine throughout the cortex. Histamine-only projections also excite GABAergic neurons in the preoptic area (POA) of the hypothalamus; these GABA neurons in turn are believed to supress sleep-active GABA neurons that project back to the TMN area that inhibit the histamine neurons. Within the POA, certain GABAergic cells project to the PFC and support wakefulness, and some glutamate cells in the POA also send excitatory projections to the histamine neurons to reinforce wakefulness. The TMN area also contains probably many wake-active glutamatergic and GABAergic neurons in addition to those that are histaminergic/GABAergic or histamine only. The contribution of these cells to wakefulness is not known. Based on Yu et al. (2015) and Chung et al. (2017). (B) During NREM sleep, the histaminergic neurons and probably some of the other cell types in the TMN area are inhibited by GABAergic projections (green) from the POA area. The GABAergic sleep active neurons probably co-release peptides, including CCK, CRH, TAC1 and galanin. The function of these peptides is not known. Zolpidem can also potentiate these GABAergic inputs via its actions at the postsynaptic GABA_A receptors on histamine neurons. Adapted from Uygun et al. (2016).

Figure 2

Histamine and dopamine synthesis are under local circadian control. (A) During the less active period (the “lights on” period) of mice, the dopaminergic and histaminergic cells have lower levels of transmitter synthesis for dopamine and histamine because the levels of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and histidine decarboxylase (HDC) in the TMN are lower. The gene expression levels are controlled by clock genes in local circadian processes coordinated by the suprachiasmatic nucleus (SCN). (B) During the more active period of mice, the dark period, in histamine and dopamine cells levels of the TH and HDC proteins are higher, giving the potential for more transmitter release. (C) The relative levels of HDC and TH enzymes, as detected by immunoreactivity (IR) are shown schematically at the different times of day. Adapted from Chung et al. (2014) and Yu et al. (2014).

Figure 3

Activity-tagging demonstrates that the α2 adrenergic agonist dexmedetomidine (DEX) induces NREM sleep and hypothermia by activating neurons in the POA of the hypothalamus. (A) The activity-tagging system is shown as a simplified construct of a c-fos promoter-linked to a DREADD receptor hM3Dq-mCherry reading frame. This DNA construct is transduced into neurons of the preoptic hypothalamus by viral injection. (B) A saline injection into these mice produces or does not change the background of c-fos-hM3Dq receptor expression in the preoptic neurons. Thus when a few days after the saline injection the mice are injected with clozapine-N-oxide (CNO), the few excited neurons cause little change in either the vigilance state of the mice or their body temperature (right hand-graphs show temperature and electroencephalogram (EEG) power spectrum). When the mice are given a sedative dose of DEX it excites neurons in the POA, causing these to command a NREM-like state and hypothermia (for example, the NREM sleep could be induced by inhibitory projections to the histamine area, the TMN, or the VTA. In the DEX-activated neurons of the POA, a pulse of c-fos driven hM3Dq receptor is made during the DEX induced-sedation. When CNO is given to the mice a few days later, the tagged preoptic neurons are reactivated/excited by CNO and induce NREM sleep and hypothermia. Giving CNO to naïve mice not expressing the CNO receptor has no effect on the EEG or body temperature (Zhang et al., 2015). (C) Our hypothesized mechanism for DEX to act in the hypothalamus by dis-inhibition of local sleep-promoting GABAergic neurons. These local GABA neurons are predicted to inhibit the GABA neurons which induce NREM sleep by sending projections to the ascending aminergic neurons. DEX activates α2a receptors on, for example, the terminals of the local inhibitory GABA neurons to reduce GABA release onto GABA projection neurons. The GABA projection neurons would then be more excitable and could inhibit the ascending arousal neurons (e.g., histamine neurons in the TMN area and dopamine neurons n the VTA). The disinhibition of these GABAergic projection neurons causes them to express the c-fos gene, allowing them to be activity-tagged.

Figure 4

Hypothesis for how the α2 adrenergic agonist DEX could induce postural muscle atonia (and hence loss-of-righting reflex) by engaging the same brainstem circuitry that causes muscle atonia during REM sleep. (A) During wakefulness, motor neurons in the spinal cord release acetylcholine onto skeletal muscle to cause excitation and muscle activity. The motor neurons are commanded from the motor neocortex, but receive facilitatory and permissive (dis-inhibitory) neuromodulatory inputs from the noradrenergic locus coeruleus (LC) and orexinergic neurons in the lateral hypothalamus. (B) During REM sleep, a group of glutamatergic neurons in the pontine inhibitory area become active and drive GABAergic interneurons in the medullary inhibitory area to silence the noradrenergic neurons in the LC and also the motor neurons in the spinal cord—the net result is muscle atonia. (C) We hypothesize that DEX could activate α2a receptors, either on the soma or terminals of the noradrenergic LC neurons to inhibit noradrenaline (NA) release onto spinal motor neurons. This removes the permissive modulatory influence on motor neuron excitation. Not all the circuitry is shown, as it is not known which other cell types have the α2a receptors. Adapted and extended from McGregor and Siegel (2010); Blumberg (2013) and Zhang et al. (2015).