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 GABAA 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.

Anticholinergic and sedative medication use in older community‐dwelling people: A national population study in the Netherlands

“…For sedative medications, this is lacking. While anticholinergic effects are a result of muscarinic receptor blocking, different pharmacological pathways lead to sedation, of which most pathways are still unknown . Therefore, we based our list of sedative medications on a systematic analysis of relevant frequently reported (side) effects in relevant reference sources.…”

Pharmacosynthetic Deconstruction of Sleep-Wake Circuits in the Brain

“…While NA system produces arousal and deepens cognition, or takes part in stress-induced responses, selective pharmacological activation of α2 receptors produces deep SWS. This class of α2 receptor selective agonists belongs to prominent sedative drugs used for long-term sedation in hospital intensive care units (dexmedetomidine) or in veterinary clinics to sedate animals (xylazine) (see for review Yu et al 2018). Thus, apart from arousal-promoting functions covering various physiological and cognitive processes or emotional responding, NA can also have sleep-promoting contributions (Grivel et al 2005).…”

Galanin neurons in the hypothalamus link sleep homeostasis, body temperature and actions of the α2 adrenergic agonist dexmedetomidine

“…On entering NREM sleep, the neocortex of rats and mice cools rapidly (33,34). NREM sleep and low body temperature can also be brought together pharmacologically: a2 adrenergic agonists induce an arousable NREM sleep-like profile 5 (26,(35)(36)(37)(38), which in humans resembles stage 2/3 NREM sleep (39)(40)(41), but with the complication of sustained hypothermia (26,35). The metabotropic a2A receptor mediates both the NREM sleep-like state and the hypothermic effects of dexmedetomidine (42,43).…”

“…These a2 adrenergic agonists are increasingly favored over benzodiazepines for long-term sedation (44). Although it used to be thought that dexmedetomidine induces sedation by inhibiting noradrenaline release from neurons in the locus ceruleus (43,45,46), there is building evidence that this is not the case (26,36,47). Dexmedetomidine induces cFOS expression in the preoptic hypothalamic nuclei (26,48), and can induce sedation even when noradrenaline release from the locus ceruleus is genetically removed (47).…”