Histamine H₃ Receptors and Sleep-Wake Regulation

Abstract

The histaminergic system fulfills a major role in the maintenance of waking. Histaminergic neurons are located exclusively in the posterior hypothalamus from where they project to most areas of the central nervous system. The histamine H 3 receptors are autoreceptors damping histamine synthesis, the firing frequency of histamine neurons, and the release of histamine from axonal varicosities. It is noteworthy that this action also extends to heteroreceptors on the axons of most other neurotransmitter systems, allowing a powerful control over multiple homeostatic functions. The particular properties and locations of histamine H 3 receptors provide quite favorable attributes to make this a most promising target for pharmacological interventions of sleep and waking disorders associated with narcolepsy, Parkinson's disease, and other neuropsychiatric indications. Sleep and WakingWakefulness and consciousness depend on perturbation of intrinsic cortical activity that is achieved through ascending activating systems taking a ventral route, the ascending reticular activating system of Moruzzi and Magoun, and a dorsal route whose main station is the hypothalamus. Both pathways send direct projections to the cortex and indirect ones through the thalamus, the door to perception of sensory input. Both waking and paradoxical sleep (REM) are conscious states and need activation by subcortical structures, although in different ways.Cholinergic neurons of the brainstem and the basal forebrain discharge tonically during both wakefulness and paradoxical sleep, can directly excite cortical neurons, and facilitate the thalamo-cortical transmission by inhibiting the thalamic reticular sleep-onset generator. Brainstem and basal forebrain cholinergic neurons are excited by glutamatergic, noradrenergic, and histaminergic neurons; they are particularly important in cortical electroencephalogram arousal, but do not seem to be essential for the waking state (Szymusiak and McGinty, 1986;Lin, 2000).Monoaminergic ascending projections containing catecholamines and serotonin are involved in sleep-waking regulation and the pathophysiology of major psychiatric disorders, schizophrenia, and depression, all of which include disturbance in sleep-waking. Inhibition of catecholamine synthesis decreases waking, and psychostimulants, such as amphetamine, increase waking through accumulation of catecholamines. A lesion of the serotonergic dorsal raphe causes insomnia. These aminergic systems mediate different behavioral expressions during waking, activate immediate early genes, and facilitate locomotion, perception, and cognition (reviewed in Jones, 2005).

11C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

“…Moreover, occupancy may also serve as a correlate of pharmacodynamic and safety parameters, as has been assessed extensively with other systems such as the dopamine D 2 receptor (26). Because there is no need for arterial sampling to reliably quantify the binding potential for 11 C-MK-8278 with good T-RT variability (,4%), this suggests this tracer may be a valuable tool for quantification of H3 receptor availability in proof-of-principle experiments in various relevant diseases such as Alzheimer disease (6,27) and sleep disorders (4,28).…”

Waking with the hypothalamus

“…A high degree of molecular and functional heterogeneity through different transcriptional and posttranscriptional processing (splice variants) is prototypic for the H3receptor [4,54]. H3receptor-related drugs are being developed largely for the treatment of sleep disorders [65].…”

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…With its unique pharmacological properties the H 3 receptor is a major target for development of drugs against various disorders of the brain (Passani et al, 2007;Lin et al, 2011b). H 3 receptor inverse agonists decrease alcohol intake in alcohol-preferring (Lintunen et al, 2001) and normal (Galici et al, 2011) rats and modulate alcohol-induced place preference and locomotory activation in mice (Nuutinen et al, 2010), but not amphetamine-induced place preference (Vanhanen et al, 2015), suggesting new possibilities to treat alcohol dependence.…”