Biology Reference
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The tuberomamillary nucleus (TMN) in the hypothalamus is the site of
neurons that express histamine—the only neural source of histamine in the
brain. TMN histamine-expressing neurons project widely, innervating
many of the wake-promoting brain stem neuromodulatory systems. 58 These
TMN neurons are wake-active 59 and histamine itself is wake-promoting. 60
Over-the-counter antihistamines are very commonly used medications to
induce sleep, providing prime facie evidence for the important role of hista-
mine in wake regulation. Commonly used antihistamines (e.g., diphenhy-
dramine) not only block the effects of histamine on TMN H1 histamine
receptors but also have effects on cholinergic receptors, leading to side
effects such as dry mouth and urinary retention, as well as peripheral H1
histamine receptors that are involved in response to histamine released by
mast cells and basophils. As such, much research has been done to develop
molecules that act as agonists or antagonists at the H3 histamine receptor. 61
The H3 histamine receptor is an autoreceptor present only on TMN
histamine-expressing neurons, thereby obviating any drug effect on periph-
eral histamine transduction. 62 As part of an autoinhibitory regulatory feed-
back loop, activation of the H3 histamine receptor leads to decreased
activity of TMN neurons, while inhibition of the H3 histamine receptor
leads to increased activity of TMN neurons and increased release of hista-
mine. 63 As such, molecules that agonize the H3 histamine receptor are
predicted to decrease brain histamine release and result in increased sleep-
iness, while molecules that antagonize this receptor would increase brain
histamine release and increase alertness. Early studies have confirmed this
conjecture 64 and may lead to a new method of treating insomnia and
hypersomnia, respectively.
Unlike most of the systems thus far discussed, the VLPO and the
temperature-sensitive anterior hypothalamic area are regions involved in
the promotion of sleep, rather than wake. The VLPO is a GABA-expressing
group of cells that inhibit the firing of most wake-promoting neurons,
including the TMN, LC, raphe, and periaqueductal gray. 65 The VLPO is
also preferentially active during sleep. 66 It has been hypothesized that the
VLPO is a key player in the determination whether a brain is in the wake
or sleep state. This has been modeled as a “flip-flop” switch in which the
VLPO drives the presence of sleep and is itself controlled by the reciprocal
activity of the TMN, raphe, and LC. 67 It is the reciprocal inhibition between
the wake-promoting neurons and those of the VLPO that are hypothesized
to create a binary environment (either wake or sleep) in which ambiguous
states are neurochemically selected against.
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