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In-Depth Information
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
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.
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The H3 histamine receptor is an autoreceptor present only on TMN
histamine-expressing neurons, thereby obviating any drug effect on periph-
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-
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
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,
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
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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