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HISTAMINE AND RESTLESS LEGS SYNDROME (RLS)
By Regina Patrick, RPSGT
H
istamine is a compound derived from the amino acid histidine and is found in virtually all body tissues. Excessive
amounts of histamine in the respiratory tract, which occurs in
some people during the hay fever/pollen season, can result in
a runny or stuffy nose, wheezing and sneezing. Antihistamine
drugs are used to relieve these symptoms. Some people with
seasonal allergies who also have the sleep disorder restless legs
syndrome note that antihistamines worsen their leg movements. Histamine may play a role in movement, which could
explain the worsening of leg movements during sleep with
antihistamine use in people with restless legs syndrome (RLS).
HISTAMINE & HISTAMINE RECEPTORS
In the brain, histamine acts as an excitatory neurotransmitter
and plays a role in wakefulness and in the
transition between sleep and wakefulness; in
the stomach it stimulates gastric secretion;
and in the lungs, it plays a role in airway
constriction. These varied functions result
from the activation of four types of histamine
receptors (labeled H1, H2, H3 and H4). H1
receptors modulate neuronal firing in the
brain. H2 receptors primarily play a role in
stimulating gastric secretion. H3 receptors
inhibit the release of histamine from
histaminergic neurons and may modulate the
release of other neurotransmitters in other
types of neurons. H4 receptors were discovered
in 2001;1 scientists have not fully determined
their function.
A high density of H3 receptors exists on the striatum of the
brain. The striatum is a group of specialized cells located near
the thalamus that is part of the basal ganglia (several groups of
cells at the base of the brain). It plays a role in movement.
The striatum contains neurons that are GABAergic (i.e.,
releasing the neuroinhibitor gamma-aminobutyric acid),
dopaminergic (i.e., releasing the excitatory neurotransmitter
dopamine), and glutamatergic (i.e., releasing the excitatory
neurotransmitter glutamate). The striatal H3 receptors are
found on the terminals of GABAergic, dopaminergic and
glutamatergic neurons. The presence of H3 receptors on
dopaminergic and glutamatergic neurons appears to play a role
in inhibiting the release of dopamine and glutamate from their
respective neurons.
Two types of dopamine receptors – D1 and D2 – lie in close
proximity to the histamine receptors in the striatum, which
may allow for interactions between these receptors. Scientists
are unsure if the interaction between histamine and dopamine
receptors is antagonistic (i.e., blocking) or agonistic (i.e.,
activating). However, some research suggests that it may be
antagonistic.
Carla Ferrada and associates found that activation of the
H3 receptors may modulate dopamine receptor activity.2
These researchers subcutaneously injected mice with reserpine
(which depletes dopamine stores from a neuron) to block the
activity of all striatal dopamine receptors. After treatment
with reserpine, the researchers injected the mice with drugs
that specifically blocked H3 receptor activity, D1 receptor
activity, or D2 receptor activity; and with drugs
that specifically activated these receptors. The
researchers used the locomotor activity of the
mice as a measure of dopaminergic activation.
Increased locomotor activity indicated
increased dopaminergic activation. Since the
animals were previously treated with reserpine,
locomotor activity from dopamine receptor
activation was considered an exogenous effect
of the drug rather than an endogenous effect.
They found that when the H3 receptor
activity was blocked and either the D1 or D2
receptors were activated, the locomotor activity
of the mice increased from its baseline level.
When the H3 receptor was activated and
either the D1 or D2 receptor was activated, the locomotor
activity of the mice decreased from its baseline level; however,
the decrease was greater with activation of the D2 receptors.
When they blocked H3 receptor activity but simultaneously
activated the D1 and D2 receptors, the activity level of the
mice increased to approximately twice that of when either
dopamine receptor was activated alone. Since locomotor
activity shows a greater increase with the absence of H3 input,
Ferrada and colleagues concluded that histaminergic receptors
may modulate the activity of dopaminergic receptors in the
striatum.
Changes in the striatum, such as a loss of neurons in the
tissue, have been noted in other movement disorders such
as Parkinson’s disease.3 Since RLS is a movement disorder,
some scientists have suspected that the striatum also may be
involved in this disorder. Studies are beginning to confirm this
hypothesis.4,5
Animal studies
reveal that
histamine
levels in the
brain are
higher during
wake than
during sleep.
Regina Patrick, RPSGT
Regina Patrick, RPSGT, has been in the
sleep field for 22 years and works as a
sleep technologist at St. Vincent Mercy
Sleep Disorders Center in Toledo, Ohio.
LINKING HISTAMINE TO RLS
RLS involves creepy, crawly, uncomfortable leg sensations
that usually manifest in the evening or at night, often when a
person is sitting quietly or lying down in bed. The sensations
are only momentarily relieved by massaging the legs, rubbing them against the bedsheets, stretching, walking or other
activity. Often an RLS sufferer feels compelled to move the
legs around, hence the name “restless legs syndrome.” These
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uncomfortable sensations typically subside soon before the
onset of sleep or with the onset of sleep.
Reports of antihistamine-induced RLS began to appear in
the medical literature in the late 1980s to early 1990s. For
example in 1989, Korean researcher In-Ho Paik and colleagues
reported the sudden development of RLS in three patients
taking mianserin, a serotonin-antagonist antidepressant drug
that also has antihistamine activity.6 The RLS symptoms ended
once the patients stopped taking the drug. In 1993 O’Sullivan
and Greenberg related the case of a female patient who developed RLS symptoms and oral dyskinesia (i.e., uncontrolled
mouth movements) after taking the H2 antagonist drug cimetidine for 10 years to treat esophageal reflux.7 She described
the leg sensations as feeling “like nerves being pulled apart.”
Despite such reports, scientists remain unsure of the extent
to which antihistamine drugs either may be inducing RLS or
may be unmasking dysfunctional histaminergic activation in
people with RLS.
Recently, a team of Johns Hopkins researchers investigated
the activation of histaminergic pathways in the brain of 12
individuals with RLS.8 The subjects were given either the antihistamine medication diphenhydramine, or as a control they
were given a non-histamine sedative to induce drowsiness,
which is a common effect of antihistamine use. They found
that the RLS subjects who had taken the antihistamine drug
had three to four times more leg activity than the subjects who
had taken the sedative.
In another aspect of their study, the researchers microscopically examined the autopsied brains of RLS sufferers. They
found that in 83 percent of the subjects, the substantia nigra
(i.e., a thin layer of pigmented cells in the brainstem that is
thought to play a role in movement) had an increased amount
of H3 receptors. They believe that the increased presence of H3
receptors in the substantia nigra may lead to increased stimulation of histaminergic pathways, resulting in increased leg
movements in RLS sufferers.
In the brain, the histaminergic neural pathway originates
in the tuberomammillary nucleus of the hypothalamus. The
tuberomammillary nucleus is a group of cells that play a role
in locomotion and in the regulation of sleep and wakefulness.
From the tuberomammillary nucleus, the neurons project to
the thalamus, the suprachiasmatic nucleus, the basal ganglia,
the hypothalamus and the brainstem. Animal studies reveal
that histamine levels in the brain are higher during wake than
during sleep. For example, German researchers Nora Sittig
and Helga Davidowa found that tuberomammillary nucleus
cells in rat subjects released histamine during the dark period
(i.e., the animal’s wake phase) but decreased their production
during the light period (i.e., the animal’s sleep phase).9 The
tuberomammillary nucleus’ connections with the suprachiasmatic nucleus may play a role in the cells’ cyclical release of
histamine on a circadian rhythm.
CLINCAL RELEVANCE
An estimated 12 million Americans are affected by RLS.10
Lifestyle changes such as avoiding the stimulant effects of caffeine, tobacco and alcohol before bedtime helps reduce symptoms in some people. Nutritional deficiencies in iron, folate or
magnesium may play a factor in some cases of RLS. Supplementation of these nutrients helps to reduce the uncomfort-
able nocturnal leg movements in some people with RLS. If
these do not work, drug therapy may offer relief.
Drug treatment for RLS currently involves the use of dopamine agonists (e.g., ropinirole, pramipexole), benzodiazepines
(e.g., clonazepam), anticonvulsants (e.g., gabapentin) and
opioids (e.g., hydrocodone). However, some patients report
difficulties with side effects (e.g., nausea, dizziness, daytime
sleepiness). Therefore, therapeutic modulation of histaminergic
pathways may offer another option for treating this disorder.
However, studies have yet to determine if altering H3 receptor activity modulates dopamine receptor activity and reduces
nocturnal leg movements in RLS. For now, scientists are
focusing on understanding the exact role of histamine in RLS.
References
1. Nguyen T, Shapiro DA, George SR, et al. Discovery of
a novel member of the histamine receptor family. Mol
Pharmacol. 2001 Mar; 59(3):427–433.
2. Ferrada C, Ferre S, Casado V, et al. Interactions between
histamine H3 and dopamine D2 receptors and the
implications for striatal function. Neuropharmacology.
2008 Aug;55(2):190-7. Epub 2008 May 16.
3. Berg D, Godau J, Walter U. Transcranial sonography
in movement disorders. Lancet Neurol. 2008
Nov;7(11):1044-55.
4. Thomas C. Wetter TC, Eisensehr I, Claudia Trenkwalder
C. Functional neuroimaging studies in restless legs
syndrome. Sleep Med. 2004 Jul;5(4):401-6.
5. Godau J, Wevers AK, Gaenslen A, et al. Sonographic
abnormalities of brainstem structures in restless legs
syndrome. Sleep Med. 2008 Oct;9(7):782-9. Epub 2007
Nov 19.
6.
Paik IH, Lee C, Choi BM, et al. Mianserininduced restless legs syndrome. Br J Psychiatry. 1989
Sep;155:415-7.
7. O’Sullivan RL, Greenberg DB. H2 antagonists, restless
leg syndrome, and movement disorders. Psychosomatics.
1993 Nov-Dec;34(6):530-2.
8.
Johns Hopkins University. Press Release: Histaminergic
clinical and autopsy abnormalities in restless legs
syndrome. Washington, DC: Washington Convention
Center; 2008 Nov 15-19; Program #143.13, Poster #U7.
Available online at: http://www.hopkinsmedicine.org/
Press_releases/2008/11_14_08.html. Accessed March 30,
2009.
9.
Sittig N, Davidowa H. Histamine reduces firing and
bursting of anterior and intralaminar thalamic neurons
and activates striatal cells in anesthetized rats. Behav
Brain Res. 2001 Oct 15;124(2):137-43.
10. National Institutes of Health (NIH). National Institute
of Neurological Disorders and Stroke (NINDS). Restless
Legs Syndrome Fact Sheet. 2001 Apr. NIH Publication
No. 01-4847. Available online at: http://www.ninds.
nih.gov/disorders/restless_legs/detail_restless_legs.htm.
Accessed March 30, 2009. 
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