Download the neurochemistry of sleep paralysis

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THE NEUROCHEMISTRY OF SLEEP PARALYSIS
By Regina Patrick, RST, RPSGT
M
uscle atonia (i.e., loss of muscle tone) is a feature of rapid
eye movement (REM) sleep. If a person is simultaneously
awake and in REM sleep, muscle atonia is experienced as
sleep paralysis (i.e., the person is awake but unable to move
voluntarily). Which neurotransmitter in the brain is responsible
for REM sleep muscle atonia has long perplexed scientists. For
a long time, scientists have believed that the amino acid glycine
may be responsible for REM sleep muscle atonia.1 Recent
studies now indicate that glycine and another neurotransmitter,
gamma-aminobutyric acid (GABA), are simultaneously needed
to induce muscle atonia in REM sleep. This finding may impact
treatment for narcolepsy-cataplexy and other disorders that
involve a dysfunction in REM sleep (e.g., Parkinson’s disease
and REM-sleep behavior disorder).
Narcolepsy-Cataplexy
Cataplexy — the sudden, temporary loss of muscle tone — is
one of four symptoms of the sleep disorder narcolepsy. Other
symptoms of narcolepsy are excessive daytime sleepiness,
hypnagogic hallucinations (i.e., vivid dream imagery that occurs
with sleep onset), and sleep paralysis. A person with narcolepsy
does not have to have all four symptoms to be diagnosed
with the disorder. Of all symptoms, cataplexy can be the most
debilitating since it can endanger the life of the person with
narcolepsy or other people. For example, the sudden loss of
muscle tone while a person is driving may result in an accident.
Cataplexy is triggered by strong positive emotions (e.g., mirth)
or negative emotions (e.g., anger). Affected muscles may involve
all skeletal muscles (resulting in the person falling to the floor)
or involve only a group of muscles (e.g., leg muscles may weaken
and cause the person to stagger during the episode). Scientists
believe that during a cataplexy attack, a person is simultaneously
experiencing the muscle paralysis of REM sleep while fully
alert.1
Parkinson’s Disease
Parkinson’s disease (PD) is a progressive neurological disorder
that is associated with the degeneration of the basal ganglia.
The basal ganglia are several specialized groups of neurons
at the base of the brain. Certain basal ganglia play a role in
REGINA PATRICK, RST, RPSGT
Regina Patrick, RST, RPSGT, has been
in the sleep field for more than 20 years
and works as a sleep technologist at
the Wolverine Sleep Disorders Center in
Tecumseh, Mich.
movement and are dopaminergic (i.e., respond to or produce
the neurotransmitter dopamine). Loss of basal ganglia neurons
consequently results in decreased dopamine levels and affects
movement. In people with PD, reduced dopamine levels play
a role in tremor; muscular rigidity; impaired balance and
coordination; slow, imprecise movements (i.e., bradykinesia); or
the inability to voluntarily move (i.e., akinesia). Approximately
80 percent of dopamine-producing cells are lost before the motor
symptoms of PD appear.2
REM-Sleep Behavior Disorder
For many people with PD, the sleep disorder REM-sleep
behavior disorder occurs several decades before the onset of
their PD symptoms. REM-sleep behavior disorder may reflect
impaired dopamine transmission resulting from the loss of basal
ganglia neurons. Without sufficient levels of dopamine, REM
sleep muscle atonia does not occur and a person with REMsleep behavior disorder is able to act out dreams. The dreams
typically have themes of danger such as being attacked or chased.
As a result, the person with REM-sleep behavior disorder
may jump out of bed, shout, scream, hit, punch, run, etc. while
dreaming. The person may be hurt on acting out the dreams and/
or a bed partner may be hurt if the person unwittingly strikes the
bedpartner while acting out a dream.
Animal studies have indicated that glycine and GABA inhibit
neuronal and spinal motoneuron activity.3-6 As an offshoot of this
finding, scientists have examined the neurochemistry of REM
sleep muscle atonia.
For example, Yoshio Nakamura7 and colleagues found that
administering glycine to the reticular formation (a brain
structure that plays a role in the onset of REM sleep) activated
trigeminal motoneurons during non-REM sleep, but inhibited
the motoneurons during REM sleep. Peter Soja8 and colleagues
examined the effect of strychnine on the hyperpolarization
(i.e., inhibition) of lumbar motoneurons during REM sleep in
cats. Strychnine is a toxin that causes muscle contractions and
antagonizes glycine. Soja hypothesized that signals originating
from the brain during REM sleep would hyperpolarize
spinal motoneurons. Soja applied strychnine to the lumbar
motoneurons in one group of cats but not in another group of
cats (i.e., the control). Soja found that, during REM sleep, the
lumbar motoneurons that had not been exposed to strychnine
received inhibitory signals from the brain and became
hyperpolarized during REM sleep — the activity of the lumbar
motoneurons decreased by 59 percent during REM sleep. In the
lumbar motoneurons that had been exposed to strychnine, the
inhibitory signals from the brain were blocked and therefore
hyperpolarization was markedly reduced during REM sleep
— the activity of the strychnine-exposed motoneurons was
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slightly higher during REM sleep than during non-REM
sleep. Soja concluded that glycine was the neurotransmitter
responsible for the hyperpolarization of motoneurons during
REM sleep. (However, he conceded the possibility that a
nonglycinergic inhibitory neurotransmitter could be responsible
for hyperpolarization of the motoneurons during REM sleep.)
tone by 78 percent. Despite this reduction in tone, the activity
of the muscle was greater than the muscle activity during REM
sleep. Because baclofen administration did not reduce muscle
activity to the level that occurs in REM sleep, the researchers
concluded that GABAB receptor activation alone does not
completely trigger muscle atonia during REM sleep.
Based on these and similar research findings, scientists initially
concluded that REM sleep muscle atonia resulted only from
the glycinergic inhibition of motoneurons. However, some
researchers later demonstrated in animal studies that REM sleep
muscle atonia could persist after blocking the glycine receptors
on motoneurons.9,10 This indicated that REM sleep muscle
atonia is triggered by an unidentified inhibitory mechanism.
The simultaneous administration of GABAA, GABAB, and
glycine antagonists reversed motor paralysis and resulted in a
105 percent increase in masseter muscle tone during REM sleep.
The muscle tone level during REM sleep was similar to the level
observed during normal non-REM sleep. This indicated that
REM sleep muscle atonia is triggered by the combined activation
of both GABA receptors (i.e., GABAA and GABAB) and the
glycine receptor. Brooks and Peever believe their results refute
the long-standing idea that only one transmitter (i.e., glycine) is
responsible for REM sleep muscle atonia.
Canadian researchers Patricia Brooks and John Peever1 aimed
to identify the neurotransmitter and receptor mechanisms
involved in REM sleep muscle atonia. They focused on the
neurotransmitters glycine and GABA in their study for several
reasons: (1) brainstem circuits that control REM sleep contain
GABAergic and glycinergic neurons; (2) somatic motoneurons
express GABA and glycine receptors that on activation trigger
cellular hyperpolarization; and (3) conflicting reports11 had
indicated that GABAA receptors or GABAB receptors were
responsible for REM sleep muscle atonia, which indicated that
the phenomenon may be activated by specific GABA receptors.
To investigate these factors, Brooks and Peever used the
following drugs to modify the activity of the GABAA, GABAB,
and glycine receptors: bicuculline and CGP52432 (GABAA and
GABAB receptor antagonists, respectively); baclofen (GABAB
receptor agonist); and strychnine (glycine receptor antagonist).
All drugs were dissolved in artificial cerebral spinal fluid and
administered through a cannula to the trigeminal nucleus (i.e.,
the root of the trigeminal nerve [cranial nerve V] in the brain).
To monitor the muscular effect of the drugs, they measured
the activity of the masseter muscle (i.e., a powerful jaw muscle
that is involved in chewing and is innervated by the trigeminal
nerve). Each drug was perfused onto the trigeminal nucleus for
2–4 hours. After each drug treatment, the animal underwent (at
minimum) a two-hour washout period with artificial cerebral
spinal fluid.
Brooks and Peever found that GABAB receptors, when activated
by baclofen, significantly reduced the waking masseter muscle
REFERENCES
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Brooks PL, Peever JH. Identification of the transmitter
and receptor mechanisms responsible for REM sleep
paralysis. The Journal of Neuroscience. 2012;32(29):97859795.
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Goldenberg MM. Medical management of Parkinson's
disease. P T. 2008;33(10):590-606.
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Chase MH, Soja PJ, Morales FR Evidence that glycine
mediates the postsynaptic potentials that inhibit lumbar
motoneurons during the atonia of active sleep. The
Journal of Neuroscience. 1989;9(3):743-751.
4.
Curtis DR. Pharmacological investigations upon
inhibition of spinal motoneurones. Journal of Physiology.
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A2 Zzz 22.4 | December 2013
 Continued on Page 14
To investigate the role of the GABAB receptors in REM muscle
atonia, the researchers perfused baclofen (GABAB receptor
agonist) into the trigeminal motor nucleus (which is a portion of
the trigeminal nucleus) while measuring masseter muscle activity.
They antagonized the receptor with CGP52432. To determine
if glycine and GABA are simultaneously needed to induce
REM sleep muscle atonia, the authors simultaneously perfused
GP52432, bicuculline, and strychnine onto the trigeminal
nucleus motoneurons during sleep and during wake.
Because the finding that both glycine and GABA may be needed
to induce REM sleep muscle atonia is so recent, no studies
have investigated to what extent manipulating GABAergic
and glycinergic systems can improve sleep disorders associated
with alterations in REM sleep. A greater understanding of
how REM sleep muscle atonia occurs could result in better
treatment of disorders associated with a dysfunction in REM
sleep. For example, altering the activity of glycine and GABA
receptors, in addition to increasing the brain levels of dopamine,
may more effectively improve symptoms in people with REMsleep behavior disorder or Parkinson’s disease. Simultaneously
targeting the glycinergic and GABAergic systems may lead
to the development of less addictive treatments for cataplexy.
(The drug sodium oxybate, a form of GABA, effectively reduces
cataplexy attacks in some people with narcolepsy but it is very
addictive.) For now, scientists continue studies to determine
the role of glycine, GABA, and other neurotransmitters (e.g.,
dopamine) in REM sleep muscle atonia.
 Continued from Page 13
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excitation of spinal neurones by certain acidic amino
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Soja PJ, Lopez-Rodriguez F, Morales FR, Chase
MH. The postsynaptic inhibitory control of lumbar
motoneurons during the atonia of active sleep: effect
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25%
OFF
9.
Kubin L, Kimura H, Tojima H, et al. Suppression of
hypoglossal motoneurons during the carbachol-induced
atonia of REM sleep is not caused by fast synaptic
inhibition. Brain research. 1993;611(2):300-312.
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tone during REM sleep, REM sleep behavior disorder
and cataplexy/narcolepsy. Archives Italiennes de Biologie.
2011;149(4):454-466. 
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