Chapter 10: Disorders of sleep and their tx Flashcards
what is the arousal spectrum regulated by
histamine
dopamine
norepinephrine
serotonin
acetylcholine
GABA
orexin
sx of deficient arousal
inattention
cognitive dysfunction
sleepiness
sx of excessive arousal
hypervigilance
cognitive dysfunction
panic/fear
hallucinations/psychosis
how do wake-promoting drugs target histamine
enhancement of histamine release
how do sleep-promoting drugs target histamine
blockage of H1 receptors
which 2 enzymes terminate the action of histamine
-MAOB converts N-methylhistamine to N-methyltransferase
-in the periphery it is terminated by diamine oxidase
what is best known as targets for antihistamines
postsynaptic H1 receptors
what are well known targets of heartburn medicine
postsynaptic H2 receptors
which receptor functions as an autoreceptor for histamine
presynaptic H3 receptors
what does histamine do at NMDA receptors
alter the action of glutamate
where do all histamine neurons arise
small area in the hypothalamus called the tuberomammillary nucleus
what brain structure regulates arousal, wakefulness, and sleep
tuberomammillary nucleus in the hypothalamus
what is the difference between orexin and hypocretin
nothing. 2 scientists discovered at the same time and named two different things
what does hypocretin usually refer to
gene or genetic products
what does orexin typically refer to
peptide neurotransmitters themselves
which neurons are localized exclusively in hypothalamic areas
orexin/hypocretin
what happens when there is diminished release of orexins/hypocretins onto downstream wake-promoting neurotransmitters
destabilized wakefulness
which neurons degenerate in narcolepsy
orexin/hypocretin
what receptors regulate the postsynaptic actions of orexin A and B
orexin1 and orexin 2 receptors
which type of orexin binds to orexin 1 receptors and what does that do
orexin A binds and leads to increased intracellular calcium and activation of the sodium-calcium exchanger
which orexins bind to orexin recepto 2 and what does that do
orexin A and B
either increased expression of NMDA glutamate receptors or inactivation of G-protein-regulated potassium channels
what functions does orexin play a role in
stabilizing wakefulness and regulating feeding behavior and reward
how do orexin neurons fire during wakefulness
fire with tonic frequency to maintain arousal
where does orexin stimulate acetylcholine release from
basal forebrain
pendunculopontine and laterodorsal tegmental area
where does orexin stimulate dopamine release from
VTA
where do orexins stimulate release of norepinephrine from
locus coeruleus
where does orexins stimultate srotonin release from
raphe nuclei
where does orexin stimulate release of histamine from
tuberomammillary nucleus
how does the homeostatic sleep drive work
adenosine starts to accumulate as as the person tires throughout the day which ultimately lead to disinhibition of ventrolateral preoptic nucleus and release of GABA in the sleep circuit
what mediates the circadian wake drive
light acting on the suprachiasmatic nucleus
what happens when light acts on the suprachiasmatic nucleus
stimulates release of orexin which enhances release of other wake-promoting neurotransmitters
where is histamine released in the circadian wake drive and what does that do
released onto neurons throughout the cortex and VLPO and it inhibits the release of GABA
what happens in the circadian wake drive when light fades
NE and 5HT are released onto neurons in the hypothalamus causing negative feedback to inhibit orexin release. Without orexin wakefulness is no longer stabilized
how many times do ultradian cycles repeat during one night
4-5 times
what are the 5 ultradian cycles
REM
NREM stages 1-4
which regions of the brain are activated during REM sleep
thalamus
visual cortex
limbic regions
Role of GABA in ultradian cycles
it is on all night and rises for the first few hours of sleep, plateaus, and steadily declines before arousal
role or orexin in ultradian cycles
decreases during first few hours of sleep, plateaus, then steadily rises before arousal
acetylcholine levels in ultradian cycles
lowest levels during stage 4 NREM
levels peak during REM
levels of dopamine, norepinephrine, serotonin, and histamine in ultradian cycles
lowest during REM
peaks during stage 2 NREM
what effect can disordered sleep have on your health
circulating levels of leptin (anorectic) and ghrelin (orexigenic) are disrupted leading to dysfunctional insulin, glucose, and lipid metabolism that increases risk for DM, obesity, cardio disease
cognitive effects of disordered sleep
24h sleep deprivation same as legal intoxication
what does REM sleep modulate
memory consolidation
what is NREM sleep good for
declarative and procedural memory
neurobiological effects of sleep disturbance
impairs hippocampal neurogenesis which may explain the behavioral effects of sleep disturbance
what happens in insomnia in relation to sleep/wake circuits
more a problem with not being able to shut off arousal circuits than inability to initiate sleep circuits
what subunits must receptors contain to be sensitive to benzodiazepines
two B subunits
a Y subunit
two A subunits
where do benzodiazepine bind to GABAA receptors
allosteric sites
how do benzodiazepines work to improve sleep
facilitate GABA neurotransmission in inhibitory sleep circuits arising from the hypothalamus and the VLPO
what receptor subunit is targeted by all GABAA PAMs
a1
what are the 2 dual orexin receptor antagonists (DORAs)
suvorexant
lemborexant
how does suvorexant work differently than benzos and Z drugs
inhibits ability of orexin to promote release of wake-promoting neurotransmitters rather than increase GABA
what type of inhibitor are suvorexant and lemborexant
reversible. Inhibition is reversed as natural orexin builds up in the morning
what is the serotonergic hypnotic used for insomnia
trazadone
what receptors does trazadone antagonize
5HT2A, a1, and H1
how does Trazadone work
blocks serotonin, norepinephrine, and histaine to reduce arousal rather than stimulate sleep drive
what is the H1 receptor antagonist that is used as a hypnotic
doxepin at low doses
GABAA receptor occupancy threshold for inducing sleep
25-30%
DORA receptor occupancy threshold for sleep induction
around 65%
behavioral treatments for insomnia
sleep hygiene
relaxation training
stimulus control therapy
sleep restriction therapy
intensive sleep retraining
what is one of the most common causes of daytime sleepiness
obstructive sleep apnea
central disorders of hypersomnolence
idiopathic hypersomnia
narcolepsy
diagnostic criteria for idiopathic hypersomnia
-excessive daytime sleepiness for at least 3 months
-short sleep-onset latency period
-fewer than 2 periods of REM at onset of sleep (polysomnography)
what is cataplexy
sudden loss of muscle tone often triggered by strong emotions
why does cataplexy occur in narcolepsy
profound loss of orexin neurons in the hypothalamus causes low daytime levels which destabilizes motor function resulting in intrusion of motor inhibition and loss of motor tone during wakefulness
which polymorphism is present in 90% of those with narcolepsy
HLA DQB1-0602
4 circadian rhythm disorders
shift work disorder
advanced sleep phase disorder
delayed sleep phase disorder
non-24-hour sleep-wake disorder
what does shift work disorder increase your risk of
cardiometabolic issues
cancer
GI disease
mood disorders
what is advanced sleep phase disorder
go to sleep earlier than desired
wake earlier than desired
usually by 6h outside normal sleep/wake times
how do you dx advanced sleep phase disorder
sleep and/or actigraphy for at least 1wk
morningness-eveningness questionnaire (MEQ)
what is delayed sleep phase disorder
unable to sleep until early morning hours then sleep late into the day
delayed sleep phase disorder is associated with polymorphisms in what gene
CLOCK
who is primarily affected by non-24-hour sleep-wake disorder
blind people
circadian treatment for delayed sleep phase disorder and shift work disorder
morning light/evening melatonin
circadian treatment for advance sleep phase disorder
early evening light and early morning melatonin
how does melatonin regulate circadian rhythm
acts at M1 and M2 sites on the suprachiasmatic nucleus
melatonergic hypnotic that improves sleep onset but not necessarily maintenance
ramelteon
Classification of ramelteon
M1/M2 agonist
what is the worlds most widely consumed psychoactive drug
caffeine
how does caffeine promote wakefulness
blocks the effects of adenosine buildup and restores affinity of D2 for dopamine over adenosine. Enhanced dopamine is wake-promoting
which neurotransmitters are enhanced by amphetamine and methylphenidate
dopamine
norepinephrine
wake-promoting action of methylphenidate
NDRI
wake-promoting action of amphetamines
dopamine releasers and competitive VMAT2 inhibitors
what is approved for the treatment of narcolepsy but not OSA or shift work disorder
amphetamine
what is approved for treatment of narcolepsy AND OSA and shift work disorder
Modafinil
armodafinil
modafinil and DAT
weak inhibitor with incomplete occupancy
what properties of modafinil allow it to promote wakefulness without promoting abuse
slow rise in plasma levels w/ incomplete DAT occupancy
how does dopamine release from modafinil cause arousal
cortex is aroused by dopamine release leading to downstream release of histamine and further activation of lateral hypothalamus with orexin with orexin release
does modafinil still work in patients with a loss of hypothalamic orexin neurons in narcolepsy
yes
effectiveness of modafinil for narcolepsy
effective but not as much as methylphenidate or amphetamine
wake-promoting NDRI that is more potent than wellbutrin but less potent than amphetamines and has a short half-life
solriamfetol
classification of pitolisant
H3 presynaptic antagonist
how does pitolisant work
blocks normal action of presynaptic H3 autoreceptors to inhibit histamine release. This causes disinhibition of presynaptic histamine which is wake-promoting
what is the thought behind why sodium oxybate (GHB) works to treat disorders of hypersomnia
rather than waking you up, it promotes such good sleep you are more alert during the day
how is GHB formed
from GABA
actions of sodium oxybate
full agonist at GHB receptors
partial agonist at GABAB receptors
what med can reduce hypnagogic hallucinations and sleep paralysis
sodium oxybate
