treatments for insomnia - saint louis universitystarklab.slu.edu/neuro/treatments for...
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Treatments forInsomniaAlejandro M. Ramirez
BLA-41504 April 2007
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Sleeping Disorders Insomnia Sleep Apnea Restless Legs Syndrome Narcolepsy
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Insomnia
Transient: Short time Intermittent: Comes and goes Chronic: Occurs most nights for periods longer
than a monthPrimarySecondary
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Insomnia, Introduction
40% of American adults suffer fromintermittent insomnia
10-15% suffer from chronic insomnia A person suffering from chronic insomnia
experiences on frequent basis:Problems falling asleep.Problems staying asleepExperiences nonrestorative sleep
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Introduction
7.5 hours is the average amount of sleeprequired by an individual.
Decreased amount of sleep leads todecreased amount of energy, mentalalertness, and mood levels.
Immune response is bolstered by sleep,therefore health is affected as well.
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Consecuences
People with chronic insomnia are more likely todevelop psychiatric problems.
Long-term sleep deprivation may increase theseverity of chronic diseases, such as high bloodpressure and diabetes.
According to the National Highway Traffic SafetyAdministration, more than 100,000 crashes eachyear are due to drivers falling asleep at thewheel.
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Causes
Anxiety Depression Stimulants Change in environment Change in schedule Long term use of sleep medications Medical conditions causing pain Eating too much before sleeping
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Causes, Age
As age increases, changes occur whichmay affect sleepChange in sleep patternsChange in activityChange in health
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Treatment
Abstention Relaxation therapy Sleep restriction Reconditioning Drugs
Barbiturates Benzodiazepines Miscellaneous Sedatives and hypnotics
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Barbiturates
Amobarbital (Amytal) Butabarbital (Butisol) Pentobarbital
(Nembutal) Phenobarbital
(Solfoton) Secobarbital
(Seconal)
Produce drowsinessand prolong sleepduration by slowingCNS functioning.
Cause mild sedationand a hypnotic state.
Short term use
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Benzodiazepines
Estozolam (ProSom) Flurazepam (Dalmane) Quazapam (Doral) Temazepam (Restoril) Triazolam (Halcion)
Ability to: speed sleep onset Reduce number of
awakenings Increase total sleep
duration
Should not discontinueabruptly because ofrebound insomnia.
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Miscellaneous Sedatives andHypnotics Eszopiclone
(Lunesta) Ramelteon (Rozerem) Zaleplon (Sonata) Zolpidem (Ambien
and Ambien CR)
Difficult to grouptogether Different mechanisms Mechanisms unknown
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Inhibitory Neurotransmitters
GABA Serotonin Glycine Taurine
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Excitatory Neurotransmitters
Acetylcholine Glutamate Norepinephrine Epinephrine Phenylethylamine Histamine
Dopamine
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Stimulatory, Excitatory
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Serotonin
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Dopamine
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GABA
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Glycine, Histamine
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Thalamus, Hypothalamus andBrainstem
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Hypothalamus
Serotoninergic, adrenergic, and histamminergicactivity is high during wakeful states, decreasesduring NREM, and is almost eliminated withREM sleep.
Cholinergic activity remains high in thebrainstem during REM sleep.
Posterior and midbrain hypothalamic junctionlesions result in sleepiness.
Anterior inflammation resulted in insomniacstate.
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Superchiasmatic Nuclei
Light has importantrole in circadian clock
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GABA-A Receptor
Mediates tonic inhibition Alpha, beta, delta, and gamma subunits Alpha, beta, and gamma are encoded by
same cluster of genes on chromosome 5.Composition of these subunits determines
affinity of the receptor to ligandDistribution of subunits also varies depending
on tissue and location
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GABA-A Receptor
Five protein subunits. Form central pore permeable in the most part to
Chloride ions. GABA, benzodiazepines, barbiturates and
anaesthetic steroids bind to Chloride channel. GABA is the most improtant inhibitory transmitter
in the CNS, and is virtually absent outside thebrain and spinal chord.
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Some Methods for Studying GABA-A Receptors Immunohistochemistry Knock-out, knock-in mice PCR, RT-PCR
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Immunohistochemistry
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GABA-A Receptor, Subunits
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Benzodiazepines
Benzodiazepines donot open the chloridechannel directly.
Binds indirectly toalpha and increasesthe capacity of GABAto bind to it’s receptoron the beta subunit.
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Benzodiazepines
Produce their therapeutic effect on the GABA-Areceptors, but tolerance and dependence aremore complicated than simply downregulating.
Long term exposure causes differential changesin the expression of GABA-A receptor genes.
Poor memory and loss of motor function fromabuse. e.g. Flunitrazepam (Rophypnol).
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GABAergic vs. Cholinergic Study
Cholinergic system in nucleus pontis oralis(NPO) is critically important in production ofREM sleep.
Ach release in NPO is greater during REMsleep.
Neurons show increased dischrge rate duringsleep.
Lesions to such cholinergic neurons eliminateREM sleep.
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GABAergic vs. Cholinergic Study
GABA mediated inhibition has negative effect onpre-synaptic release of ACh in the NPO.
Pontine GABAergic system functions tosuppress active sleep and promote wakefulness.
Cholinergic activation of Pontine waves stemfrom the pons to the hippocampus andamygdala.
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How?
Use cholinergic and Gabaergic agonistsand antagonists:Muscimol: GABA-A agonistBicuculline: GABA-A antagonistCarbachol: mACh receptor agonistScopolamine: mACh receptor antagonist
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Reference
http://www.chemistry.emory.edu/justice/seminar/gaba.htm
http://www.ninds.nih.gov/disorders/brain_basics/understanding_sleep.htm
http://www.neurorelief.com http://www.drugdigest.org http://www.mayoclinic.com/health/insomnia http://homepage.psy.utexas.edu/homepage/class/Psy332/Salinas/Neurotransmitters/Slide14.GIF
http://universe-review.ca/I10-67-circadianclock2.jpg