Treatments forInsomniaAlejandro M. Ramirez

BLA-41504 April 2007

Sleeping Disorders Insomnia Sleep Apnea Restless Legs Syndrome Narcolepsy

Insomnia

Transient: Short time Intermittent: Comes and goes Chronic: Occurs most nights for periods longer

than a monthPrimarySecondary

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

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.

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.

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

Causes, Age

As age increases, changes occur whichmay affect sleepChange in sleep patternsChange in activityChange in health

Treatment

Abstention Relaxation therapy Sleep restriction Reconditioning Drugs

Barbiturates Benzodiazepines Miscellaneous Sedatives and hypnotics

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

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.

Miscellaneous Sedatives andHypnotics Eszopiclone

(Lunesta) Ramelteon (Rozerem) Zaleplon (Sonata) Zolpidem (Ambien

and Ambien CR)

Difficult to grouptogether Different mechanisms Mechanisms unknown

Inhibitory Neurotransmitters

GABA Serotonin Glycine Taurine

Excitatory Neurotransmitters

Acetylcholine Glutamate Norepinephrine Epinephrine Phenylethylamine Histamine

Dopamine

Stimulatory, Excitatory

Serotonin

Dopamine

GABA

Glycine, Histamine

Thalamus, Hypothalamus andBrainstem

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.

Superchiasmatic Nuclei

Light has importantrole in circadian clock

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

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.

Some Methods for Studying GABA-A Receptors Immunohistochemistry Knock-out, knock-in mice PCR, RT-PCR

Immunohistochemistry

GABA-A Receptor, Subunits

Benzodiazepines

Benzodiazepines donot open the chloridechannel directly.

Binds indirectly toalpha and increasesthe capacity of GABAto bind to it’s receptoron the beta subunit.

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).

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.

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.

How?

Use cholinergic and Gabaergic agonistsand antagonists:Muscimol: GABA-A agonistBicuculline: GABA-A antagonistCarbachol: mACh receptor agonistScopolamine: mACh receptor antagonist

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