***Aspects of Sleep Research (Some More Sleep History):
    The earliest definition of sleep was the "absence of wakefulness."  Early scientists deduced that when the senses were active, one was a wake and when they became inactive, one was asleep.    This led to the hypothesis that sleep comes from deafferentation.  Scientists then began to search for a region of the brain that controlled sleep.  The thalamus, the periventricular gray matter, and a mesodiencephalaic area extending to the hypothalmus were all found to play a key role (thanks to the discoveries of Gayet, Mauthner, and von Economo).  The deafferentation hypothesis was then supported by research done by Bremer using the encephale isole preparation on cats.  When he cut the cat's brain just below the medulla, he saw alternating sleep and wakefulness.  But when he cut the midbrain between the colliculi using the cerveau isole preparation, there were continous sleep patterns.  Other research then made alterations to this hypothesis:  Work done by Moruzzi and Magoun, who studied the reticular formation, found that this part of the brain was what controlled sleep. 
    New research soon began to show that sleep was not necessarily a passive process, as was thought before.  Instead, researchers hypothesized that it was an active one.  Stimulation and EEG recordings helped to show this.  The idea of sleeping being an active process was supported by the discovery of REM sleep, which is a type of active sleep.  REM sleep is controlled by the pons, and has an EEG similar to that of an awake state.  EEGs have been important in much sleep research, especially once the 5 patterns of sleep were outlined.  It was found that there were physiological differences between the various stages of sleep, especially REM sleep when compared with the other stages.  Sleep can be considered an instinct or a motive and much research has also been done on its functions.  Some say that sleep has a restorative function, others say that sleep consolidates memories.  Still, other research makes different proposals. 

Pharmacology: 

Drugs play an important role in sleep research and have been around for quite some time.  They help to understand the pharmacology of sleep and figure out some of sleep's mechanisms.  By looking at how various drugs act on sleep, we can better see how sleep is influenced by both internal and external factors. 

One of the first types of drugs developed that relates to sleep is hypnotic substances.  Hypnotics have been around for quite some time and are used as sedatives.  These types of drugs are used to induce unconsciousness and look at the comparisons between unconsciousness and sleep. 

Research done on:

• Rats and Mice:  Early experiments were done primarily with rats and mice to look at the anesthetic effects of drugs such as thalidomide, flurazepam hydrochloride, phenobarbital, and diazepam (among many others).  Using rats and mice allow for a larger sample size and better results, although rats are sometimes difficult to use because it his hard to get good electrophysiological recordings. 
• Cats:  Cats have also been used a lot within neurophysiological research because they are relatively simple to draw conclusions from.  Something that is interesting to note is that though cats have been used in studies of hypnotic agents, cats react much differently than humans when they are given benzodiazepines.  Another reason cats pose a problem to research is that they are a species that is naturally prone to be sleeping most of the time.  To correct this, some researchers have made attempts to periodically arouse the cats so that they stay awake longer and give better results.  One experiment looked at the effects of various drugs on cats when they were in normal sleeping patterns (35% of time awake) and when they were being consistently aroused (95 % of time awake). 
• Monkeys:  Some experiments have been done with rhesus monkeys; however monkeys appear to be somewhat resistant to most drugs tested.  The cebus monkey has also been used, and researchers have been able to monitor sleep patterns in these monkeys and record EEGs.  CNS depressants have been tested on cebus monkeys and it has been found that the effects/doses of these drugs is similar in monkeys as in humans.
  

Difficulties in Studying Sleep Pharmacology in Humans: 

DRUG EFFECTS: 

1.  Sedative-Hypnotic Agents:  These drugs generally have calming effects and CNS-depressant effects.  They result in sedation at low doses and hypnosis at high doses.  Some tolerance is seen after the drugs are repeatedly administered, and withdrawal syndorome occurs after high dosages.
   
Types:

• Barbiturates (Amobarbital, Heptobarbital, Nealbarbital, Pentobarbital, Phenobarbital, Secobarbital, Thiopental, Barbiturate mixtures)
• Benzodiazepines (Bromazepam, Chlorodiazepoxide, Diazepam, Flunitrazepam, Flurazepam, Lorazepam, Nitrazepam, Oxazepam, Temazepam, Triazolam)
• Other Nonbarbiturates (Alpha Chloralose, Benzamide Compound, Benzoctamine, Chloral Hydrate, Chlormethiazole, Diphenhydramine, Glutethimide, Hexapropymate, Mandrax, Mebutamate, Meprobamate, Methaqualone, Methprylon, Perlapine)
• Alcohol (tested in both non-alcoholic and alcoholic subjects)
• Nonprescription Sedative-Hypnotics (Scopolamine, Sominex)

2.  Analgesic Agents:  Researchers looked at the effects of opiates (which are derivatives of the poppy).  Opiates have effects on the CNS--the compounds affect the entire system, which is why they are important to study.  The effects are more stimulant than sedative, and considerable tolerance/withdrawal effects develop. 

Types:

• Morphine
• Heroin
• Methadone

3.  Stimulants:  They are important to study because amphetamines were once used to treat narcolepsy.  Amphetamine and similar compounds have also been used to help treat Parkinson's and depression, among other things.  These drugs clearly have stimulating effects, thus reducing sleep.  Caffeine and Methamphetamine are also often tested in research relevant to sleep in the fruit fly Drosophila melanogaster:  See article summaries here

Types:

• Amphetamine
• Caffeine
• Chlorphentermine
• Cocaine
• Diethylpropion
• Fenfluramine
• Methyl Phenidate
• Other Stimulants

4.  Antidepressant Agents:  Depression is usually associated with sleep abnormalities, so studying the effects of antidepressant drugs on sleep is pertinent. 

Types: 

• Tricyclic Antidepressants (Amitriptyline, Desipramine, Imipramine, Iprindole, Maprotiline)
• Lithium
• MAO Inhibitors (Phenelzine)
• Other Antidepressants (Doxepin, Opipramol, CI-579, CI-600)

5.  Antipsychotic Agents:  There are also many sleep abnormalities in psychotic illnesses, especially schizophrenia.  Decreased delta sleep is extremley common. 

Types: 

• Phenothiazines (Butaperazine, Chlorpromazine,  Dixyrazine, Fluphenazine, Mesoridazine, Promethazine, Thioridazine, Trifluoperazine)
• Thioxanthenes (Chlorprothixene, Thiothixene)
• Butyrophenones (Haloperidol)
• Other Antipsychotic Agents (Clozapine, Molindone, Propanolol, Sulpiride)
• Reserpine

Some other studies: 

Long-term effects of psychotropic drugs:  Ernest Hartmann, MD looked at the long-term effects of the drugs reserpine, chlorpromazine, chloral hydrate, amitriptyline, and chlordiazepoxide (and placebo) on human sleep.  Hartmann used 14 male subjects (ages 21-35) and recorded a total of 1125 nights of sleep for each subject.  Each subject was administered each drug for a 60-day period.  The subjects filled out a sleep log every morning.  It was found that reserpine increased sleep disturbance, amitriptyline produced changes in EEG recordings, chlorpromazine produced basically no change, chlora hydrate increased sleep time and decreased sleep latency, and chlordiazepoxide produced EEG changes as well as a long-term reduciton in both slow-wave and REM sleep. 

Anxiolytic vs. Hypnotic Drugs:  Turan M. Itil, MD, compared the effects of hypnotic versus anxiolytic drugs on sleep by looking at EEGs and analyzing them via the computer.  30 male subjects, ages 20-44 were used in the study and the following drugs were administered:  diazepam, chloazepate dipotassium, flurazepam, methaqualone, U-31,889 (a triazolobenzodiazepene), triazolam, and placebo.  EEG recordings were made all night.  These recordings were scored.  It was found that all drugs used affected the sleep profile.  Both types of drugs shortened the time it took for sleep onset.  There was a significant decrease in stage 4 sleep in all drugs except for fluroazepam.  All drugs were concluded to reduce deep sleep and increase light sleep, except for fluorazepam, which was found to do the opposite.  The overall conclusion was that hypnotics and anxiolytics have similar effects on sleep in humans. 

***Information from: 
Williams, Robert L. and Ismet Karacan (eds).  Pharmacology of Sleep.   New York : Wiley, c1976.

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Modern Drugs: 

Benzodiazepine sedative hypnotics:

Estazolam (ProSom)
Flurazepam (Dalmane)
Quazepam (Doral)
Temazepam (Restoril)
Triazolam (Halcion)

Non-benzodiazepine sedative hypnotics:  These are the most commonly prescribed because they act on similar parts of the brain as benzodiazepines do but have less side effects. 

Zolpidem(Ambien)
Zalepon (Sonata)
Eszopiclone (Lunesta)


Melatonin receptor agonist hypnotic: 

Rozerem:  Most effective on people who have difficulty falling asleep, similar to the hormone melatonin-acts as an agonist

http://www.helpguide.org/life/sleep_aids_medication_insomnia_treatment.htm