Psychopharmacology of Sleep and Wakefulness: Understanding Neurotransmitters and Pathways in Clinical Practice

Author: Flavio Guzman, MD
Last updated: February 9, 2018

This tutorial integrates neurotransmitters involved in sleep and arousal with the pharmacology of specific psychotropic agents.

We review neurotransmitters that promote wakefulness (dopamine, norepinephrine, serotonin, acetylcholine, histamine, orexin/hypocretin) and summarize how current drugs influence each system.

We also discuss neurotransmitters that promote sleep (adenosine, GABA, melatonin).

This is an integration between the different neurotransmitters that regulate sleep physiology and pharmacological interventions commonly used in clinical practice.

This can be divided in two parts, the study of neurotransmitters that promote wakefulness and a summary how drugs influence each system. A shorter, second part where discuss neurotransmitters that promote sleep.

We will see each drug class in more detail in other presentations.

Sleep is regulated by neurotransmitters that promote wakefulness and sleep. Treatments for insomnia act on these systems by reducing wakefulness or by promoting sleep.

So, what are the neurotransmitters involved in wakefulness? This is just a preview, but we can list six molecules, the monoamines dopamine, norepinephrine, serotonin, norepinephrine, histamine and the neuropeptide
orexin, also known as hypocretin.

The neurotransmitters that promote sleep are: adenosine, GABA, melatonin and galanin




Dopamine is released from neurons in the substantia nigra, ventral tegmental area and ventral periaqueductal grey.


Dopaminergic projections to the cortex and other regions are involved in: wakefulness, motivation, reward, learning and motor function, among other processes.


As you know, most antipsychotics are D2 antagonists, they reduce dopaminergic neurotransmission in different regions, including those involved in wakefulness.
Here we have some examples. For first-generation antipsychotics: haloperidol and chlorpromazine. Chlorpromazine also has strong affinity for histamine 1 receptors.

Second-generation antipsychotics such as olanzapine, quetiapine and risperidone are commonly used off-label for the treatment of insomnia. Olanzapine and quetiapine have also affinity for histamine 1 receptors.


What about drugs that enhance dopaminergic neurotransmission?
This image shows the mechanism of action of methylphenidate as an example of how stimulants increase dopaminergic activity. Stimulants are used for the treatment of ADHD, they enhance noradrenergic and dopaminergic neurotransmission. One of most common side effects of stimulants is insomnia.

Modafinil is a wakefulness promoting agent approved for excessive sleepiness associated with narcolepsy, obstructive sleep apnea and shift work disorder. Its mechanism of action is unknown but it is thought to involve dopamine reuptake inhibition.





Norepinephrine is produced by several brain nuclei, but the major source of norepinephrine to the forebrain is the locus coeruleus.


Noradrenergic projections to the cortex are involved in wakefulness and arousal in a way that optimizes attention and task performance.


What is the effect of noradrenergic drugs on sleep?
Drugs that stimulate noradrenergic neurotransmission can cause insomnia as side effect. Examples include bupropion and stimulants.

On the other hand, the alpha 1 antagonist 10 has been reported to be effective in the management of sleep symptoms of PTSD. These include vivid nightmares and nighttime arousal.




Serotonin is released from neurons in the dorsal raphe nucleus and other nuclei.


These neurons innervate regions such as preoptic area, cortex, basal forebrain, hypothalamus, thalamus.

Studies suggest that serotonin promotes wakefulness and suppresses REM sleep.


In fact, the use of SSRIs such as fluoxetine and citalopram has been linked to increased wakefulness and reduced reduced REM sleep.




Cholinergic neurons are located in the basal forebrain and the laterodorsal and peducunculopontine tegmental nuclei.


These neurons have projections to the cortex, thalamus, hypothalamus and brainstem.


These cholinergic projections are involved in wakefulness, REM sleep, learning and memory.


The role of acetylcholine in sleep physiology has been explored in pharmacological studies. Acetylcholine, nicotine and muscarinic receptor agonists produce desynchronized cortical activity and increased wakefulness.




Histamine is an essential neurotransmitter in wakefulness. The tuberomammillary nucleus is the brain center that contains histamine neurons projecting to the forebrain and brainstem.


Histamine neurotransmission is involved in promoting wakefulness, REM sleep, learning and memory.


Blockade of histamine 1 receptors is part of the pharmacological treatment of insomnia.

Diphenhydramine is an over-the-counter drug commonly used as sedative, it is an ingredient in common cold and pain medications.

Tricyclic antidepressants have high affinity for histamine 1 receptors. Doxepin is a tricyclic that is available in a low dose formulation for the treatment of insomnia.

Some antipsychotics block histamine 1 receptors, chlorpromazine is an example of a first generation antipsychotic. Quetiapine and olanzapine are second generation antipsychotics used off-label for insomnia.




The orexin system involves the excitatory neuropeptides orexin-A and orexin-B. These neuropeptides are synthesized by neurons in the lateral and posterior hypothalamus.


These neurons have projections to the arousal regions we just saw, mainly the locus ceruleus and the tuberomammillary nucleus.


The orexin system is a system for sustaining wakefulness and increasing arousal in motivating conditions. Clinical findings show that patients with narcolepsy with cataplexy have severe loss of orexin neurons and very low CSF levels of orexin-A.


Orexins have affinity for two receptors, orexin receptor 1 and 2. The orexin receptor 1 shows higher affinity for orexin A than orexin B. The orexin 2 receptor binds both orexin A and orexin B with similar affinities.


Suvorexant was approved in 2014 for the treatment of insomnia. Suvorexant is a reversible dual orexin receptor antagonist. It blocks orexin 1 and orexin 2 receptors.


Sleep promoting systems




This diagram shows the relationship between light, the suprachiasmatic nucleus, melatonin and sleep.

Light impacts the retina, this signal travels to the suprachiasmatic nucleus, which is connected to the pineal gland. During daytime, melatonin secretion is inhibited by this system.

During nighttime, the absence of light stimulation to the suprachiasmatic nucleus allows melatonin secretion.


What is the effect of melatonin on sleep?

First, we should note that melatonin binds to MT1 and MT2 receptors. Melatonin induces sleep but under the influence of the circadian phase. The transition phase from wakefulness / arousal to high sleep propensity matches with the nocturnal rise of endogenous melatonin.


Currently there are two melatonergic agents available.

Ramelteon is a hypnotic that is a MT1 and MT2 agonist.

Agomelatine is an antidepressant that is not available is the US. It is a MT1, MT2 agonist and a 5HT2C antagonist.




Our last neurotransmitter is GABA. GABA is a major inhibitory neurotransmitter. Most sleep pharmacology is focused on the GABA-A receptor. At the cellular level, GABA causes neuronal inhibition by increasing chloride ion conductance.

GABA facilitates sleep by inhibiting brain regions involved in wakefulness.


Benzodiazepine receptor agonists include benzodiazepines and Z drugs. We see these drugs in more detail in other presentations.



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