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The Neurochemistry of Sleep

Understanding how your brain works when it comes to sleep is important for helping you understand why you might have trouble sleeping. In this article, we go in depth into how the sleep-wake cycle works and how different neurochemicals affect your sleep.

Dr. Robert Pastore
Last updated on
Fact Checked by Dr. Robert Pastore
The Neurochemistry of Sleep

Table of Contents

Falling Asleep

  • The Neurochemistry of Sleepiness
  • The Neurochemistry of Insomnia


  • NREM Sleep
  • The Neurochemistry of NREM Sleep
  • REM Sleep
  • The Neurochemistry of REM Sleep

Waking Up

  • The Neurochemistry of Waking Up

Sleep and waking result from a dynamic interplay - a tug of war - between regions which are involved in keeping your brain awake, and regions which are involved in keeping your brain in a state of sleep. Sleep happens when your sleep promoting regions are active - when they are “winning”.

Falling Asleep

When you are awake, the electrochemical activity which generates your thoughts, feelings and decisions generates a series of chemical byproducts. Over the waking day, the level of these chemicals - or sleep promoting factors as they are called - increases.

This build up generates a sleep propensity - a need for sleep - which, when it reaches a threshold level, helps block the activity in other regions of your brain which are making sure that you stay awake. They also contribute to the activation of sleep promoting regions to set in motion the night-time regime of sleeping.

The Neurochemistry of Sleepiness

Many different sleep promoting factors have been identified. These include chemicals such as adenosine, nitric oxide, prostaglandin D2, and a variety of cytokines (cells made by your immune system).


    GABA is the main inhibitory neurotransmitter involved in switching off state of wakefulness. Although it does not so much act as chemical marker for the end of the day, it is critically involved in coordinating the actual process of falling asleep via its action within preoptic cells which inhibit the activity of wake-promoting brain regions.


    Adenosine is a byproduct of metabolic and electrical activity within your neurons. This means that the level of adenosine in particular regions of your brain is an indication of the amount of time you have spent awake that day.

    Adenosine promotes sleep by influencing various sleep-wake pathways in the brain. One of it’s main routes of action is by directly inhibiting regions which are tasked with keeping the brain awake, in particular specialized cells in the hypothalamus which contain the chemical orexin/hypocretin, as well as cholinergic cells (containing the neurotransmitter acetylcholine) in the brain stem.

    In addition, adenosine is also able to send excitatory messages to the preoptic region, which in turn inhibits wake-promoting regions.

    Nitric Oxide

    Nitric oxide is actually a small gaseous molecule which is synthesized by enzymes in the brain. It promotes sleep through a variety of mechanisms but one of the main ones is by promoting the release of adenosine and therefore initiating the kind of sleep-promoting effects described above.


    Melatonin is produced by a particular gland located at the base of your brain called your pineal gland. It is mainly released during the night under the regulation of your Suprachiasmatic Nucleus.

    Melatonin release is also sensitive to light signals from the retina and works to entrain your internal sleep-wake cycle to an external clock. This is one of the reasons why melatonin supplements are commonly used to treat circadian disturbances, such as those caused by jet lag.

    The Neurochemistry of Insomnia

    On the other hand, there are neurochemicals that can keep us from falling asleep easily. There are generally the excitatory neurotransmitters that form the neurochemical balance.

      Norepinephrine, Epinephrine, Cortisol

      During the day, you are faced with various physical, social, emotional or mental challenges which cause your brain and body to release a series of chemicals which prepare you for action.

      Neurotransmitters such as norepinephrine (and it’s related hormone epinephrine) help to put your brain in a state of high alert and up-regulate activity in wake-promoting regions to ensure that they stay awake and alert.

      In addition, the hormone cortisol which is released from your brain-to-body HPA (hypothalamic-pituitary-adrenal) axis in a time of high-stress - as well as morning waking - can act to ensure you remain in a state of wakefulness (but not always in a good way!).

      Orexin / Hypocretin

      Cells containing Orexin/hypocretin, a wake promoting factor,  are especially busy when you are standing up, walking around, or generally being out and about.  This is one of the mechanisms through which your brain makes sure that you don’t just spontaneously fall asleep at an inopportune moment, even if you are very tired.


      REM-NREM Sleep

      Sleep is divided into two main phases - non-rapid eye movement sleep (NREM) and rapid eye movement (REM) sleep. During the night you cycle repeatedly between NREM and REM sleep at regular intervals.

      NREM Sleep

      NREM sleep is the type of sleep which is associated with slow rolling eye movements. There are several sub-stages of NREM sleep but one of the most important stages is usually considered to be deep sleep, or slow wave sleep (stage 3-4) where the brain waves are oscillating at a low (~1-4Hz) frequency. 

      This is thought to be the one of the main stages of sleep where all the events and activities of the waking day are consolidated into your memory to ensure that they can be properly remembered at a later date. The stages of NREM sleep also contain their own characteristic patterns of neural activity, for example, K-complexes and sleep spindles.

      The Neurochemistry of NREM Sleep

      GABA / Galanin

      Sleep is associated with activation of the preoptic area which predominantly uses the neurotransmitter GABA and the neuropeptide galanin as it’s chemical messengers. NREM sleep is therefore predominantly associated with these two neurochemicals.


      During NREM sleep, one of the actions of serotonin is to inhibit acetylcholine signals which predominantly support REM sleep. In this sense, serotonin helps to regulate the onset of REM sleep during the night.

      REM Sleep

      Traditionally REM sleep has been associated with dreaming, although some forms of dreaming do also take place in NREM sleep. REM sleep is exemplified, not only by rapid eye movements but also by a form of movement paralysis - something that you can sometimes consciously experience if woken suddenly from a dream.

      During REM sleep, some of the brain systems which are more typically associated with being an awake state of mind become active. One particular region of your brain stem - the Pons - is particularly important in generating REM sleep and contains so called “REM-on” cells.

      The Neurochemistry of REM Sleep


      The main neurochemical which is released from these “REM-on” cells in the pons is the neurotransmitter acetylcholine. Activation of these acetylcholine cells creates a particular oscillating pattern of electrical activity - so called PGO waves - abbreviated from Ponto-Geniculo-Occipital.

      These waves pass from your pons through to areas of your brain which are involved in visual processing (your occipital cortex) and help to create the vivid imaginary world which plays out inside your dreams.


      Waking Up

      Within and surrounding your brainstem, there is a set of regions (called nuclei) which collectively form your “ascending reticular activating system”, or ARAS for short. This forms a significant chunk of your brain’s “wake system”. 

      During sleep, your ARAS system is being inhibited by sleep promoting regions in the brain, predominantly your preoptic area. Waking occurs when this inhibition is weakened, which allows the ARAS to start “firing” again. Activation of the various chemical nuclei within the ARAS also initiates a widespread network of brain signals which arouse your body and brain into a state of wakefulness.

      The Neurochemistry of Waking Up

      There are a variety of “wake-promoting” chemicals which act to coordinate the process of waking up. These include Orexin/Hypocretin, as well as corticotrophin-releasing factor and adrenocorticotrophic hormone. 

      These two latter chemicals form part of a physiological axis within your body (called the hypothalamo-pituitary adrenal axis, HPA) which is more commonly associated with your stress response, but also plays an important role in waking, and gearing you up for the day ahead.

      When the ARAS is active, it not only keeps you awake, it also inhibits your brain’s “sleep promoting” regions, such as the preoptic area. Neurons sent out from the ARAS and other wake promoting regions, carry neurochemicals such as norepinephrine, acetylcholine, serotonin and histamine. These have an inhibitory effect on the preoptic area, stopping you from falling asleep during the day.

      Orexin / Hypocretin

      Orexin/Hypocretin, is found in cells within a particular subregion of the hypothalamus. Orexin/Hypocretin works by switching on the various neurochemical nuclei in the ARAS, effectively “waking them up”.

      This includes nuclei which release neurochemicals such as serotonin, norepinephrine, histamine, acetylcholine as well as dopamine (from the ventral tegmental area) which together form large-scale neuronal networks which extend throughout the brain to support your daily waking behaviours.


      In addition to its role in REM sleep, the neurotransmitter Acetylcholine (ACh) also plays an important role in the process of waking you up and keeping you awake, as activation of ACh cells generates “fast brain waves” which are a hallmark of being in an awake state (as opposed to the slower waves associated with NREM/deep sleep) and which help to support multiple functions including attention, memory, sensory processing.


      Norepinephrine is one of your brain’s “ready for action” chemical. In that way it increases your brain’s level of arousal and helps contribute to your state of wakefulness throughout the day.


      Serotonin is an important chemical in supporting the process of waking you up and some wake-promoting serotonin cells are themselves sensitive to light.

      The role of serotonin in wakefulness can be seen in people who take selective serotonin reuptake inhibitors (SSRIs) - which act to elongate the duration of serotonin action in their synapses - and who have problems sleeping.

      Activation of serotonin cells also leads to the activation of other wake-promoting cells to reinforce the process of staying awake throughout the day. Serotonin is also involved in regulating your body temperature and is involved in the mechanisms by which being cold wakes you up.


      Histamine, released from a subregion of the hypothalamus called the tuberomammillary nucleus is critically involved in regulating wakefulness and in sustaining a state of brain arousal during the day, something that has been known since the discovery of the sedative effect of antihistamine drugs.

      This is in part due to the fact that histamine-containing-cells work together with cells containing acetylcholine and orexin/hypocretin which together have widespread wake-promoting effects in the brain.


      Although not specifically part of the reticular activating system, dopamine, released from various midbrain nuclei such as the ventral tegmental area, also plays an important role in waking up and keeping you awake during the day.

      In particular, its role in wakefulness is thought to be linked to the way that dopamine motivates you to take action and seek out rewards, something that necessitates being an wakeful and active state of mind.