Explanation of Neurotransmitters

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Medications for insomnia and hypersomnia usually act on neural systems and affect, in some manner, neurotransmitters. Sleep aids tend to work on the GABA receptors in the brain, or melatonin receptors. Stimulants usually work on dopamine or acetylcholine systems.

This website covers all aspects of sleep; neurotransmitters are involved in sleep, waking, and the transitions between them. Brain chemistry is very complicated and scientists don’t totally understand how all the pieces fit together. Here we give a short description of major neurotransmitters.

Neurons (commonly called nerves) are a specific type of cell found in the body and the brain that carries electrical information. Their job is to receive a signal from a cell, convert it to an electric signal called an action potential and transmit this electric signal to another cell that could also be another neuron. When they need to communicate to another cell or neuron, the first neuron sends a chemical called a neurotransmitter across the space between the two, over to the next cell. Once at the second cell, the neurotransmitter binds to a receptor, telling the second cell what to do or telling another neuron if to send a signal and whether it should be a strong or a weak signal.

Among other things, neurotransmitters are responsible for spinal reflexes and sleep regulation. There are currently conflicting classifications of which chemicals in the brain are considered to be neurotransmitters. Following are neurotransmitters of interest to sleep researchers and that scientists agree are actually neurotransmitters.

GABA (gamma aminobuytric acid) is an amino acid derivative that acts as an inhibitory neurotransmitter, preventing or reducing certain nerve signals. It controls nervous signals in the retina and the central nervous system, so insufficient GABA usually causes anxiety and even epileptic seizures. Drugs can temporarily increase GABA levels and in turn reduce anxiety, and offer anti-convulsive effects. Some medicinal and recreational drugs reduce the natural level of GABA; these include alcohol, barbiturates and cannabinoids. The drugs that reduce GABA combined with serotonin depletion can cause depression which keeps addicts in the cycle of addiction. Patients with spastic cerebral palsy have damaged nerves in the central nervous system that cannot properly absorb GABA, affecting motor or muscular skills.

GABA is not found in any significant amounts outside the brain. Indeed, GABA is pretty much unique to the central nervous system of mammals. Many sedatives and hypnotics are GABA agonists.

Glutamic acid, also known as glutamate, is an amino acid and is the most common neurotransmitter in the body. 80% of the brain’s neurons release glutamate. Glutamate’s most vital function as a neurotransmitter is in cognitive activities like memory and learning. Scientists have pointed the finger at glutamic acid as being involved in epileptic seizures, probably since glutamate can also be a precursor for the synthesis of GABA.

Glutamate is involved arousal and anesthetic drugs seem to work at least partly by reducing neurotransmission normally regulated by glutamate. Lower-than-normal levels of oxygen in the blood – such as apnea causes – stimulates production of glutamate.

Acetylcholine was the first neurotransmitter to be discovered by scientists and its major function is in the voluntary movement of muscles, although it also has many other functions. It is involved in the scheduling of REM sleep. The onset of Alzheimer’s disease happens when some regions of the brain have depleted acetylcholine. Neurons that interact with acetylcholine are found in plenty in the pons (above the medulla) and in the basal forebrain. The preoptic area and anterior hypothalamus (together sometimes called POAH) are important in both REM and in regulation of the body’s temperature during sleep. It is also to make the causal direction go the other way – by manipulating the POAH it is possible to include insomnia or sleepiness, and if the POAH is artificially warmed, the brain is induced to go into deep sleep.

The temperature of both the brain and the body fall during NREM sleep.  The longer the NREM-sleep episode, the more the temperature falls. By contrast, brain temperature increases during REM sleep.

Norepinephrine is the neurotransmitter most involved in the “fight or flight” response and other stressful situations, since it increases heart rate and blood pressure. A catecholamine, It is intertwined with arousal, wakefulness, attentiveness, sleep and it is also involved in the formation of memories. Studies have shown that elevated norepinephrine levels are implicated in symptoms in some mood disorders. Neurons in the locus coeruleus in the bottom of the brain stem respond to norepinephrine. When these neurons are stimulated, the cortical area of the brain becomes more active. Norepinephrine is therefore thought to be instrumental in causing people to wake up. Indeed, the level of this neurotransmitter in the brain seems to rise in response to new stimuli. The concept of vigilance is tied up with norepinephrine although scientists don’t understand how.

Now when a person is in REM sleep, the cortex is aroused, but the levels of norepinephrine do not rise, in contrast to what happens during waking. Actually, the levels are at their lowest during REM and drugs that mimic norepinephrine affect sleep architecture by shortening the REM sleep period. Norepinephrine antagonists make the period longer.

Dopamine is another inhibitory neurotransmitter involved in voluntary movement and motivation. Sometimes called the “salience chemical” dopamine plays important roles in pleasure and subjective feelings of happiness. Alcohol, nicotine and some recreational drugs increase the level of dopamine. Schizophrenia is linked to elevated levels of dopamine in the frontal lobes of the brain. Conversely, low levels of dopamine in the motor areas of the brain are implicated in Parkinson’s disease, causing muscle rigidity and uncontrollable muscle tremors. Animal models of Parkinson’s disease and schizophrenia have found that dopamine plays an important role in regulating sleep. Mice altered to have high dopamine levels in their brains are more sensitive than normal to caffeine and modafinil and have a stronger recovery reaction to sleep deprivation: following prolonged wakefulness they have move slow-wave sleep and total sleep than other mice.

Serotonin is involved in several important body functions such as memory, emotions, moods, appetite and thermoregulation, so it comes as no surprise the neurotransmitter is important in regulating sleep and waking also. It makes people feel contented and safe. Serotonin deficiencies have been linked to depression, anger, OCD, sleep disturbances, irritable bowel syndrome and many other emotional and physical disturbances. Serotonin is involved in arousal and keeping the higher brain functions operating during waking.

Does serotonin make one more sleepy or more awake?  Seemingly both. But given we need to sleep sometimes and to be awake at times, maybe more serotonin is generally a good thing.  Scientists have found that serotonin directly promotes wakefulness and also promotes the formation of sleep-promoting brain factors, perhaps as part of an evolutionary negative feedback look.  Orexinergic wake-promoting neurons also stimulate serotonergic neurons.

Experiments on animals that artificially increase levels of 5-Hydroxytryptophan (a biochemical precursor for both serotonin and melatonin) increase wakefulness immediately, followed by an increase in non-REM sleep.  Serotonergic neurons inhibit sleep-promoting neurons and when serotonin levels increase, REM time decreases. In normal brain function, the release of serotonin is highest during wakefulness and has been found to decrease during NREM sleep. It slows significantly during REM sleep, which is interesting given the possible connection between REM sleep and depression. (Antidepressant drugs seem to suppress REM.)

Steroids also participate in sleep regulation. Cortisol increases propensity to REM sleep and estrogen supplements appear to help post-menopausal women sleep, although this may be due to an indirect mechanism. Growth hormone-releasing hormone (GHRH) and corticotropin-releasing hormone also play parts in sleep regulation.

Orexin (Hypocretin) refers to several brain chemicals. They are excitatory neuropeptides that promote waking and suppress sleep. The perifornical hypothalamic area of the brain is rich in neurons that have orexin receptors. Animal tests involving orexin injections into the pontine reticular formation produced an increase in wakefulness and an increase in GABA levels. Narcoleptics have fewer orexin neurons. More on orexins.

Adenosine is produced by the body as a normal product of metabolism. We produce more when awake and active than when sleeping. Adenosine plays a part in the sleep homeostatic process as it inhibits wake-promoting neurons. These neurons are in the basal forebrain, and damage or changes to these neurons seems to play a part in the development of Alzheimer’s Disease. Caffeine seems to work by affecting adenosine.

Melanin is a common pigment in the body (it’s what makes tanned skin darker, among other things).  It is not the same as melatonin, although both are amino-acid derivatives, and melatonin was discovered by a dermatologist investigating skin pigmentation. Melanin-concentrating hormone is a cyclic neuropeptide that influences the distribution of melanin in the body.

Like melatonin, melanin-concentrating hormone (MCH) is also produced by the pituitary and is part of the weight (and maybe sleep) homeostatic processes.  Scientists have identified two receptors in the body that are activated by the hormone, and there has been interest in developing antagonists to treat obesity and mental health problems. (Too much MCH is correlated with obesity.) Detailed investigation has found MCH increases water intake and sugar intake

Recent research has suggested MCH plays a part in the complex sleep regulation system. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080035/) The receptor cells are spread throughout the central nervous system.  More research is required to figure this all out, but given the close association between appetite and sleep regulation, it would not be surprising if MCH plays a part in sleep.

Arousal and Sedation

Acetylcholine, dopamine, glutamate, histamine, norepinephrine, orexin, and serotonin are all active in promoting wakefulness. Some neurons (brain cells) specialize in releasing certain neurotransmitters and scientists have found the firing rates of those neurons can vary with wakefulness and sleep. Glutamate and histamine neuron firing rates are high during wakefulness and low during sleep

Orexin neurons have high firing rates during waking, especially during movement. They release orexins during quiet waking and are the lowest during sleep. Cholinergic cells (neurons that release acetylcholine) are more active during waking. Dopamine release does not seem to vary with waking or sleeping. and serotonin, which is important in promoting both wakefulness and sleepiness is a more complex story. Certain serotonergic neurons fire more during waking while others show different patterns.

Adenosine builds up over the course of the waking period, as it is a byproduct of metabolism. Its concentration variation can be a proxy for the homeostatic sleep drive.

The neurons in the median preoptic nucleus of the hypothalamus and the ventrolateral preoptic area of the hypothalamus (VLPO) release GABA at command of the suprachiasmatic nuclease when it is time to sleep. The immune system is also activated by lack of sleep and cytokines essentially function as sleep promoters in the brain. Melatonin, varying in concentration with the circadian cycle, promotes sleep.

Further study of neurotransmitters and how they work will likely lead to treatments of nervous system disorders, depression and possibly even diseases like Alzheimer’s. Research on neurotransmitters is illuminating the causes of and possible treatments for chemical addictions. There are probably neurotransmitters involved in sleep that are yet undiscovered.

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