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Under a Creative Commons license Open access Highlights• LC-NE system is involved in motivation and cognition in humans. •This system participates in mechanisms of stress response. •LC-NE system may be connected to the cognitive and motivational deficits of SCZ. •A combination of methodological approaches is proposed to answer open questions.
AbstractSeveral lines of evidence have suggested for decades a role for norepinephrine (NE) in the pathophysiology and treatment of schizophrenia. Recent experimental findings reveal anatomical and physiological properties of the locus coeruleus-norepinephrine (LC-NE) system and its involvement in brain function and cognition. Here, we integrate these two lines of evidence. First, we review the functional and structural properties of the LC-NE system and its impact on functional brain networks, cognition, and stress, with special emphasis on recent experimental and theoretical advances. Subsequently, we present an update about the role of LC-associated functions for the pathophysiology of schizophrenia, focusing on the cognitive and motivational deficits. We propose that schizophrenia phenomenology, in particular cognitive symptoms, may be explained by an abnormal interaction between genetic susceptibility and stress-initiated LC-NE dysfunction. This in turn, leads to imbalance between LC activity modes, dysfunctional regulation of brain network integration and neural gain, and deficits in cognitive functions. Finally, we suggest how recent development of experimental approaches can be used to characterize LC function in schizophrenia. KeywordsSchizophrenia Locus coeruleus Norepinephrine Dopamine Cognition Cited by (0)© 2020 The Author(s). Published by Elsevier Ltd. Serotonin acts as a neurotransmitter, a type of chemical that helps relay signals from one area of the brain to another. Although serotonin is manufactured in the
brain, where it performs its primary functions, some 90% of our serotonin supply is found in the digestive tract and in blood platelets. Serotonin is made via a unique
biochemical conversion process. It begins with tryptophan, a building block to proteins. Cells that make serotonin use tryptophan hydroxylase, a chemical reactor which, when combined with tryptophan, forms 5-hydroxytryptamine, otherwise known as serotonin. As a neurotransmitter, serotonin helps to relay messages from one area of the
brain to another. Because of the widespread distribution of its cells, it is believed to influence a variety of psychological and other body functions. Of the approximately 40 million brain cells, most are influenced either directly or indirectly by serotonin. This includes brain
cells related to mood, sexual desire and function, appetite, sleep, memory and learning, temperature regulation, and some social behavior. In terms of our body function, serotonin can also affect the functioning of our cardiovascular system, muscles, and various elements in the endocrine system. Researchers have also found evidence that serotonin may play a role in regulating milk production in the
breast, and that a defect within the serotonin network may be one underlying cause of SIDS (sudden infant death syndrome). There are many researchers who believe that an imbalance in serotonin levels may influence mood in a way that leads to depression. Possible problems
include low brain cell production of serotonin, a lack of receptor sites able to receive the serotonin that is made, inability of serotonin to reach the receptor sites, or a shortage in tryptophan, the chemical from which serotonin is made. If any of these biochemical glitches occur, researchers believe it can lead to depression, as well as obsessive-compulsive
disorder, anxiety, panic, and even excess anger. One theory about how depression develops centers on the regeneration of brain cells -- a process that some believe is mediated by serotonin, and ongoing throughout our lives. According to
Princeton neuroscientist Barry Jacobs, PhD, depression may occur when there is a suppression of new brain cells and that stress is the most important precipitator of depression. He believes that common antidepressant
medications known as SSRIs, which are designed to boost serotonin levels, help kick off the production of new brain cells, which in turn allows the depression to lift. Although it is widely believed that a serotonin deficiency plays a role in depression, there is no way to measure its levels in the living brain. Therefore, there have not been
any studies proving that brain levels of this or any neurotransmitter are in short supply when depression or any mental illness develops. Blood levels of serotonin are measurable -- and have been shown to be lower in people who suffer from depression - but researchers don't know if blood levels reflect the brain's level of serotonin. Also, researchers don't know whether the
dip in serotonin causes the depression, or the depression causes serotonin levels to drop. Antidepressant medications that work on serotonin levels -- SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin and
norepinephrine reuptake inhibitors) -- are believed to reduce symptoms of depression, but exactly how they work is not fully understood. It can, but in a roundabout way. Unlike
calcium-rich foods, which can directly increase your blood levels of this mineral, there are no foods that can directly increase your body's supply of serotonin. That said, there are foods and some nutrients that can increase levels of tryptophan, the amino acid from which serotonin is made. Protein-rich foods, such as meat or chicken, contain high
levels of tryptophans. Tryptophan appears in dairy foods, nuts, and fowl. Ironically, however, levels of both tryptophan and serotonin drop after eating a meal packed with protein. Why? According to nutritionist Elizabeth Somer, when you eat a high-protein meal, you "flood the blood with both tryptophan and its competing amino acids," all fighting for entry into the brain. That means only a small amount of tryptophan gets through -- and serotonin levels don't rise. But eat a
carbohydrate-rich meal, and your body triggers a release of insulin. This, Somer says, causes any amino acids in the blood to be absorbed into the body -- but not the brain. Except for, you guessed it -- tryptophan! It remains in the bloodstream at high levels following a carbohydrate meal, which means it can freely enter the brain and cause serotonin levels to rise, she says. What can also help: Getting an adequate supply of vitamin B-6, which can influence the rate at which tryptophan is
converted to serotonin. Exercise can do a lot to improve your mood -- and across the board, studies have shown that regular exercise can be as effective a treatment for depression as antidepressant medication or
psychotherapy. In the past, it was believed that several weeks of working out was necessary to see the effects on depression, but new research conducted at the University of Texas at Austin found that just a single 40-minute period of exercise can have an immediate effect on mood. That said, it remains unclear of the exact mechanism by which exercise
accomplishes this. While some believe it affects serotonin levels, to date there are no definitive studies showing that this is the case. 7. Do men and women have the same amount of serotonin -- and does it act the same way in their brain and body?Studies show that men do have slightly more serotonin than women, but the difference is thought to be negligible. Interestingly, however, a study published in September 2007 in the journal Biological Psychiatry showed there might be a huge difference in how men and women react to a reduction in serotonin -- and that may be one reason why women suffer from depression far more than men. Using a technique called "tryptophan depletion," which reduces serotonin levels in the brain, researchers found that men became impulsive but not necessarily depressed. Women, on the other hand, experienced a marked drop in mood and became more cautious, an emotional response commonly associated with depression. While the serotonin processing system seems the same in both sexes, researchers now believe men and women may use serotonin differently. Although studies are still in their infancy, researchers say defining these differences may be the beginning of learning why more women than men experience anxiety and mood disorders, while more men experience alcoholism, ADHD, and impulse control disorders. There is also some evidence that female hormones may also interact with serotonin to cause some symptoms to occur or worsen during the premenstrual time, during the postpartum period, or around the time of menopause. Not coincidentally, these are all periods when sex hormones are in flux. Men, on the other hand, generally experience a steady level of sex hormones until middle age, when the decline is gradual. In much the same way that we lose bone mass as we age, some researchers believe that the activity of neurotransmitters also slows down as part of the aging process. In one international study published in 2006, doctors from several research centers around the world noted a serotonin deficiency in brains of deceased Alzheimer's patients. They hypothesized that the deficiency was because of a reduction in receptor sites -- cells
capable of receiving transmissions of serotonin -- and that this in turn may be responsible for at least some of the memory-related symptoms of Alzheimer's disease. There is no evidence to show that increasing levels of serotonin will prevent
Alzheimer's disease or delay the onset or progression of dementia. However, as research into this area continues, this could also change. SSRI antidepressants are generally considered safe. However, a rare side effect of SSRIs called
serotonin syndrome can occur when levels of this neurochemical in the brain rise too high. It happens most often when two or more drugs that affect serotonin levels are used simultaneously. For example, if you are taking a category of
migraine medicines called triptans, at the same time you are taking an SSRI drug for depression, the end result can be a serotonin overload. The same can occur when you take SSRI supplements, such as St. John's wort. Problems are most likely to occur when you first start a medication or increase the dosage. Problems can also occur if you combine the older depression medications (known as MAOIs) with SSRIs. Finally, recreational drugs such as ecstasy or LSD have also been linked to serotonin syndrome. Symptoms can occur within minutes to hours and generally
include restlessness, hallucinations, rapid heartbeat, increased body temperature and sweating, loss of coordination, muscle
spasms, nausea, vomiting, diarrhea, and rapid changes in
blood pressure. Although not a common occurrence, it can be dangerous and is considered a medical emergency. Treatment consists of drug withdrawal, IV fluids, muscle relaxers, and drugs to block serotonin production. Which disorder is associated with having too few serotonin and norepinephrine?Researchers have linked serotonin deficiency with depression and potentially a wide range of other conditions. Drugs that boost serotonin levels or activity, such as selective serotonin reuptake inhibitors (SSRIs), can help manage depression and anxiety, as well as migraine and some other conditions.
What is the main difference between generalized anxiety disorder and phobic disorder?While phobias are focused on a specific object or situation, generalized anxiety disorder is much more broadly based. Those with generalized anxiety disorder worry excessively over a variety of day to day situations.
Which neurotransmitters are most important in the development of mood disorders?Neurotransmitters that play an important function in mood disorders are serotonin and norepinephrine, which are decreased in episodes of depression. Serotonin is the neurotransmitter most commonly associated with depression.
Which of the following neurotransmitters plays a major role in depression?Noradrenaline is one of the neurotransmitters that plays a role in mood changes. If the level of noradrenaline is low for some reason, then the signal-sending activity becomes low, and the person suffers from depression.
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