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553 lines
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<h1></h1>
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<p>
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<strong>Serotonin, depression, and aggression</strong>: <strong>The problem of brain energy</strong>
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</p>
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<p>
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Extremely serious mistakes about the nature of the solar system didn't matter too much until interplanetary
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travel became a possibility. Extremely serious mistakes about brain "transmitters" and "receptors" didn't
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matter too much until the drug industry got involved.
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</p>
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<hr />
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<p>
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"Three years before Prozac received approval by the US Food and Drug Administration in late 1987, the German
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BGA, that country's FDA equivalent, had such serious reservations about Prozac's safety that it refused to
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approve the antidepressant based on Lilly's studies showing that previously nonsuicidal patients who took
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the drug had a fivefold higher rate of suicides and suicide attempts than those on older antidepressants,
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and a threefold higher rate than those taking placebos."
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</p>
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<p>
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"Using figures on Prozac both from Lilly and independent research, however, Dr. David Healy, an expert on
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the brain's serotonin system and director of the North Wales Department of Psychological Medicine at the
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University of Wales, estimated that "probably 50,000 people have committed suicide on Prozac since its
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launch, over and above the number who would have done so if left untreated."
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</p>
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<p>The Boston Globe, 2000.</p>
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<hr />
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<p>
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Anyone who has been reading the mass media and watching television in recent decades is familiar with the
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use of tryptophan as an antidepressant. Tryptophan is easily converted to serotonin and melatonin in the
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body. The most popular kind of antidepressant, the "serotonin reuptake inhibitor", is said to act by
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increasing the action of serotonin in the brain. Many people have read articles in popular science magazines
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explaining that a deficiency of serotonin can cause depression, suicide, and aggression. Estrogen is often
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said to achieve its "wonderful" effects by increasing the effects of serotonin.
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</p>
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<p>
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Reserpine is an ancient tranquilizer, derived from a plant used in India for centuries. It has a powerful
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tranquilizing action, has been used to treat hypertension, and was found to be an antidepressant (Davies and
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Shepherd, 1955). It lowers the concentration of serotonin in the brain and other tissues. Isoniazid, an
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antidepressant that came into use in the 1950s, is effective, but it probably has no effect on serotonin.
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When those drugs were popular, serotonin wasn"t recognized as a "neurotransmitter." It wasn"t until the
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1960s that our present set of doctrines regarding serotonin"s effects on mood and behavior came into being.
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</p>
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<p>
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Serotonin research is relatively new, but it rivals estrogen research for the level of incompetence and
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apparent fraudulent intent that can be found in professional publications.
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</p>
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<p>
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This is partly because of the involvement of the drug industry, but the U.S. government also played a role
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in setting a pattern of confused and perverse interpretation of serotonin physiology, by its policy of
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denigrating and incriminating LSD, a powerful serotonin (approximate) antagonist, by any means possible, for
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example claiming that it causes genetic damage and provokes homicidal or suicidal violence. The issue of
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genetic damage was already disproved in the 1960s, but this was never publicly acknowledged by the National
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Institutes of Mental Health or other government agency. The government"s irresponsible actions helped to
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create the drug culture, in which health warnings about drugs were widely disregarded, because the
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government had been caught in blatant fraud. In more recent years, government warnings about tryptophan
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supplements have been widely dismissed, because the government has so often lied. Even when the public
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health agencies try to do something right, they fail, because they have done so much wrong.
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</p>
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<p>
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In animal studies LSD, and other anti-serotonin agents, increase playfulness and accelerate learning, and
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cause behavioral impairment only at very high doses. While reserpine was used medically for several decades,
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and was eventually found to have harmful side effects, medical research in LSD was stopped before its actual
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side effects could be discovered. The misrepresentations about LSD, as a powerful antiserotonin agent,
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allowed a set of cultural stereotypes about serotonin to be established. Misconceptions about serotonin and
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melatonin and tryptophan, which are metabolically interrelated, have persisted, and it seems that the drug
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industry has exploited these mistakes to promote the "new generation" of psychoactive drugs as activators of
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serotonin responses. If LSD makes people go berserk, as the government claimed, then a product to amplify
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the effects of serotonin should make people sane.
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</p>
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<p>
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The "serotonin reuptake inhibitors" are called the "third generation" of antidepressants. The monoamine
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oxidase (MAO) inhibitors, that came into use in the 1950s, are called the "first generation." When their
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patents expire on a "generation" of drugs, the drug companies find reasons for claiming that the new drugs
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are better. Every doctor in the country seems to know that the old MAO-inhibitors are dangerous because they
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can raise blood pressure if you eat certain kinds of cheese while taking them. <strong>In fact, statistics
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show that they are safer than the new generation of antidepressants.</strong> It is hardly possible for
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a physician to prescribe the most appropriate drug, because the medical licensing boards are thoroughly
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indoctrinated by the drug companies, to believe that the safest and most effective drugs are those whose
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patents are still in force.
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</p>
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<p>
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While it is true that the newer antidepressants increase the actions of serotonin, it is not true that this
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explains their antidepressant action. This is a culturally conditioned promotional construction. Since
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different antidepressants increase, decrease, or don"t affect the actions of serotonin, a radically new kind
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of theory of depression and the antidepressants is needed. Theories based on "transmitter" substances and
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"receptors" are favored by the drug industry, but that kind of thinking is hardly better than the belief in
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demons and their exorcism. If an herbal tea cures depression because the demon doesn"t like its smell, at
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least the patient never has to abandon a remedy because a tea patent has expired.
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</p>
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<p>
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In the world of "neurotransmitters" and "receptors," there is ample room for the development of speculative
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mechanisms of drug action. Serotonin is regulated by the rate of its synthesis and degradation, by its
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uptake, storage, and release, and by its transporters, and its effects are modified by a great variety of
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receptors, by the number of these receptors, and by their binding affinities and competitive binders.
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"Different receptors" are defined by the effects of chemicals other than serotonin; this means that
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serotonin itself hypothetically gains some of the properties of every substance that shows some binding
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competition with serotonin. This complexity*note 1 has made it possible to argue that a given condition is
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caused by either an excess or a deficiency of serotonin.
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</p>
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<p>
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The drug companies like to call some of their new products SSRI, "selective serotonin reuptake inhibitors,"
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meaning that they don"t indiscriminately increase all the biogenic amines, the way the old MAO inhibitors
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supposedly did. Every drug does many things, each a little differently, so it"s technically true to say that
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they "selectively" do this or that. But the term "antidepressant," as distinguished from "tranquilizer,"
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says that the drug is intended to relieve depression. Injecting serotonin never does that, but sometimes
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adrenalin or dopamine does, and these "SSRI" drugs increase the activities of those other amines enough that
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those changes could explain the altered mood, if it weren"t for the need to speak of a "new generation of
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drugs." Injecting serotonin, or increasing its activity, can cause sedation, helplessness, or apathy, but
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these drugs have that effect only some of the time. Therefore, they aren"t called tranquilizers. If they
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were really selective for serotonin, they just wouldn"t be antidepressants. And chemicals that antagonize
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serotonin do seem to function as antidepressants (Martin, et al., 1992). When an SSRI is used to treat
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irritability and aggression, it is appropriate to call it a tranquilizer. When drugs are used empirically,
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without really understanding the disease or the drug, classifications, descriptions, and names are
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subjective. The serotonin situation reminds me of the history of DES: For almost twenty years, this
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synthetic estrogen was marketed for the prevention of abortions; then it came out as the "morning after"
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contraception/abortion pill. "If increasing serotonin isn"t the cure, then maybe decreasing serotonin will
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be the cure."
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</p>
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<p>
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To begin to understand serotonin, it"s necessary to step back from the culture of neurotransmitters, and to
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look at the larger biological picture.
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</p>
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<p>
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Serotonin and estrogen have many systematically interrelated functions, and women are much more likely to
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suffer from depression than men are. Serotonin and histamine are increased by estrogen, and their activation
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mimics the effects of estrogen. Serotonin is closely involved in mood disorders, but also in a great variety
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of other problems that affect women much more frequently than men. These are probably primarily energy
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disorders, relating to cellular respiration and thyroid function. Liver disease and brain disease, e.g.,
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Alzheimer"s disease, are both much more common in women than in men, and serotonin and estrogen strongly
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affect the energetic processes in these organs. Liver disease can increase the brain"s exposure to
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serotonin, ammonia, and histamine. It isn"t just a coincidence that these three amines occur together and
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are neurotoxic; they are all stress-related substances, with natural roles in signaling and regulation.
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</p>
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<p>
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There are good reasons for thinking that serotonin contributes to the nerve damage seen in multiple
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sclerosis and Alzheimer"s disease.
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</p>
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<p>
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The high incidence of multiple sclerosis in women, and its onset during their reproductive years, is well
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known. The number of brain lesions is associated with the ratio of estrogen to progesterone. Estrogen
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activates mast cells to release histamine and serotonin, and activated mast cells can produce brain edema
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and demyelination. Blood clots have been microscopically associated with brain lesions like those in
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multiple sclerosis, and the platelets in clots release neurotoxic serotonin.
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</p>
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<p>
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In Parkinson"s disease, the benefits seen from increasing the concentration of dopamine could result from
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dopamine"s antagonism to serotonin; anti-serotonin drugs can alleviate the symptoms, and 5-hydroxytryptophan
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can worsen the symptoms (Chase, et al., 1976). Other movement disorders, including akathisia and chorea, can
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be produced by serotonin. In autism, repetitive motions are a common symptom, and serotonin is high in the
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blood serum and platelets of autistic children and their relatives. Irritable bowel syndrome, another kind
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of "movement disorder," can be treated effectively with anti-serotonin agents. This syndrome is very common
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in women, with premenstrual exacerbations, when estrogen is highest. One of the side effects of oral
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contraceptives is chorea, uncontrollable dancing movements. Some research has found increased serotonin in
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people with Huntington"s chorea (Kish, et al., 1987), and positive results with bromocriptine have been
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reported (Agnoli, et al., 1977).
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</p>
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<p>
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The neurosteroid, allopregnanolone, for which progesterone is the precursor, facilitates the inhibitory
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action of GABA, which is known to be deficient in some disorders of mood and movement. This suggests that
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progesterone will be therapeutic in the movement disorders, as it is in various mood problems. Progesterone
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has some specific antiserotonin actions (e.g., Wu, et al., 2000).
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</p>
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<p>
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The "serotonin reuptake inhibitors" "are presumed" to have the same effect on the brain that they have on
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blood platelets. They inhibit the ability of platelets to retain and concentrate serotonin, allowing it to
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stay in the plasma. This uptake-inhibited condition is a model of the platelet behavior seen in multiple
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sclerosis and Alzheimer"s disease.
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</p>
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<p>
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Serotonin and its derivative, melatonin, are both involved in the biology of torpor and hibernation.
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Serotonin inhibits mitochondrial respiration. Excitoxic death of nerve cells involves both the limitation of
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energy production, and increased cellular activation. Serotonin has both of these actions.
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</p>
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<p>
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In hibernating animals, the stress of a declining food supply causes increased serotonin production. In
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humans and animals that don"t hibernate, the stress of winter causes very similar changes. Serotonin lowers
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temperature by decreasing the metabolic rate. Tryptophan and melatonin are also hypothermic. In the winter,
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more thyroid is needed to maintain a normal rate of metabolism.
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</p>
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<p>
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Increased serotonin interferes with the consolidation of learning. Hypothermia has a similar effect. Since
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estrogen increases serotonergia, and decreases body temperature, these effects help to explain the
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long-observed interference of estrogen with learning.
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</p>
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<p>
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Although ammonia, produced by fatigue or liver inefficiency, creates torpor, it can also cause convulsions.
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It synergizes with serotonin, and both of these promote excitotoxicity.
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</p>
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<p>
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Serotonin"s other names include thrombotonin, thrombocytin, enteramine, and 5-HT, its chemical name
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(5-hydroxytryptamine). These historical names derive from its role in the intestine and in blood vessels. In
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1951, it was discovered that enteramine and thrombotonin were a single substance, and its involvement in
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circulatory disease, especially hypertension and vascular spasms, was the focus of research. (The increase
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in the number of "cardiovascular events" recently seen in the study of women using estrogen is what might be
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expected from something which increases serotonin dominance.) It causes vasoconstriction and vasospasm, and
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promotes clotting, when it"s released from platelets. Especially when it is released from mast cells, it is
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considered to be an inflammatory mediator, along with histamine. Edema, bronchoconstriction,
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immunosuppression, and joint swelling are produced by the release of serotonin from platelets or other
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cells. As inflammatory mediators, serotonin and histamine are directly involved in asthma, hives,
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gastrointestinal damage from alcohol, nerve cell damage, edema, and shock.
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</p>
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<p>
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The broadly protective effects of antihistamine drugs have been energetically exploited by the drug industry
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for fifty years. Why haven"t antiserotonin drugs been similarly emphasized?
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</p>
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<p>
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Research on LSD and its derivatives led to drugs such as bromocriptine, which oppose the effects of
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histamine and estrogen. Some of bromocriptine"s effects are clearly antagonistic to serotonin, though
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bromocriptine is usually called a "dopamine agonist"; dopamine is pretty generally a serotonin antagonist.
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Methysergide, a related drug with antiserotonin activity, is effective in protecting the brain from the
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effects of strokes. But there is a general disinclination to understand the broad biological meaning of
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these effects.
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</p>
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<p>
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I think the corrupt campaign against LSD played a large role in this: If the therapeutic value of LSD and
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related drugs (e.g., methysergide) with expired patents,*note2 used as antiserotonin agents, became widely
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known, the existing system of power and profit would be threatened. The war on drugs has always had its
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ulterior motives,including justifying domestic and foreign interventions in issues that have nothing to do
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with drugs. And in the case of the serotonin/antiserotonin mythology, this "war" has been rewarding to the
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drug industry--Lilly makes over $2 billion annually on Prozac. Each suicide caused by Prozac would appear to
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be balanced by several hundred thousand dollars earned by the corporation. If the war on drugs were serious,
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this would be a good place to start. And in weighing what corporate punishments might be appropriate, this
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corporation"s financial support for universal capital punishment should be taken into account. Many
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experiments have shown that estrogen is very important for aggressive behavior in animals, and estrogen
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promotes serotonin"s actions. Some research shows that increased serotonin is associated with certain types
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of increased aggressiveness, and antiserotonin agents decrease aggresiveness (Ieni, et al., 1985; McMillen,
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et al., 1987) but the clearest research has to do with the crucial role of serotonin in learned
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helplessness. Learned helplessness is a biological condition that is created by inescapable stress. In this
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state, animals that would normally swim for hours will stop swimming after a few minutes and allow
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themselves to drown. They simply don"t have enough mental or physical energy to overcome challenges.
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</p>
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<p>
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In learned helplessness, the level of serotonin is high, and an excess of serotonin helps to create the
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state of learned helplessness.
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</p>
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<p>
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Serotonin activates glycolysis, forming lactic acid. Excess lactic acid tends to decrease efficient energy
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production by interfering with mitochondrial respiration.
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</p>
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<p>
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Heart failure, hypertension, muscle hyperalgesia (Babenko, et al., 2000), some panic reactions, and other
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maladaptive biological events associated with problems of energy metabolism, are promoted by excessive
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serotonin.
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</p>
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<p>
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Autistic children and their relatives have high concentrations of serotonin in their serum and platelets.
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Members of a family tend to eat the same foods and to share other environmental conditions. Prenatal
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hypothyroidism and various kinds of imprinting, including hyperestrogenism, could account for this. Some
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studies have reported that thyroid supplements help autistic children, and anti-serotonin drugs have caused
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improvement in both children and adults.
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</p>
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<p>
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Serotonin tends to cause hypoglycemia, and hypoglycemia inhibits the conversion of thyroxine into the active
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T3 hormone. Hypoglycemia and hypothyroidism increase noradrenaline, and autistic people have been found to
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have more noradrenaline than normal. These changes, along with the general hypometabolism caused by excess
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serotonin, seem to justify the use of a thyroid supplement in autism and other serotonin-excess syndromes.
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</p>
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<p>
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Overdose with the serotonin reuptake inhibitors, or with 5-hydroxytryptophan, which has effects similar to
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serotonin, can cause the sometimes fatal "serotonin syndrome." Symptoms can include tremors, altered
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consciousness, poor coordination, cardiovascular disturbances, and seizures. Treatment with anti-serotonin
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drugs can alleviate the symptoms and usually can prevent death.
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</p>
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<p>
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The serotonin syndrome has been reported in users of St. John"s wort as an antidepressant. Since the other
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large neutral amino acids compete with tryptophan for entry into cells, the branched chain amino acids have
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some anti-serotonin activity, and this could be a justification for their use by athletes, since tryptophan
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and serotonin decrease glycogen stores and reduce endurance.
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</p>
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<p>
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The only amino acid that has ever been found to be carcinogenic is tryptophan. Its ability to mimic estrogen
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in promoting the release of prolactin is probably responsible.
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</p>
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<p>
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A large carbohydrate meal increases the ratio of tryptophan to the competing amino acids, and it has been
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proposed that this can shift the body"s balance toward increased serotonin. In an animal study,
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bromocriptine, which shifts the balance away from serotonin, reduced obesity and insulin and free fatty
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acids, and improved glucose tolerance.
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</p>
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<p>
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All of these observations are easiest to understand in terms of the suppression of cellular energy.
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Serotonin, like estrogen, lowers cellular ATP and interferes with oxidative metabolism.
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</p>
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<p>
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Serotonin, like histamine, has its proper physiological functions, but it is a mediator of stress that has
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to be systematically balanced by the systems that support high energy respiratory metabolism. The use of
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supplements of tryptophan, hydroxytryptophan, or of the serotonin promoting antidepressant drugs, seems to
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be biologically inappropriate.
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</p>
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<p>
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Many of the symptoms produced by excess serotonin are also the symptoms of hypothyroidism. Thyroid,
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progesterone, and high quality protein nutrition are central to protection against the serotonin syndromes.
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(Progesterone, like LSD, can inhibit the firing of serotonergic nerves, but an overdose, unlike LSD, never
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produces hallucinations.)
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</p>
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<p>
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One of the many actions of the "SSRI" (such as fluoxetine, Prozac), which aren"t related to their effect on
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serotonin, is to increase the concentration of allopregnanolone in the brain, imitating the action of
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increased progesterone. Following this discovery, Lilly got Prozac approved as a treatment for premenstrual
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syndrome. Since the production of allopregnanolone and progesterone depends on the availability of
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pregnenolone and cholesterol, a low cholesterol level would be one of the factors making this an
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inappropriate way to treat PMS.
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</p>
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<p>
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If we think biologically, starting with the role of serotonin as a damage-induced inflammatory mediator, we
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can speculate that an infinite number of irritating substances will be "serotonin reuptake inhibitors." The
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particular history of the "third generation antidepressants" is one that should disturb our tranquility.
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</p>
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<p><strong>SOME NOTES AND SOURCES</strong></p>*Note 1: I don"t want to imply that the receptor theory is wrong
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just because it allows for the introduction of innumerable experimental artifacts; it is primarily wrong because
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it is tied to the profoundly irrelevant "membrane theory" of cell regulation.*Note 2: Preparation for Lysergic
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Acid Amides: United States Patent Office 2,736,728 Patented February 28, 1956 Richard P. Pioch, Indianapolis,
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Indiana, assignor, to Eli Lilly and Co., Indianapolis, Indiana, a corporation of Indiana. No drawing.
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Application December 6, 1954, Serial No. 473,443. 10 claims. (Cl. 260-285.5)From the PDR on Prozac<strong
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>:</strong> "Pharmacodynamics: The antidepressant and antiobsessive-compulsive action of fluoxetine is <strong
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>presumed</strong> to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically
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relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin<strong>
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into human platelets</strong>. Studies in animals also suggest that fluoxetine is a much more potent uptake
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inhibitor of serotonin than of norepinephrine."The Lancet 269 (1955): 117"20. <strong>"Reserpine in the
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Treatment of Anxious and Depressed Patients,"</strong> Davies DL and Shepherd M.Gen Pharmacol 1994
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Oct;25(6):1257-1262.<strong>
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Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of plasma
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hemoglobin; the protective action of calmodulin antagonists.</strong> Koren-Schwartzer N, Chen-Zion M,
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Ben-Porat H, Beitner R Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. <strong>1. Injection
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of serotonin (5-hydroxytryptamine) to rats, induced a dramatic fall in brain ATP level, accompanied by an
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increase in P(i). Concomitant to these changes, the activity of cytosolic phosphofructokinase, the
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rate-limiting enzyme of glycolysis, was significantly enhanced. Stimulation of anaerobic glycolysis was also
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reflected by a marked increase in lactate content in brain. 2. Brain glucose</strong> 1,6-bisphosphate level
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was decreased, whereas fructose 2,6-bisphosphate was unaffected by serotonin. 3. All these serotonin-induced
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changes in brain, which are characteristic for cerebral ischemia, were prevented by treatment with the
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calmodulin (CaM) antagonists, trifluoperazine or thioridazine. 4. Injection of serotonin also induced a marked
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elevation of plasma hemoglobin, reflecting lysed erythrocytes, which was also prevented by treatment with the
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CaM antagonists. 5. The present results suggest that CaM antagonists may be effective drugs in treatment of many
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pathological conditions and diseases in which plasma serotonin levels are known to increase.J Neural Transm
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1998;105(8-9):975-86. <strong>Role of tryptophan in the elevated serotonin-turnover in hepatic
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encephalopathy.</strong> Herneth AM, Steindl P, Ferenci P, Roth E, Hortnagl H Department of Internal
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Medicine IV, Gastroenterology and Hepatology, University of Vienna, Austria. The increase of the brain levels of
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5-hydroxyindoleacetic acid (5-HIAA) in hepatic encephalopathy (HE) suggests an increased turnover of serotonin
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(5-HT). To study the role of tryptophan on the increased brain 5-HT metabolism in HE, we attempted to monitor
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brain levels of tryptophan in rats with thioacetamide-induced acute liver failure by intravenous infusion of
|
|
branched-chain amino acids (BCAA). The effect of this treatment on 5-HT synthesis and metabolism was
|
|
investigated in five brain areas. BCAA-infusions (1 and 2 gm/kg/24 h) increased the ratio BCAA/aromatic amino
|
|
acids in plasma two- and fourfold, respectively, and lowered both plasma and brain levels of tryptophan. At the
|
|
higher BCAA-dose all parameters suggesting an altered brain 5-HT metabolism (increased brain levels of 5-HT and
|
|
5-HIAA, increased 5-HIAA/5-HT ratio) were almost completely normalized. These results provide further evidence
|
|
for the role of tryptophan in the elevation of brain 5-HT metabolism and for a potential role of BCAA in the
|
|
treatment of HE.Tugai VA; Kurs'kii MD; Fedoriv OM. <strong>[Effect of serotonin on Ca2+ transport in
|
|
mitochondria conjugated with the respiratory chain].</strong> Ukrainskii Biokhimicheskii Zhurnal, 1973
|
|
Jul-Aug, 45(4):408-12.Kurskii MD; Tugai VA; Fedoriv AN.<strong>
|
|
[Effect of serotonin and calcium on separate components of respiratory chain of mitochondria in some rabbit
|
|
tissues].</strong> Ukrainskii Biokhimicheskii Zhurnal, 1970, 42(5):584-8.Watanabe Y; Shibata S; Kobayashi B.
|
|
<strong>Serotonin-induced swelling of rat liver mitochondria.</strong> Endocrinologia Japonica, 1969 Feb,
|
|
16(1):133-47.Mahler DJ; Humoller FL. <strong>The influence of serotonin on oxidative metabolism of brain
|
|
mitochondria.</strong> Proceedings of the Society for Experimental Biology and Medicine, 1968 Apr,
|
|
127(4):1074-9.Eur J Pharmacol 1994 Aug 11;261(1-2):25-32. <strong>The effect of alpha 2-adrenoceptor antagonists
|
|
in isolated globally ischemic rat hearts.</strong> Sargent CA, Dzwonczyk S, Grover G.J. "The alpha
|
|
2-adrenoceptor antagonist, yohimbine, has been reported to protect hypoxic myocardium. Yohimbine has several
|
|
other activities, including 5-HT receptor antagonism, at the concentrations at which protection was found."
|
|
"Pretreatment with yohimbine (1-10 microM) caused a concentration-dependent increase in reperfusion left
|
|
ventricular developed pressure and a reduction in end diastolic pressure and lactate dehydrogenase release. The
|
|
structurally similar compound rauwolscine (10 microM) also protected the ischemic myocardium. In contrast,
|
|
idozoxan (0.3-10 microM) or tolazoline (10 microM) had no protective effects. The<strong>
|
|
cardioprotective effects of yohimbine were partially reversed by 30 microM 5-HT. These results indicate that
|
|
the mechanism for the cardioprotective activity of yohimbine may involve 5-HT receptor antagonistic
|
|
activity."
|
|
</strong>Zubovskaia AM. <strong>[Effect of serotonin on some pathways of oxidative metabolism in the
|
|
mitochondria of rabbit heart muscle].</strong> Voprosy Meditsinskoi Khimii, 1968 Mar-Apr,
|
|
14(2):152-7.Warashina Y. <strong>[On the effect of serotonin on phosphorylation of rat liver
|
|
mitochondria</strong>]. Hoppe-Seylers Zeitschrift fur Physiologische Chemie, 1967 Feb, 348(2):139-48.Eur
|
|
Neuropsychopharmacol 1997 Oct;7 Suppl 3:S323-S328. <strong>Prevention of stress-induced morphological and
|
|
cognitive consequences</strong>. McEwen BS, Conrad CD, Kuroda Y, Frankfurt M, Magarinos AM, McKittrick C,
|
|
Laboratory of Neuroendocrinology, Rockefeller University, New York, NY 10021, USA. Atrophy and dysfunction of
|
|
the human hippocampus is a feature of aging in some individuals, and this dysfunction predicts later dementia.
|
|
There is reason to believe that adrenal glucocorticoids may contribute to these changes, since the elevations of
|
|
glucocorticoids in Cushing's syndrome and during normal aging are associated with atrophy of the entire
|
|
hippocampal formation in humans and are linked to deficits in short-term verbal memory. We have developed a
|
|
model of stress-induced atrophy of the hippocampus of rats at the cellular level, and we have been investigating
|
|
underlying mechanisms in search of agents that will block the atrophy. Repeated restraint stress in rats for 3
|
|
weeks causes changes in the hippocampal formation that include suppression of 5-HT1A receptor binding and
|
|
atrophy of dendrites of CA3 pyramidal neurons, as well as impairment of initial learning of a radial arm maze
|
|
task. <strong>Because serotonin is released by stressors and may play a role in the actions of stress on nerve
|
|
cells, we investigated the actions of agents that facilitate or inhibit serotonin reuptake.</strong>
|
|
Tianeptine is known to enhance serotonin uptake, and we compared it with fluoxetine, an inhibitor of 5-HT
|
|
reuptake, as well as with desipramine. Tianeptine treatment (10 mg/kg/day) prevented the stress-induced atrophy
|
|
of dendrites of CA3 pycamidal neurons, whereas neither fluoxetine (10 mg/kg/day) nor desipramine (10 mg/kg/day)
|
|
had any effect. Tianeptine treatment also prevented the stress-induced impairment of radial maze learning.
|
|
Because <strong>corticosterone- and stress-induced atrophy of CA3 dendrites is also blocked by phenytoin, an
|
|
inhibitor of excitatory amino acid release and actions, these results suggest that serotonin released by
|
|
stress or corticosterone may interact pre- or post-synaptically with glutamate released by stress or
|
|
corticosterone, and that the final common path may involve interactive effects between serotonin and
|
|
glutamate receptors on the dendrites of CA3 neurons innervated by mossy fibers from the dentate gyrus. We
|
|
discuss the implications of these findings for treating cognitive impairments and the risk for dementia in
|
|
the elderly.</strong>J Mol Cell Cardiol 1985 Nov;17(11):1055-63. <strong>Digitoxin therapy partially
|
|
restores cardiac catecholamine and brain serotonin metabolism in congestive heart failure.</strong> Sole MJ,
|
|
Benedict CR, Versteeg DH, de Kloet ER. The effect of therapeutic doses of digitalis in modifying neural activity
|
|
has been the subject of considerable controversy. In earlier studies we reported <strong>an increase both in
|
|
serotonergic activity in the posterior hypothalamus and pons-medulla and in cardiac sympathetic tone in the
|
|
failing cardiomyopathic hamster.</strong> In this study we examine the effects of doses of digitoxin, known
|
|
to be therapeutic for hamster heart failure, on monoamine neurotransmitter metabolism in the brain and heart
|
|
during the cardiomyopathy. Both digitoxin and ASI-222, a polar amino-glycoside which does not cross the<strong>
|
|
</strong>blood-brain barrier, given either acutely (6 mg/kg ip) or chronically (2 mg/kg/day ip for 10 days),
|
|
normalized the failure-induced increase in serotonin turnover in the pons-medulla but had no effect on the
|
|
changes in the posterior hypothalamus. Digitoxin therapy also reduced cardiac and adrenal sympathetic activity
|
|
partially restoring cardiac catecholamine stores. In order to more clearly define the pathways involved we
|
|
measured serotonin (microgram/g protein) in 18 brain nuclei after 10 days of digitoxin or vehicle treatment.
|
|
<strong>Heart failure was associated with an increase in serotonin in five nuclei: the mammillary bodies,
|
|
ventromedial, periventricular and paraventricular nuclei of the hypothalamus, and the centralis superior
|
|
nucleus of the raphe</strong>. Digitoxin therapy completely normalized the changes in the centralis superior
|
|
and ventromedialis nuclei; neither congestive heart failure nor digitoxin affected serotonin levels in other
|
|
nuclei. We conclude that there is an increase in activity in specific brain serotonergic nuclei in congestive
|
|
heart failure. Digitalis reduces cardiac sympathetic tone and restores the changes in two of these nuclei: the
|
|
ventromedial and the centralis superior.+2Brain Res 2000 Jan 24;853(2):275-81. <strong>Duration and distribution
|
|
of experimental muscle hyperalgesia in humans following combined infusions of serotonin and
|
|
bradykinin.</strong> Babenko V, Svensson P, Graven-Nielsen T, Drewes AM, Jensen TS, Arendt-Nielsen L.Eur J
|
|
Pharmacol 1992 Feb 25;212(1):73-8. <strong>5-HT3 receptor antagonists reverse helpless behaviour in
|
|
rats.</strong> Martin P, Gozlan H, Puech AJ Departement de Pharmacologie, Faculte de Medecine
|
|
Pitie-Salpetriere, Paris, France. The effects of the 5-HT3 receptor antagonists, zacopride, ondansetron and ICS
|
|
205-930, were investigated in an animal model of depression, the learned helplessness test. Rats previously
|
|
subjected to a session of 60 inescapable foot-shocks exhibited a deficit of escape performance in three
|
|
subsequent shuttle-box sessions. The 5-HT3 receptor antagonists administered i.p. twice daily on a chronic
|
|
schedule (zacopride 0.03-2 mg/kg per day; ondansetron and ICS 205-930: 0.125-2 mg/kg per day) reduced the number
|
|
of escape failures at low to moderate daily doses. This effect was not observed with the highest dose(s) of
|
|
zacopride, ondansetron and ICS 205-930 tested. These results indicate that 5-HT3 antagonists may have effects
|
|
like those of conventional antidepressants in rats.Neuropharmacology 1992 Apr;31(4):323-30. <strong>Presynaptic
|
|
serotonin mechanisms in rats subjected to inescapable shock.</strong> Edwards E, Kornrich W, Houtten PV,
|
|
Henn FA. "After exposure to uncontrollable shock training, two distinct groups of rats can be defined in terms
|
|
of their performance in learning to escape from a controllable stress. Learned helpless rats do not learn to
|
|
terminate the controllable stress, whereas non-learned helpless rats learn this response as readily as naive
|
|
control rats do." "These results implicate presynaptic serotonin mechanisms in the behavioral deficit caused by
|
|
uncontrollable shock. In addition, a limbic-hypothalamic pathway may serve as a control center for the
|
|
behavioral response to stress."Neurochem Int 1992 Jul;21(1):29-35.<strong>
|
|
In vitro neurotransmitter release in an animal model of depression</strong>. Edwards E, Kornrich W, van
|
|
Houtten P, Henn FA. "Sprague-Dawley rats exposed to uncontrollable shock can be separated by a subsequent shock
|
|
escape test into two groups: a "helpless" (LH) group which demonstrates a deficit in escape behavior, and a
|
|
"nonlearned helpless" (NLH) group which shows no escape deficit and acquires the escape response as readily as
|
|
naive control rats (NC) do." "The major finding concerned a significant increase in endogenous and
|
|
K(+)-stimulated serotonin (5-HT) release in the hippocampal slices of LH rats. There were no apparent
|
|
differences in acetylcholine, dopamine and noradrenaline release in the hippocampus of LH rats as compared to
|
|
NLH and NC rats. These results add further support to previous studies in our laboratory which implicate
|
|
presynaptic 5-HT mechanisms in the behavioral deficit caused by uncontrollable shock."Psychiatry Res 1994
|
|
Jun;52(3):285-93. <strong>In vivo serotonin release and learned helplessness.</strong> Petty F, Kramer G, Wilson
|
|
L, Jordan S Mental Health Clinic, Dallas Veterans Affairs Medical Center, TX. Learned helplessness, a behavioral
|
|
depression caused by exposure to inescapable stress, is considered to be an animal model of human depressive
|
|
disorder. Like human depression, learned helplessness has been associated with a defect in serotonergic
|
|
function, but the nature of this relationship is not entirely clear. We have used in vivo microdialysis brain
|
|
perfusion to measure serotonin (5-hydroxytryptamine, 5HT) in extracellular space of medial frontal cortex in
|
|
conscious, freely moving rats. Basal 5HT levels in rats perfused before exposure to tail-shock stress did not
|
|
themselves correlate with subsequent learned helplessness behavior. However, 5HT release after stress showed a
|
|
significant increase with helpless behavior. <strong>These data support the hypothesis that a cortical
|
|
serotonergic excess is causally related to the development of learned helplessness.</strong>Pharmacol
|
|
Biochem Behav 1994 Jul;48(3):671-6. <strong>Does learned helplessness induction by haloperidol involve serotonin
|
|
mediation?</strong> Petty F, Kramer G, Moeller M Veterans Affairs Medical Center, Dallas 75216. Learned
|
|
helplessness (LH) is a behavioral depression following inescapable stress. Helpless behavior was induced in
|
|
naive rats by the dopamine D2 receptor blocker haloperidol (HDL) in a dose-dependent manner, with the greatest
|
|
effects seen at 20 mg/kg (IP). Rats were tested 24 h after injection. Haloperidol (IP) increased release of
|
|
serotonin (5-HT) in medial prefrontal cortex (MPC) as measured by in vivo microdialysis. Perfusion of HDL
|
|
through the probe in MPC caused increased cortical 5-HT release, as did perfusion of both dopamine and the
|
|
dopamine agonist apomorphine. Our previous work found that increased 5-HT release in MPC correlates with the
|
|
development of LH. The present work suggests that increased DA release in MPC, known to occur with both
|
|
inescapable stress and with HDL, may play a necessary but not sufficient role in the development of LH. Also,
|
|
this suggests that increased DA activity in MPC leads to increased 5-HT release in MPC and to subsequent
|
|
behavioral depression.Stroke 1991 Nov;22(11):1448-51. <strong>Platelet secretory products may contribute to
|
|
neuronal injury.</strong> Joseph R, Tsering C, Grunfeld S, Welch KM Department of Neurology, Henry Ford
|
|
Hospital and Health Sciences Center, Detroit, MI 48202. BACKGROUND: We do not fully understand the mechanisms
|
|
for neuronal damage following cerebral arterial occlusion by a thrombus that consists mainly of platelets. The
|
|
view that certain endogenous substances, such as glutamate, may also contribute to neuronal injury is now
|
|
reasonably well established. Blood platelets are known to contain and secrete a number of substances that have
|
|
been associated with neuronal dysfunction. Therefore, we hypothesize that a high concentration (approximately
|
|
several thousand-fold higher than in plasma, in our estimation) of locally released platelet secretory products
|
|
derived from the causative thrombus may contribute to neuronal injury and promote reactive gliosis. SUMMARY OF
|
|
COMMENT: We have recently been able to report some direct support for this concept. When organotypic spinal cord
|
|
cultures were exposed to platelet and platelet products, a significant reduction in the number and the size of
|
|
the surviving neurons occurred in comparison with those in controls. We further observed that serotonin, a major
|
|
platelet product, has neurotoxic properties. There may be other platelet components with similar effect.<strong>
|
|
CONCLUSIONS: The hypothesis of platelet-mediated neurotoxicity gains some support from these recent in vitro
|
|
findings. The concept could provide a new area of research in stroke, both at the clinical and basic
|
|
levels.</strong>J. Clin Psychopharmacol 1991 Aug; 11(4):277-9.<strong>
|
|
Disseminated intravascular coagulation and acute myoglobinuric renal failure: a consequence of the
|
|
serotonergic syndrome.</strong> Miller F, Friedman R, Tanenbaum J, Griffin A. LetterChronobiol Int 2000
|
|
Mar;17(2):155-72. <strong>Association of the antidiabetic effects of bromocriptine with a shift in the daily
|
|
rhythm of monoamine metabolism within the suprachiasmatic nuclei of the Syrian hamster.</strong> Luo S, Luo
|
|
J, Cincotta AH.<strong>
|
|
"Bromocriptine, a dopamine D2 agonist, inhibits seasonal fattening and improves seasonal insulin resistance
|
|
in Syrian hamsters."
|
|
</strong>"Compared with control values, bromocriptine treatment significantly reduced weight gain (14.9 vs. -2.9
|
|
g, p < .01) and the areas under the GTT glucose and insulin curves by 29% and 48%, respectively (p < .05).
|
|
Basal plasma insulin concentration was markedly reduced throughout the day in bromocriptine-treated animals
|
|
without influencing plasma glucose levels. Bromocriptine reduced the daily peak in FFA by 26% during the late
|
|
light span (p < .05)." "Thus, bromocriptine-induced resetting of daily patterns of SCN neurotransmitter
|
|
metabolism is associated with the effects of bromocriptine on attenuation of the obese insulin-resistant and
|
|
glucose-intolerant condition. A large body of corroborating evidence suggests that such bromocriptine-induced
|
|
changes in SCN monoamine metabolism may be functional in its effects on metabolism."Eur J Pharmacol 1982 Jul
|
|
30;81(4):569-76.<strong> Actions of serotonin antagonists on dog coronary artery.</strong> Brazenor RM, Angus
|
|
JA. Serotonin released from platelets may initiate coronary vasospasm in patients with variant angina. If this
|
|
hypothesis is correct, serotonin antagonists without constrictor activity may be useful in this form of angina.
|
|
We have investigated drugs classified as serotonin antagonists on dog circumflex coronary artery ring segments
|
|
in vitro. Ergotamine, dihydroergotamine,<strong>
|
|
bromocriptine, lisuride, ergometrine, ketanserin, trazodone, cyproheptadine and pizotifen caused
|
|
non-competitive antagonism of serotonin concentration-response curves</strong>. In addition, ketanserin,
|
|
trazodone, bromocriptine and pizotifen inhibited noradrenaline responses in concentrations similar to those
|
|
required for serotonin antagonism. All drugs with the exception of ketanserin, cyproheptadine and pizotifen
|
|
showed some degree of intrinsic constrictor activity. Methysergide antagonized responses to serotonin
|
|
competitively but also constricted the coronary artery. The lack of a silent competitive serotonin antagonist
|
|
precludes a definite characterization of coronary serotonin receptors at this time. However, the profile of
|
|
activity observed for the antagonist drugs in the coronary artery differs from that seen in other vascular
|
|
tissues. Of the drugs tested, ketanserin may be the most useful in variant angina since it is a potent 5HT
|
|
antagonist, lacks agonist activity and has alpha-adrenoceptor blocking activity.Eur J Pharmacol 1985 May
|
|
8;111(2):211-20. <strong>Maternal aggression in mice: effects of treatments with PCPA, 5-HTP and 5-HT receptor
|
|
antagonists.</strong> Ieni JR, Thurmond JB. Drug treatments which influence brain serotonergic systems were
|
|
administered to lactating female mice during the early postpartum period, and their effects on aggressive
|
|
behavior, locomotor activity and brain monoamines were examined. P-chlorophenylalanine (200 and 400 mg/kg) and
|
|
5-hydroxytryptophan (100 mg/kg) inhibited fighting behavior of postpartum mice toward unfamiliar male intruder
|
|
mice. These drug-treated postpartum females showed increased latencies to attack male intruders and also reduced
|
|
frequencies of attack. In addition, <strong>postpartum mice treated with the serotonin receptor antagonists,
|
|
mianserin (2 and 4 mg/kg), methysergide (4 mg/kg) and methiothepin (0.25 and 0.5 mg/kg), displayed
|
|
significantly less aggressive behavior than control mice, as measured by reduced number of attacks.</strong>
|
|
Whole brain monoamine and monoamine metabolite levels were measured after drug treatments. The behavioral
|
|
results are discussed in terms of drug-induced changes in brain chemistry and indicate a<strong>
|
|
possible role for serotonin in the mediation of maternal aggressive behavior of mice.
|
|
</strong> Naunyn Schmiedebergs Arch Pharmacol 1987 Apr;335(4):454-64.<strong>
|
|
Effects of gepirone, an aryl-piperazine anxiolytic drug, on aggressive behavior and brain monoaminergic
|
|
neurotransmission. McMillen BA, Scott SM, Williams HL, Sanghera MK.
|
|
</strong>
|
|
<hr />
|
|
<strong>In support of this conclusion was the observed potentiation of antiaggressive effects by blocking 5HT
|
|
receptors</strong> wit small doses of methiothepin or methysergide, which would exacerbate the decreased
|
|
release of 5HT caused by gepirone. These results are in harmony with reports that decreased serotonergic
|
|
activity has anxiolytic-like effects in animal models of anxiety.Farmakol Toksikol 1975 Mar-Apr;38(2):148-51.
|
|
<strong>[Participation of the serotonin-reactive brain structure in certain forms of behavior in golden
|
|
hamsters].
|
|
</strong>Popova NK, Bertogaeva VD.<strong>
|
|
A viviacious play of young hamsters is shown to be accompanied by a drop of the serotonin level in the brain
|
|
stem and the subsequent slumber - by its rise</strong>, while the corticosteroids content of the peripheral
|
|
blood with the playful behavior experiences no changes. <strong>Iprazid and 5-oxytryptophan inhibit the playful
|
|
activity,</strong> while dioxyphenylalanina (DOPA) does not influence it. A similar depression of the
|
|
serotonin level in the brain stem was also noted in an aggressive behavior and stress conditions arising when
|
|
adult male-hamsters are grouped together. A conclusion is drawn to the effect that changes in the content of
|
|
serotonin in the brain stem are <strong>not associated with the emotional colouration of the condition, but
|
|
rather reflect the transition from the somnolence to a highly active behavior.</strong>Biol Psychiatry 1985
|
|
Sep;20(9):1023-5 <strong>Triiodothyronine-induced reversal of learned helplessness in rats.</strong> Martin P,
|
|
Brochet D, Soubrie P, Simon P.<p>
|
|
© Ray Peat Ph.D. 2012. All Rights Reserved. www.RayPeat.com
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