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    <head><title>Intelligence and metabolism</title></head>
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        <h1>
            Intelligence and metabolism
        </h1>

        <p>
            <hr />
            <hr />
        </p>

        <p>
            <strong>Appropriate stimulation is an essential part of the developmental process. Inappropriate stimulation
                is a stress that deforms the process of growth. Mediators of stress, such as serotonin, can cause
                persistent distortions of physiology and behavior.</strong>
        </p>
        <p>
            <strong>Education can either activate or suppress mental energy. If it is mainly obedience training, it
                suppresses energy. If it creates social dislocations, it disturbs mental and emotional energy.</strong>
        </p>
        <p>
            <strong>Stress early in life can impair learning, cause aggressive or compulsive behavior, learned
                helplessness, shyness, alcoholism, and other problems.</strong>
        </p>
        <p>
            <strong>Serotonin activates the glucocorticoid system, which can produce brain atrophy. Antiserotonin agents
                protect against brain atrophy and many other effects of stress. The brain-protecting neurosteroids,
                including pregnenolone and progesterone, which are increased by some kinds of stimulation, are decreased
                by isolation stress, and in their absence, serotonin and the glucocorticoids are relatively unopposed.
            </strong>
        </p>
        <p>
            <strong>Since excess serotonin can cause thrombosis and vasospasms, and the excess cortisol resulting from
                hyperserotonemia can weaken blood vessels and the immune system, a person's longevity is likely to be
                shortened if something doesn't intervene to alter the patterns induced by stress early in life.</strong>
        </p>

        <p>
            <hr />
            <hr />
        </p>
        <p>
            <strong>Baroness Blatch: "My Lords, the levels of achievement are well above the national average of our own
                state schools."
            </strong>
        </p>
        <p>
            <strong>"This is a school which attained 75 per cent A to C passes in 1998, and 63.9 per cent in 1999. Those
                figures are well above national averages. There is no truancy; and there is the highest possible level
                of parental satisfaction with the school. When those parents are paying their money and know what they
                are paying for, who are we to take a different view about the philosophy of education in a private
                school?"</strong>
        </p>
        <p>
            <strong>Comment during debate in House of Lords, June 30, 1999, on Chief Inspector of Schools Woodhead's
                threat to close Summerhill, a democratic school which had been started in 1921.
            </strong>
        </p>
        <p>
            <strong>In 1927, the government inspectors had recommended that 'all educationalists' should come to
                Summerhill to see its 'invaluable' research, which demonstrated that students' development is better
                when they regulate themselves and are not required to attend lessons.</strong>
        </p>

        <p>
            <hr />
            <hr />
        </p>
        <p>
            Having written about animal intelligence, and the ways in which it is similar to human intelligence, now I
            want those ideas to serve as a context for thinking about human intelligence without many of the usual
            preconceptions.
        </p>
        <p>
            Intelligence is an interface between physiology and the environment, so it's necessary to think about each
            aspect in relation to the other. Things, both biochemical and social, that enhance intelligence enhance life
            itself, and vice versa.
        </p>
        <p>
            Psychologists have tried to give their own definitions to words like idiot, imbecile, moron, and genius, but
            they have just been refining the clich"s of the culture, in which "dummy" is one of the first words that
            kids in the U.S. learn. Many psychologists have tried to create "culture-free" tests of intelligence, making
            it clear that they believe in something like innate animal intelligence, though they usually call it
            "genetic" intelligence. Other psychometrists have transcended not only biology but even rationality, and
            have catalogued the <strong><em>preferences</em></strong>

            of people that they define as intelligent, and designed "I.Q. tests" based on the selection of things that
            were preferred by "intelligent people." This behavior is remarkably similar to the "psychometry" of the
            general culture, in which "smart" people are those who do things the "right" way.
        </p>
        <p>
            About thirty years ago, someone found that the speed with which the iris contracts in response to a flash of
            light corresponds very closely to the I.Q. measured by a psychologist using a standard intelligence test.
            The devices used to measure reaction time in drivers' education courses also give a good indication of a
            person's intelligence, but so does measuring their heart rate, or taking their temperature. Colleges would
            probably be embarrassed to admit students on the basis of their temperature (though they commonly award
            scholarships on the basis of the ability to throw a ball). Colleges, to the extent that they are serious
            about the business of education, are interested in the student's ability to master the culture.
        </p>
        <p>
            The way a person has learned during childhood can shape that person's manner of grasping the culture. To
            simply accelerate the learning of a standard curriculum will increase that person's "I.Q." on a conventional
            test, but the important issue is whether it is really intelligent to learn and to value the things taught in
            those curricula. Some educators say that their purpose is to socialize and indoctrinate the students into
            their discipline, others believe their purpose is to help their students to develop their minds. Both of
            these approaches may operate within the idea that "the culture" is something like a museum, and that
            students should become curators of the collection, or of some part of it. If we see the culture
            metaphorically as a mixture of madhouse, prison, factory, and theater, the idea of "developing the student's
            mind" will suggest very different methods and different attitudes toward "the curriculum"
        </p>
        <p>
            Even sophisticated people can fall into stereotyped thinking when they write about issues of intelligence.
            For example, no one considers it a sign of genius when a slum kid is fluent in both Spanish and English, but
            when some of history's brightest people are discussed, the fact that they learned classical Greek at an
            early age is always mentioned. No one mentions whether they were competent in idiomatic Spanish.
        </p>

        <p>
            One of the old cultural stereotypes is that child prodigies always "burn out," as if they were consuming a
            fixed amount of mental energy at an accelerated rate. (This idea of burn-out is isomorphic with the other
            cultural stereotypes relating aging to the "rate of living," for example that people with slow heart beats
            will live longer.) Some of the men who have been considered as the world's brightest have, in fact, gone
            through a crisis of depression, and Terman's long-term study of bright people found that "maladjustment" did
            increase with I.Q., especially among women. But the facts don't support the concept of "burn-out" at all. I
            think the facts reveal instead a deep flaw in our ideas of education and professional knowledge.
        </p>
        <p>
            In a world run by corporation executives, university presidents ("football is central to the university's
            mission"), congressmen, bankers, oilmen, and agency bureaucrats, people with the intelligence of an ant (a
            warm ant) might seem outlandishly intelligent. This is because the benighted self-interest of the
            self-appointed ruling class recognizes that objective reality is always a threat to their interests. If
            people, for example, realized that estrogen therapy and serotonin-active drugs and x-rays and nuclear power
            and atomic bomb tests were beneficial only to those whose wealth and power derive from them, the whole
            system would lose stability. Feigned stupidity becomes real stupidity.
        </p>
        <p>
            But apart from ideologically institutionalized stupidity, there are real variations in the ability to learn,
            to remember and to apply knowledge, and to solve problems. These variations are generally metabolic
            differences, and so will change according to circumstances that affect metabolism. Everyday social
            experiences affect metabolism, stimulating and supporting some kinds of brain activity, suppressing and
            punishing others. All of the activities in the child's environment are educational, in one way or another.
        </p>
        <p>
            Some of the famous prodigies of history illustrate the importance of ideology in the development of
            intellect. Family ideology, passing on the philosophical orientations of parents and their friends, shapes
            the way the children are educated.
        </p>
        <p>
            Some of these family traditions can be traced by considering who the child's godfather was. Jeremy Bentham
            was John Stuart Mill's godfather, Mill was Bertrand Russell's; Ralph Waldo Emerson was William James'
            godfather, James was W. J. Sidis's. Willy Sidis was educated by his parents to demonstrate their theory of
            education, which grew out of the philosophies of Emerson and James. His father, Boris Sidis, was a pioneer
            in the study of hypnosis, and he believed that suggestion could mobilize the mind's "reserve energy." Willy
            learned several languages and advanced mathematics at an early age. After he graduated from Harvard at the
            age of 16, he tried teaching math at Rice Institute, but he was displeased by the attitudes of his students
            and of the newspaper and magazine writers who made a profession of mocking him. He attended law school at
            Harvard, and would have been imprisoned as a conscientious objector if the war hadn't ended.
        </p>
        <p>
            Antisemitism probably played a role in his sense of isolation when he was at Harvard and Rice. In 1912 Henry
            Goddard, a pioneer in intelligence testing (and author of <strong><em>The Kallikak Family: A Study in the
                    Heredity of Feeble- Mindedness</em>)</strong>, administered intelligence tests to immigrants and
            determined that 83 percent of Jews and 87 percent of Russians were "feeble-minded." By the standards of the
            time, it was highly inappropriate for the child of extremely poor Jewish immigrants from eastern Europe to
            be so bright.
        </p>
        <p>
            Sidis hid from the press, and worked as a bookkeeper and clerk, while he studied and wrote. During his years
            of obscurity, he wrote books on philosophy and American history. Eventually, the journalists discovered him
            again, and after prolonged lawsuits against the magazines for invasion of privacy and slander, he died of a
            stroke at the age of 46.
        </p>
        <p>
            Sidis is probably the culture's favorite example of the child prodigy who burns out, but people (Robert
            Persig, Buckminster Fuller) who have read his books have said favorable things about them. The journalists'
            emphasis on the fact that Sidis never held a prestigious job nicely illustrates their clich" mentality: "If
            you're so smart, why aren't you rich?" But throughout history, intelligent nonconformists have supported
            themselves as craft-workers or technicians--Socrates as a stone mason, Spinoza as a lens grinder, Blake as
            an engraver, Einstein as a patent examiner, for example.
        </p>

        <p>
            In conventional schools (as in conventional society) 10,000 questions go unanswered, not only because a
            teacher with many students has no time to answer them, but also because most teachers wouldn't know most of
            the answers.
        </p>
        <p>
            The parents of W. J. Sidis and J. S. Mill were remarkably well educated people who, because they dissented
            from society's ideology, chose to spend much of their time educating their children. Whenever a question
            about Euclidean geometry or Greek grammar occurred to the child, it could be answered immediately. It was
            only natural that progress would be fast, but there were more important differences.
        </p>
        <p>
            When questions are answered, curiosity is rewarded, and the person is enlivened. In school, when following
            instructions and conforming to a routine is the main business, many questions must go unanswered, and
            curiosity is punished by the dulling emptiness of the routine.
        </p>
        <p>
            Some schools are worse than others. For example, slum children were given I.Q. tests when they started
            school, and each subsequent year, and their I.Q.s dropped with each year of school. In a stimulating
            environment, the reverse can happen, the I.Q. can rise each year. Since the tests aren't "culture free,"
            their scores reflected the material that they were being taught, but they undoubtedly also reflected the
            increasing boredom and despair of the children in a bad school, or the increasing liveliness of the children
            in the stimulating environment.
        </p>
        <p>
            I have spoken with people in recent years who still held the idea of a fixed genetic mental potential, who
            believe that poor children fall behind because they are reaching their "genetic limit." For them, the I.Q.
            represents an index of intrinsic quality, and is as important as distinguishing between caviar and frogs'
            eggs. The rat research of Marion Diamond and others at the University of California, however, showed that
            the structure, weight, and biochemistry of a rat's brain changes, according to the amount of environmental
            stimulation and opportunity for exploration. This improvement of brain structure and function is passed on
            to the next generation, giving it a head-start. It isn't likely that rats are more disposed than humans to
            benefit from mental activity, and in the years since Diamond's research there have been many discoveries
            showing that brains of all sorts complexify structurally and functionally in response to stimulation.
        </p>

        <p>
            Rats isolated in little boxes, generation after generation--the normal laboratory rats--were the standard,
            but now it's known that isolation is a stress that alters brain chemistry and function.
        </p>
        <p>
            Willy Sidis and John Stuart Mill were being stimulated and allowed to develop in one direction, but they
            were being isolated from interaction with their peers. When Mill was twenty he went into a depression, and
            later he wrote that it was because he discovered that he was unable to <strong><em>feel.</em></strong> He
            had developed only part of his personality.
        </p>
        <p>
            Bertrand Russell (1872-1970), orphaned at the age of four, went to live with his grandmother, who chose not
            to send him to school, but provided tutors. He didn't experience a sense of academic pressure, and was able
            to read whatever he wanted in his late grandfather's library. He didn't realize that he was unusually bright
            until he went to Cambridge. The unusual freedom of his childhood must have contributed to his willingness to
            hold unpopular opinions. In 1916 he was fined, and in 1918 imprisoned for 6 months, for opposing the war.
        </p>

        <p>
            In 1927, Russell and his wife, Dora Black, started a school. He later wrote that, although the average
            student at the school was very bright, an exceptionally bright student was likely to be ostracized by the
            less bright students. He commented on the harm done to the brightest students by their social isolation,
            probably thinking about his own education in relative isolation. A psychologist (Leta Hollingworth, 1942)
            has made similar observations about the isolation that can be produced by a large difference of I.Q. She did
            a series of studies of very bright children, beginning in 1916, including working with some of them in a
            program she designed in a New York public school. Her empathy allowed her to discover things that weren't
            apparent to her contemporaries.
        </p>
        <p>
            During this time Lewis Terman was studying bright children, and wanted to disprove some of the popular
            stereotypes about intelligent people, and to support his ideology of white racial superiority. In 1922 he
            got a large grant, and sorted out about 1500 of the brightest children from a group of 250,000 in
            California. He and his associates then monitored them for the rest of their lives (described in <strong><em
                >Genetic Studies of Genius</em></strong>). His work contradicted the stereotype of bright people as
            being sickly or frail, but, contrary to his expectation, there was an association between maladjustment and
            higher I.Q.; the incidence of neurotic fatigue, anxiety, and depression increased along with the I.Q. The
            least bright of his group were more successful in many ways than the most bright. He didn't really confront
            the implications of this, though it seriously challenged his belief in a simple genetic racial superiority
            of physique, intellect, and character.
        </p>
        <p>
            I.Q. testing originated in a historical setting in which its purpose was often to establish a claim of
            racial superiority, or to justify sterilization or "euthanasia," or to exclude immigrants. More recently,
            the tests have been used to assign students to certain career paths. Because of their use by people in power
            to control others, the I.Q. tests have helped to create misunderstanding of the nature of intelligence. A
            person's "I.Q." now has very strong associations with the ideology of schooling as a road to financial
            success, rather than to enrichment of a shared mental life.
        </p>
        <p>
            If a bad school resembles, on the intellectual level, a confining rat box, the educational isolation of
            Mill, Russell, and Sidis was emotionally limiting, almost like solitary confinement. Once when Willy Sidis
            was arrested for marching in a May Day parade, his father was able to keep him from going to prison, but
            Willy apparently would have preferred the real prison to life with his parents.
        </p>

        <p>
            None of these three famous intellects was known for youthful playfulness, though playfulness is a quality
            that's closely associated with intelligence in mammals and birds. (Russell, however, in middle age developed
            many new interests, such as writing short stories, and had many new loves even in old age.) Stress early in
            life, such as isolation, reduces the playfulness of experimental animals. Playfulness is contagious, but so
            is the inability to play.
        </p>
        <p>
            In schools like Summerhill, which was founded in 1921 by A. S. Neill, students aren't required to attend
            classes when they would rather do something else, but at graduation they usually do better on their
            standardized national examinations than students who have dutifully attended classes for years. For
            students, as for rats, freedom and variety are good for the brain, and tedious conformity is harmful. When a
            school is very good, it can spread a contagion of playfulness along with an interest in learning.
        </p>
        <p>
            An environment that fosters optimal intelligence will necessarily promote the development of emotional
            health, and will almost certainly foster good physical health and longevity, because no part of the
            physiological system can thrive at the expense of another part. And within the boundaries of life-enriching
            environments, there are infinite possibilities for variety.
        </p>
        <p>
            There is a common belief in the rigidity of the adult nervous system, in analogy with feral cats or dogs,
            that supposedly can't be tamed if they have grown up without knowing humans. But people who have had the
            inclination to understand wild animals have found that, even when the animals have been captured as adults,
            they can become as sociable as if they had grown up in domestication. The "horse whisperer" demonstrated
            this sort of empathetic approach to animals. Sometimes, these people have a similar ability to communicate
            with people who are retarded, or autistic, or demented, but the professionalization of society has made it
            increasingly unlikely that people with the need for intuitive help will encounter someone who is able to
            give it. The closest psychology has come to professionally recognizing the importance of empathy was in Carl
            Rogers' work, e.g., <em>
                Client-Centered Therapy.</em>
        </p>
        <p>
            Rogers showed that a sense of solidarity must exist between therapist and client for the therapy to be
            helpful. A similar solidarity has to exist between teacher and student, for education to be successful. If
            ordinary family and social contacts could occur within such an atmosphere of mutual respect, psychopathology
            (including learning difficulties) would be much less common.
        </p>
        <p>
            Although three individuals don't prove an argument, I think the lives and situations of Sidis, Mill, and
            Russell are usefully symbolic. Sidis, who grew up under intense pressure and social isolation and in extreme
            poverty, died at the age of 46. Mill, who was educated mainly by his father, in secure financial
            circumstances, experienced social isolation and moderate pressure, and lived about 20 years longer than
            Sidis did. Russell, who grew up in the highest circles of the ruling class, experienced no pressure, and
            only the mild kind of social isolation that wasn't exceptional for his class. He lived to be 97.
        </p>
        <p>
            The psychopathology of social isolation has been studied in a variety of animals, and many features are
            similar across species, including humans. Aggression, helplessness, and reduced ability to learn are
            typically produced in animals by social isolation, and it's clear that certain kinds of family environment
            produce the same conditions in children. Schools seldom help, and often hinder, recovery from such early
            experiences.
        </p>
        <p>
            "Vital exhaustion," decreased slow wave sleep, and anger, which are associated with the "type A personality"
            and with circulatory and heart disease, appear to have their origin in childhood experiences. Low income and
            financial insecurity are strongly associated with anger, sleep disturbances, and circulatory disease. In
            animals stressed by social isolation, similar features emerge, under the influence of decreased
            neurosteroids, and increased serotonin and activity of the glucocorticoid system.
        </p>
        <p>
            The "smart drug" culture has generally been thinking pharmaceutically rather than biologically. Behind that
            pharmaceutical orientation there is sometimes the idea that the individual just isn't trying hard enough, or
            doesn't have quite the right genes to excel mentally.
        </p>
        <p>
            Many stimulants--amphetamine and estrogen, for example--can increase alertness temporarily, but at the
            expense of long range damage. The first principle of stimulation should be to avoid a harmful activation of
            the catabolic stress hormones. Light, play, environmental variety and exploratory conversations stimulate
            the whole organism in an integral way, stimulating repair processes and developmental processes.
        </p>
        <p>
            Any chemical support for intelligence should take into account the mind-damaging stresses that our culture
            can impose, and provide defense against those. In darkness and isolation, for example, the stress hormones
            increase, and the brain-protective steroids decrease. The memory improvement that results from taking
            pregnenolone or thyroid (which is needed for synthesizing pregnenolone from cholesterol) is the result of
            turning off the dulling and brain-dissolving stress hormones, allowing normal responsiveness to be restored.
        </p>
        <p>
            If we know that rats nurtured in freedom, in an interesting environment, grow more intelligent, then it
            would seem obvious that we should experiment with similar approaches for children--if we are really
            interested in fostering intelligence. And since violence and mental dullness are created by the same social
            stresses, even the desire to reduce school violence might force the society to make some improvements that
            will, as a side effect, foster intelligence.
        </p>

        <p><h3>REFERENCES</h3></p>
        <p>
            B. Russell: "If you wish to know what men will do, you must know not only or principally their material
            circumstances, but rather the whole system of their desires with their relative strengths."
        </p>
        <p>
            John Holt, from an interview in <em>Mother Earth News,</em> July/August, 1980<strong>:</strong>
            "I suggested that we simply provide young people with schools where there are a lot of interesting things to
            look at and work with . . . but that we let the chidlren learn in their own wqys. If they have questions,
            answer the questions. If they want to know where to look for something, show them where to look."
        </p>
        <p>
            John Holt, from the introduction to his book, <em>Teach Your Own,</em> (New York: Dell, 1981)<strong
            >:</strong> "The children in the classroom, despite their rich backgrounds and high I.Q.'s, were with few
            exceptions frightened, timid, evasive, and self-protecting. The infants at home were bold adventurers."
        </p>

        <p>
            "It soon became clear to me that children are by nature and from birth very curious about the world around
            them, and very energetic, resourceful, and competent in exploring it, finding out about it, and mastering.
            In short, much more eager to learn, and much better at learning, than most adults. Babies are not blobs, but
            true scientists. Why not then make schools into places in which children would be allowed, encouraged, and
            (if and when they asked) helped to explore and make sense of the world around them (in time and space) in
            ways that most interested them?"
        </p>
        <p>
            Psychosom Med 1984 Nov-Dec;46(6):546-8. <strong>Rapid communication: whole blood serotonin and the type A
                behavior pattern.</strong> Madsen D, McGuire MT.<strong>
                In 72 young males, whole blood serotonin is shown to have a pronounced relationship with the Type A
                behavior pattern.</strong> The relationship is explored with multivariate statistical techniques.
        </p>
        <p>
            J Neurochem. 2000 Aug;75(2):732-40. Serra M, Pisu MG, Littera M, Papi G, Sanna E, Tuveri F, Usala L, Purdy
            RH, Biggio G.<strong>
                Social isolation-induced decreases in both the abundance of neuroactive steroids and GABA(A) receptor
                function in rat brain.</strong>
        </p>

        <p>
            Ann Med 2000 Apr;32(3):210-21. <strong>Role of serotonin in memory impairment.</strong> Buhot MC, Martin S,
            Segu L.
        </p>
        <p>
            Ivan Illich and Etienne Verne, <strong><em>Imprisoned in the global classroom.</em></strong>
            London, Writers and Readers Publishing Cooperative, 1976.
        </p>
        <p>
            Ivan Illich, <strong><em>Deschooling society.</em></strong> Harmondsworth: Penguin, 1976 (1971).
        </p>

        <p>
            ----Tools for Conviviality<em> </em>(1973).
        </p>
        <p><strong><em>----Toward a history of needs.</em></strong> New York, Pantheon Books, c1978.</p>
        <p>
            ----Limits to medicine. medical nemesis : the expropriation of health. Harmondsworth New York, Penguin,
            1977.
        </p>
        <p>
            <strong><em>----Celebration of awareness: a call for institutional revolution.</em></strong> Harmondsworth,
            Penguin Education, 1976. Pelican books Originally published: Garden City [N.Y.]: Doubleday, 1970; London:
            Calder and Boyars, 1971.
        </p>

        <p><strong><em>----Disabling professions.</em></strong> London, Boyars, 1977, Ideas in progress series.</p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>
        <p>
            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."
        </p>
        <p>
            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>
        </p>
        <p>
            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.
        </p>
        <p>
            Arzneimittelforschung 1975 Nov; 25(11):1737-44<strong>. [Central action of WA-335-BS, a substance with
                peripheral antiserotonin and antihistaminic activity].</strong> Kahling J, Ziegler H, Ballhause H. "In
            rats and mice the serotonin and histamine antagonistic drug <strong>. . .</strong> (WA 335-BS) caused
            stronger central sedative effects than did cyproheptadine. WA 335-BS also displayed stronger activity
            against reserpine- and central tremorine-induced effects than did cyproheptadine and it slightly enhanced
            d-amphetamine-induced<strong> </strong>

            effects:<strong>
                therefore it may have antidepressant properties. WA 335-BS proved to be</strong>
            <strong>very effective against isolation-induced aggression in male mice.</strong> The comparatively small
            anxiolytic effects may have been caused in part by the central antiserotonin properties." "The results of
            our animal studies suggest WA 335-BS to be an antidepressant with sedative properties."
        </p>
        <p>
            Neuroscience 2000;100(4):749-68<strong>. Behavioral, neurochemical and endocrinological characterization of
                the early social isolation syndrome.</strong> Heidbreder CA, Weiss IC, Domeney AM, Pryce C, Homberg J,
            Hedou G, Feldon J, Moran MC, Nelson P. "Rearing rats in isolation has been shown to be a relevant paradigm
            for studying early life stress and<strong>
                understanding the genesis of depression and related affective disorders.</strong> Recent studies from
            our laboratory point to the relevance of studying the social isolation syndrome as a function of home caging
            conditions."
        </p>

        <p>
            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. 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>
        </p>
        <p>
            Am J Psychiatry 1981 Aug;138(8):1082-5.<strong>
                Tryptophan metabolism in children with attentional deficit disorder.</strong> Irwin M, Belendiuk K,
            McCloskey K, Freedman DX The authors present the first report, to their knowledge, of hyperserotonemia in
            children with attentional deficit disorder who had normal intelligence. Hyperserotonemic children had
            significantly lower levels of plasma total and protein-bound tryptophan and a higher percentage of free
            tryptophan than those with normal serotonin levels. Plasma kynurenine did not differ, suggesting that the
            hyperserotonemia is not due to a blockade of the kynurenine pathway but may reflect on increase in tissue
            tryptophan uptake and use.
        </p>
        <p>
            J Neuropsychiatry Clin Neurosci 1990 Summer;2(3):268-74.<strong>
                Autistic children and their first-degree relatives: relationships between serotonin and norepinephrine
                levels and intelligence.</strong> Cook EH, Leventhal BL, Heller W, Metz J, Wainwright M, Freedman DX
            "Whole-blood serotonin (5-HT) and plasma norepinephrine (NE) were studied in 16 autistic children, 21
            siblings of autistic children, and 53 parents of autistic children. <strong>Both plasma NE and whole-blood
                5-HT were negatively correlated with vocabulary performance."
            </strong>

            "Eighteen subjects were hyperserotonemic (whole-blood 5-HT greater than 270 ng/ml). For these subjects,
            plasma NE was significantly higher than for subjects without hyperserotonemia."
        </p>
        <p>
            Biol Psychiatry 1998 Dec 15;44(12):1321-8. <strong>Cerebrospinal fluid monoamines in Prader-Willi
                syndrome.</strong> Akefeldt A, Ekman R, Gillberg C, Mansson JE "The behavioral phenotype of Prader-Willi
            syndrome (PWS) suggests hypothalamic dysfunction and altered neurotransmitter regulation. The purpose of
            this study was to examine whether there was any difference in the concentrations of monoamine metabolites in
            the cerebrospinal fluid (CSF) in PWS and non-PWS comparison cases." "The concentrations of<strong>
                dopamine and particularly serotonin metabolites were increased in the PWS group. The differences were
                most prominent for 5-hydroxyindoleacetic acid. The increased concentrations were found in all PWS cases
                independently of age, body mass index, and level of mental retardation." "The findings implicate
                dysfunction of the serotonergic system and possibly also of the dopamine system
            </strong>
            in PWS individuals . . . ."
        </p>
        <p>
            Pharmacol Biochem Behav 1976 Jul;5(1):55-61. <strong>The role of serotonergic pathways in isolation-induced
                aggression in mice.</strong> Malick JB, Barnett A Male mice that became aggressive following four weeks
            of social isolation were treated with seven known serotonin receptor antagonists. All of the<strong>
                antiserotonergic drugs selectively antagonized the fighting behavior of the isolated mice; the
                antiaggressive activity was selective since, at antifighting doses, none of the drugs either
                significantly altered spontaneous motor activity</strong>

            or impaired inclined-screen performance. <strong>Antagonism of 5-HTP-induced head-twitch was used as an in
                vivo measure of antiserotonergic activity and a statistically significant correlation existed between
                potency as an antiserotonergic and potency as an antiaggressive.</strong> PCPA, a serotonin depletor,
            also significantly <strong>antagonized isolation-induced aggression</strong> for at least 24 hr postdrug
            administration. The interrelationship between cholinergic and serotonergic mechanisms in the mediation of
            isolation aggression was investigated. The involvement of serotonergic systems in isolation-induced
            aggression is discussed.
        </p>
        <p>
            Probl Endokrinol (Mosk) 1979 May-Jun;25(3):49-52<strong>
                [Role of serotonin receptors of the medial-basal hypothalamus in the mechanisms of negative feedback of
                the hypophyseal-testicular complex].</strong> Naumenko EV, Shishkina GT. "Administration of serotonin
            into the lateral ventricle of the brain of male rats, against the background of complete isolation of the
            medial-basal hypothalamus was accompanied by the block of the compensatory elevation of the blood
            testosterone level following unilateral castration."
        </p>
        <p>
            Encephale 1994 Sep-Oct;20(5):521-5. <strong>[Can a serotonin uptake agonist be an authentic antidepressant?
                Results of a multicenter, multinational therapeutic trial].</strong> Kamoun A, Delalleau B, Ozun M The
            classical biochemical hypothesis of depression posits a functional deficit in central neurotransmitter
            systems particularly serotonin (5-HT) and noradrenaline. The major role suggested for 5-HT in this theory
            led to the development of a large number of compounds which selectively inhibit 5-HT uptake. Numerous
            clinical trials have demonstrated the antidepressant efficacy of such types of serotoninergic agents,
            supporting 5-HT deficit as the main origin of depression. <strong>Therefore, everything seemed clear:
                depression was caused by 5-HT deficit. Tianeptine is clearly active in classical animal models
                predictive of antidepressant activity, and is also active in behavioral screening tests: it antagonizes
                isolation induced aggression in mice and behavioral despair in rats.</strong> Biochemical studies have
            revealed that in contrast to classical tricyclic antidepressant,<strong>
                tianeptine stimulates 5-HT uptake
            </strong>
            in vivo in the rat brain. This somewhat surprising property was observed in the cortex and the hippocampus
            following both acute and chronic administrations. This increase in 5-HT uptake has also been confirmed in
            rat platelets after acute and<strong>
                chronic administrations. Moreover, in humans, a study in depressed patients demonstrated that tianeptine
                significantly increased platelet 5-HT uptake after a single administration as well as after 10 and 28
                days of treatment. The antidepressant activity of tianeptine has been evaluated in controlled studies
                versus reference antidepressants. Another study aiming to compare the antidepressant efficacy of
                tianeptine versus placebo and versus imiporamine is</strong> presented. 186 depressed patients were
            included in this trial. They presented with either Major Depression, single episode (24.6%) or Major
            Depression recurrent (66.8%) or Bipolar Disorder (depressed) (8.6%).
        </p>
        <p>
            Psychopharmacology (Berl) 1998 Oct;139(3):255-60.<strong>
                Ca2+ dependency of serotonin and dopamine release from CNS slices of chronically isolated rats.</strong>
            Jaffe EH. "We have used chronic isolated housing as an animal model of depression." "The following questions
            were addressed: first, if there is a change in the depolarization dependent release of DA and 5-HT from
            these CNS structures, and second, if the release is through the classical exocytotic mechanism. <strong>A
                significant increase in KCl stimulated release of 5-HT was observed in chronically isolated animals when
                compared to controls.
            </strong>
            5-HT release was completely abolished from controls or isolated animals, when slices were incubated with
            Krebs containing zero Ca2+/10 mM Mg2+, the inorganic Ca2+ channel blockers, Cd2+ or Ni2+ and the calmodulin
            inhibitor, trifluoperazine." <strong>"The basal release of DA and 5-HT was similar in control and isolated
                animals and was not affected by the Ca2+ channel antagonists. The results suggest that extracellular
                Ca2+-dependent release of 5-HT and, to a lesser degree, of DA, is increased in this chronic animal model
                of depression in</strong> several CNS structures."
        </p>

        <p>
            Gen Pharmacol 1994 Oct;25(6):1257-1262.<strong>
                Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of
                plasma hemoglobin; the protective action of calmodulin antagonists.</strong> Koren-Schwartzer N,
            Chen-Zion M, Ben-Porat H, Beitner R Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
            <strong>1. Injection of serotonin (5-hydroxytryptamine) to rats, induced a dramatic fall in brain ATP level,
                accompanied by an increase in P(i). Concomitant to these changes, the activity of cytosolic
                phosphofructokinase, the rate-limiting enzyme of glycolysis, was significantly enhanced. Stimulation of
                anaerobic glycolysis was also reflected by a marked increase in lactate content in brain. 2. Brain
                glucose</strong> 1,6-bisphosphate level was decreased, whereas fructose 2,6-bisphosphate was unaffected
            by serotonin. 3. All these serotonin-induced changes in brain, which are characteristic for cerebral
            ischemia, were prevented by treatment with the calmodulin (CaM) antagonists, trifluoperazine or
            thioridazine. 4<strong>.. Injection of serotonin also induced a marked elevation of plasma hemoglobin,
                reflecting lysed erythrocytes,</strong> which was also prevented by treatment with the CaM antagonists.
            5.<strong>
                The present results suggest that CaM antagonists may be effective drugs in treatment of many
                pathological conditions and diseases in which plasma serotonin levels are known to increase.</strong>
        </p>
        <p>
            Gen Pharmacol 1994 Oct;25(6):1257-1262.<strong>
                Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of
                plasma hemoglobin; the protective action of calmodulin antagonists.</strong> Koren-Schwartzer N,
            Chen-Zion M, Ben-Porat H, Beitner R Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
            <strong>1. Injection of serotonin (5-hydroxytryptamine) to rats, induced a dramatic fall in brain ATP level,
                accompanied by an increase in P(i). Concomitant to these changes, the activity of cytosolic
                phosphofructokinase, the rate-limiting enzyme of glycolysis, was significantly enhanced. Stimulation of
                anaerobic glycolysis was also reflected by a marked increase in lactate content in brain. 2. Brain
                glucose</strong> 1,6-bisphosphate level was decreased, whereas fructose 2,6-bisphosphate was unaffected
            by serotonin. 3. All these serotonin-induced changes in brain, which are characteristic for cerebral
            ischemia, were prevented by treatment with the calmodulin (CaM) antagonists, trifluoperazine or
            thioridazine. 4. Injection of serotonin also induced a marked elevation of plasma hemoglobin, reflecting
            lysed erythrocytes, which was also prevented by treatment with the CaM antagonists. 5. The present results
            suggest that CaM antagonists may be effective drugs in treatment of many pathological conditions and
            diseases in which plasma serotonin levels are known to increase.
        </p>

        <p>
            J Neural Transm 1998;105(8-9):975-86. <strong>Role of tryptophan in the elevated serotonin-turnover in
                hepatic encephalopathy.</strong> Herneth AM, Steindl P, Ferenci P, Roth E, Hortnagl H. "The increase of
            the brain levels of 5-hydroxyindoleacetic acid (5-HIAA) in hepatic encephalopathy (HE) suggests an increased
            turnover of serotonin (5-HT)." "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."
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            Watanabe Y; Shibata S; Kobayashi B. <strong>Serotonin-induced swelling of rat liver mitochondria.</strong>
            Endocrinologia Japonica, 1969 Feb, 16(1):133-47.
        </p>
        <p>
            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.
        </p>
        <p>
            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>
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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. 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. <strong>Tianeptine treatment (10 mg/kg/day) prevented the stress-induced atrophy
                of dendrites of CA3 pycamidal neurons,</strong> whereas neither fluoxetine (10 mg/kg/day) nor
            desipramine (10 mg/kg/day) had any effect. <strong>Tianeptine treatment also prevented the stress-induced
                impairment of radial maze learning.</strong>

            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>
        </p>

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