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    <h1>Intelligence and metabolism</h1>
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<p class="nav"><span class="nav-left">Listed under <a href="/ray-peat.html">Ray Peat</a>.</span><span class="nav-right"><a href="/theme.html">Theme</a></span></p>
<p>From the <a href="https://raypeat.com/articles/articles/intelligence.shtml" target="_blank">original article</a> in 2009. Author: <a href="https://raypeat.com/" target="_blank">Ray Peat</a>.</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&#39;s longevity is likely to be shortened if 
something doesn&#39;t intervene to alter the patterns induced by stress 
early in life.</strong></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&#39;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 &#39;all educationalists&#39; 
should come to Summerhill to see its &#39;invaluable&#39; research, which demonstrated 
that students&#39; development is better when they regulate themselves and 
are not required to attend lessons.</strong></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&#39;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 clichés 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&#39; education courses also give 
a good indication of a person&#39;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&#39;s ability to master the 
culture. </p>
<p>The 
way a person has learned during childhood can shape that person&#39;s manner 
of grasping the culture. To simply accelerate the learning of a standard 
curriculum will increase that person&#39;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&#39;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&#39;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&#39;s brightest have, in fact, 
gone through a crisis of depression, and Terman&#39;s long-term study of 
bright people found that “maladjustment” did increase with I.Q., 
especially among women. But the facts don&#39;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&#39;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&#39;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&#39;s 
godfather was.  Jeremy Bentham was John Stuart Mill&#39;s godfather, 
Mill was Bertrand Russell&#39;s; Ralph Waldo Emerson was William James&#39; 
godfather, James was W. J. Sidis&#39;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&#39;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&#39;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&#39;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&#39; emphasis 
on the fact that Sidis never held a prestigious job nicely illustrates 
their cliché mentality: “If you&#39;re so smart, why aren&#39;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&#39;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&#39;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&#39;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&#39; 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&#39;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&#39;t likely 
that rats are more disposed than humans to benefit from mental activity, 
and in the years since Diamond&#39;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&#39;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&#39;t experience a sense of academic pressure, and was able to read 
whatever he wanted in his late grandfather&#39;s library. He didn&#39;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&#39;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&#39;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&#39;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&#39;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&#39;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&#39;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&#39; 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&#39;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&#39;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&#39;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&#39;t trying hard enough, 
or doesn&#39;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>
<h2>References</h2>
<small>
<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.&#39;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 &quot;helpless&quot; 
(LH) group which demonstrates a deficit in escape behavior, and a &quot;nonlearned 
helpless&quot; (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&#39;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&#39;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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