Intelligence and metabolism


by Raymond Peat

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.

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.

Stress early in life can impair learning, cause aggressive or compulsive behavior, learned helplessness, shyness, alcoholism, and other problems.

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.

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.




5 -羟色胺会激活糖皮质激素系统,从而导致脑萎缩。抗血清素可以防止大脑萎缩和许多其他压力影响。保护大脑的神经类固醇,包括孕烯酮和孕酮,在某些刺激下会增加,而在孤立压力下会减少,在它们消失的情况下,血清素和糖皮质激素相对来说没有对立。


Baroness Blatch: “My Lords, the levels of achievement are well above the national average of our own state schools.”

“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?”

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.

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.





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.

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.

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 preferences 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.

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.





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”

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.

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.

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.





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.

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.

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.

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 The Kallikak Family: A Study in the Heredity of Feeble- Mindedness), 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.



这些家族的一些传统可以追溯到孩子的教父是谁。边沁是约翰·斯图亚特·密尔的教父,密尔是伯特兰·罗素的教父;拉尔夫·沃尔多·爱默生是威廉·詹姆斯的教父,詹姆斯是w·j·西迪斯的教父。威利·西迪斯受到父母的教育,要展示他们的教育理论,这一理论源于爱默生和詹姆斯的哲学。他的父亲鲍里斯·西迪斯(Boris Sidis)是研究催眠的先驱,他相信暗示可以调动大脑的“储备能量”。威利很小的时候就学会了好几种语言和高等数学。16岁从哈佛大学(Harvard)毕业后,他尝试在莱斯学院(Rice Institute)教数学,但他对学生和以嘲笑他为职业的报纸和杂志作家的态度感到不快。他曾就读于哈佛大学法学院,如果战争没有结束,他可能会作为一名出于良心拒服兵役者而被监禁。

反犹主义可能是他在哈佛和莱斯大学时感到孤立的原因之一。1912年,智力测试的先驱、《卡利卡克家族:弱智遗传研究》(The Kallikak Family: a Study In The inheritance of weak -minded)的作者亨利·戈达德(Henry Goddard)对移民进行了智力测试,结果发现83%的犹太人和87%的俄罗斯人“弱智”。以当时的标准来看,一个来自东欧的极其贫穷的犹太移民的孩子如此聪明是极不合适的。

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.

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 cliché 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.

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.

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.




西迪斯(W. J. Sidis)和密尔(J. S. Mill)的父母都是受过良好教育的人,因为他们不认同社会的意识形态,所以选择花大量时间教育孩子。每当孩子遇到欧几里得几何或希腊语法的问题时,都能马上回答。进步很快是很自然的,但还有更重要的差异。

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.

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.

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.

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.



近年来,我与一些人交谈,他们仍然认为遗传智力是固定的,他们认为贫困儿童落后是因为他们达到了“遗传极限”。对他们来说,智商代表着一种内在质量的指数,就像区分鱼子酱和青蛙蛋一样重要。然而,马里恩·戴蒙德(Marion Diamond)和加州大学(University of California)的其他人对老鼠的研究表明,老鼠大脑的结构、重量和生物化学成分会随着环境刺激的数量和探索机会的增加而改变。这种大脑结构和功能的改善会传递给下一代,使其处于领先地位。老鼠不太可能比人类更倾向于从智力活动中受益,而且自戴蒙德的研究以来,已有许多发现表明,各种各样的大脑在受到刺激时,在结构和功能上都会变得复杂。


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 feel. He had developed only part of his personality.

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.

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.




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 Genetic Studies of Genius). 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.

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.

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.




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.

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.

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.

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.


在夏山这样的学校里,如果学生想做别的事情,就不要求他们上课,但在毕业时,他们在国家标准化考试中的表现通常比那些认真上课多年的学生要好。夏山是a.s.尼尔(a.s. Neill)于1921年创建的。对学生来说,就像老鼠一样,自由和多样性对大脑有好处,而单调乏味的从众则有害。当一所学校很好的时候,它可以传播一种玩耍的传染和学习的兴趣。



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., Client-Centered Therapy.

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.

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.

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.



虽然三个人不能证明一个论点,但我认为Sidis, Mill和Russell的生活和处境是有用的象征。西迪斯在巨大的压力、社会孤立和极端贫困中长大,享年46岁。密尔主要由他的父亲教育,经济状况稳定,经历了社会孤立和适度的压力,比西迪斯多活了大约20年。罗素在统治阶级的最高圈子里长大,没有任何压力,只有轻微的社会孤立,这在他的阶级中并不罕见。他活到了97岁。


“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.

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.

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.

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.

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.







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.”


John Holt, from an interview in Mother Earth News, July/August, 1980: “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.”


John Holt, from the introduction to his book, Teach Your Own, (New York: Dell, 1981): “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.”

“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?”



Psychosom Med 1984 Nov-Dec;46(6):546-8. Rapid communication: whole blood serotonin and the type A behavior pattern. Madsen D, McGuire MT. In 72 young males, whole blood serotonin is shown to have a pronounced relationship with the Type A behavior pattern. The relationship is explored with multivariate statistical techniques.


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. Social isolation-induced decreases in both the abundance of neuroactive steroids and GABA(A) receptor function in rat brain. 社交孤立导致大鼠脑内神经活性类固醇丰度和GABA(A)受体功能下降。

Ann Med 2000 Apr;32(3):210-21. Role of serotonin in memory impairment. Buhot MC, Martin S, Segu L.

Ivan Illich and Etienne Verne, Imprisoned in the global classroom. London, Writers and Readers Publishing Cooperative, 1976.

Ivan Illich, Deschooling society. Harmondsworth: Penguin, 1976 (1971).

—-Tools for Conviviality (1973).

—-Toward a history of needs. New York, Pantheon Books, c1978.

—-Limits to medicine. medical nemesis : the expropriation of health. Harmondsworth New York, Penguin, 1977.

—-Celebration of awareness: a call for institutional revolution. Harmondsworth, Penguin Education, 1976. Pelican books Originally published: Garden City [N.Y.]: Doubleday, 1970; London: Calder and Boyars, 1971.

—-Disabling professions. London, Boyars, 1977, Ideas in progress series.

Eur J Pharmacol 1992 Feb 25;212(1):73-8. 5-HT3 receptor antagonists reverse helpless behaviour in rats. 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.

5-HT3受体拮抗剂扎可必利、恩丹司琼和ICS 205-930在抑郁症动物模型习得无助测试中的作用被研究。之前经历了60次不可避免的脚电击的大鼠在随后的3次穿梭箱电击中表现出了逃逸能力的不足。5-HT3受体拮抗剂每日腹腔注射2次(扎可必利0.03-2 mg/kg /天;ondansetron和ICS 205-930: 0.125-2 mg/kg / day)在低至中等剂量的每日剂量下减少了逃逸失败的数量。扎可必利、昂丹司琼和ICS 205-930测试的最高剂量未观察到这种效果。提示5-HT3拮抗剂对大鼠可能具有与传统抗抑郁药相同的作用。

Neuropharmacology 1992 Apr;31(4):323-30. Presynaptic serotonin mechanisms in rats subjected to inescapable shock. 不可避免的休克大鼠突触前血清素机制

Edwards E, Kornrich W, Houtten PV, Henn FA. “After exposure to uncontrollable shock training, two distinct groups of rats can be defined in terms of their performance in learning to escape from a controllable stress. Learned helpless rats do not learn to terminate the controllable stress, whereas non-learned helpless rats learn this response as readily as naive control rats do.” “These results implicate presynaptic serotonin mechanisms in the behavioral deficit caused by uncontrollable shock. In addition, a limbic-hypothalamic pathway may serve as a control center for the behavioral response to stress.”


Neurochem Int 1992 Jul;21(1):29-35. In vitro neurotransmitter release in an animal model of depression. Edwards E, Kornrich W, van Houtten P, Henn FA. “Sprague-Dawley rats exposed to uncontrollable shock can be separated by a subsequent shock escape test into two groups: a “helpless” (LH) group which demonstrates a deficit in escape behavior, and a “nonlearned helpless” (NLH) group which shows no escape deficit and acquires the escape response as readily as naive control rats (NC) do.” “The major finding concerned a significant increase in endogenous and K(+)-stimulated serotonin (5-HT) release in the hippocampal slices of LH rats. There were no apparent differences in acetylcholine, dopamine and noradrenaline release in the hippocampus of LH rats as compared to NLH and NC rats. These results add further support to previous studies in our laboratory which implicate presynaptic 5-HT mechanisms in the behavioral deficit caused by uncontrollable shock.”


Psychiatry Res 1994 Jun;52(3):285-93. In vivo serotonin release and learned helplessness. 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. These data support the hypothesis that a cortical serotonergic excess is causally related to the development of learned helplessness.

习得性无助是一种由于暴露在不可避免的压力下而导致的行为抑郁症,被认为是人类抑郁症的动物模型。与人类抑郁症一样,习得性无助也与5 -羟色胺功能缺陷有关,但这种关系的性质尚不完全清楚。我们使用体内微透析脑灌注测量了意识、自由活动大鼠内侧额叶皮质细胞外间隙的5-羟色胺(5-羟色胺,5HT)。暴露于尾震应激前灌注的大鼠的基础5HT水平本身与随后习得的无助行为无关。然而,压力后5HT的释放随着无助行为的增加而显著增加。这些数据支持皮质5 -羟色胺过量与习得性无助的发展有因果关系的假设。

Pharmacol Biochem Behav 1994 Jul;48(3):671-6. Does learned helplessness induction by haloperidol involve serotonin mediation? 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.

习得性无助是一种因不可避免的压力而导致的行为抑郁症。多巴胺D2受体阻滞剂氟哌啶醇(HDL)以剂量依赖性的方式诱导幼稚大鼠产生无助行为,20 mg/kg (IP)时效果最大。注射后24 h处死大鼠。通过体内微透析测量,氟哌啶醇(IP)可增加内侧前额叶皮层(MPC) 5-羟色胺(5-HT)的释放。通过MPC探针灌注HDL可导致皮质5-HT释放增加,灌注多巴胺和多巴胺激动剂阿波吗啡也是如此。我们之前的研究发现,MPC中5-HT释放的增加与LH的发展相关。目前的研究表明,在MPC中DA的释放增加,已知发生在不可避免的压力和HDL中,可能在LH的发展中起必要但不充分的作用。此外,这表明MPC中DA活性的增加导致MPC中5-HT释放的增加,并导致随后的行为抑郁。

Arzneimittelforschung 1975 Nov; 25(11):1737-44. [Central action of WA-335-BS, a substance with peripheral antiserotonin and antihistaminic activity]. Kahling J, Ziegler H, Ballhause H. “In rats and mice the serotonin and histamine antagonistic drug . . . (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 effects: therefore it may have antidepressant properties. WA 335-BS proved to be very effective against isolation-induced aggression in male mice. 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.”

“在大鼠和小鼠中,血清素和组胺拮抗药…(WA 335-BS)比赛庚啶引起更强的中枢镇静作用。与赛庚啶相比,WA 335-BS对利血平和中枢震颤素诱导的作用也表现出更强的活性,并轻微增强d-安非他明诱导的作用:因此它可能具有抗抑郁的特性。在雄性小鼠中,WA 335-BS被证明对隔离诱导的攻击非常有效。相对较小的抗焦虑作用可能部分是由中枢抗血清素特性引起的。“我们的动物研究结果表明,WA 335-BS是一种具有镇静作用的抗抑郁药。”

Neuroscience 2000;100(4):749-68. Behavioral, neurochemical and endocrinological characterization of the early social isolation syndrome. 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 understanding the genesis of depression and related affective disorders. Recent studies from our laboratory point to the relevance of studying the social isolation syndrome as a function of home caging conditions.”


Stroke 1991 Nov;22(11):1448-51. Platelet secretory products may contribute to neuronal injury. 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. 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.


Am J Psychiatry 1981 Aug;138(8):1082-5. Tryptophan metabolism in children with attentional deficit disorder. 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.


J Neuropsychiatry Clin Neurosci 1990 Summer;2(3):268-74. Autistic children and their first-degree relatives: relationships between serotonin and norepinephrine levels and intelligence. 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. Both plasma NE and whole-blood 5-HT were negatively correlated with vocabulary performance.” “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.”

研究人员对16名自闭症儿童、21名自闭症儿童的兄弟姐妹和53名自闭症儿童的父母进行了全血血清素(5-HT)和血浆去甲肾上腺素(NE)的研究。血浆NE和全血5-HT与词汇量呈负相关。18名受试者高血清素血症(全血5-HT大于270 ng/ml)。这些受试者的血浆NE明显高于无高血清素血症的受试者。”

Biol Psychiatry 1998 Dec 15;44(12):1321-8. Cerebrospinal fluid monoamines in Prader-Willi syndrome. 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 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 in PWS individuals . . . .”

“普瑞德威利综合征(PWS)的行为表型表明下丘脑功能障碍和神经递质调节改变。本研究的目的是检测PWS与非PWS比较病例脑脊液(CSF)中单胺代谢物的浓度是否存在差异。“在PWS组,多巴胺和特别是血清素代谢物的浓度增加了。”5-羟基吲哚乙酸的差异最为显著。在所有PWS病例中,浓度的增加与年龄、体重指数和智力迟钝水平无关。“这一发现暗示了PWS患者的血清素系统和多巴胺系统的功能障碍. . . .”

Pharmacol Biochem Behav 1976 Jul;5(1):55-61. The role of serotonergic pathways in isolation-induced aggression in mice. 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 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 or impaired inclined-screen performance. 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. PCPA, a serotonin depletor, also significantly antagonized isolation-induced aggression 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.

研究人员用7种已知的血清素受体拮抗剂对一只雄性老鼠进行了治疗。所有抗5 -羟色胺药物均选择性拮抗离体小鼠的战斗行为;抗攻击活性是选择性的,因为在抗战斗剂量下,没有药物显著改变自发运动活动或损害倾斜屏幕的表现。用拮抗5-羟色胺诱导的头抽动作为抗5-羟色胺能活性的体内测量,在抗5-羟色胺能效力和抗攻击效力之间存在统计学上显著的相关性。PCPA,一种血清素消耗者,也显著拮抗隔离诱导的攻击至少24小时后给药。探讨了胆碱能和血清素能在孤立攻击中的相互关系。讨论了5 -羟色胺能系统在隔离诱导的攻击中的作用。

Probl Endokrinol (Mosk) 1979 May-Jun;25(3):49-52 [Role of serotonin receptors of the medial-basal hypothalamus in the mechanisms of negative feedback of the hypophyseal-testicular complex]. 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.”


Encephale 1994 Sep-Oct;20(5):521-5. [Can a serotonin uptake agonist be an authentic antidepressant? Results of a multicenter, multinational therapeutic trial]. 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. 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. Biochemical studies have revealed that in contrast to classical tricyclic antidepressant, tianeptine stimulates 5-HT uptake 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 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 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%).


Psychopharmacology (Berl) 1998 Oct;139(3):255-60. Ca2+ dependency of serotonin and dopamine release from CNS slices of chronically isolated rats. 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. A significant increase in KCl stimulated release of 5-HT was observed in chronically isolated animals when compared to controls. 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.” “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 several CNS structures.”

“我们用慢性隔离住房作为抑郁症的动物模型。“我们解决了以下问题:首先,这些中枢神经系统结构中DA和5-HT的去极化依赖性释放是否发生了变化,其次,这种释放是否通过经典的胞外机制。”与对照组相比,在慢性分离动物中观察到KCl刺激释放的5-HT显著增加。当切片与含零Ca2+/10 mM Mg2+、无机Ca2+通道阻断剂、Cd2+或Ni2+和钙调素抑制剂三氟拉嗪的Krebs一起孵育时,对照或分离动物的5-HT释放完全被消除。“在对照和分离动物中,DA和5-HT的基础释放量相似,不受Ca2+通道拮抗剂的影响。”结果表明,细胞外Ca2+依赖的5-HT和DA在较低程度上的释放,在这种慢性抑郁症动物模型的几个中枢神经系统结构中增加。”

Gen Pharmacol 1994 Oct;25(6):1257-1262. Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of plasma hemoglobin; the protective action of calmodulin antagonists. Koren-Schwartzer N, Chen-Zion M, Ben-Porat H, Beitner R Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. 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 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.

1. 大鼠注射血清素(5-羟色胺)后,脑内ATP水平显著下降,P(i)升高。伴随这些变化,糖酵解的限速酶-胞质磷酸果糖激酶的活性显著增强。厌氧糖酵解的刺激也反映在脑内乳酸含量的显著增加。2. 脑葡萄糖1,6-二磷酸水平降低,而果糖2,6-二磷酸不受血清素的影响。3.上述5 -羟色胺诱导的脑内变化是脑缺血的特征,用钙调素(CaM)拮抗剂、三氟拉嗪或噻嗪治疗均可预防。4.. 注射血清素也引起血浆血红蛋白的显著升高,反映了红细胞的溶解,这也可以通过CaM拮抗剂的治疗得到预防。5. 目前的结果表明,CaM拮抗剂可能是治疗许多已知血浆血清素水平升高的病理条件和疾病的有效药物。

Gen Pharmacol 1994 Oct;25(6):1257-1262. Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of plasma hemoglobin; the protective action of calmodulin antagonists. Koren-Schwartzer N, Chen-Zion M, Ben-Porat H, Beitner R Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. 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 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.

1. 大鼠注射血清素(5-羟色胺)后,脑内ATP水平显著下降,P(i)升高。伴随这些变化,糖酵解的限速酶-胞质磷酸果糖激酶的活性显著增强。厌氧糖酵解的刺激也反映在脑内乳酸含量的显著增加。2. 脑葡萄糖1,6-二磷酸水平降低,而果糖2,6-二磷酸不受血清素的影响。3.上述5 -羟色胺诱导的脑内变化是脑缺血的特征,用钙调素(CaM)拮抗剂、三氟拉嗪或噻嗪治疗均可预防。4. 注射血清素也引起血浆血红蛋白的显著升高,反映了红细胞的溶解,这也可以通过CaM拮抗剂的治疗得到预防。5. 目前的结果表明,CaM拮抗剂可能是治疗许多已知血浆血清素水平升高的病理条件和疾病的有效药物。

J Neural Transm 1998;105(8-9):975-86. Role of tryptophan in the elevated serotonin-turnover in hepatic encephalopathy. 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.”


Tugai VA; Kurs'kii MD; Fedoriv OM. [Effect of serotonin on Ca2+ transport in mitochondria conjugated with the respiratory chain]. Ukrainskii Biokhimicheskii Zhurnal, 1973 Jul-Aug, 45(4):408-12.

Kurskii MD; Tugai VA; Fedoriv AN. [Effect of serotonin and calcium on separate components of respiratory chain of mitochondria in some rabbit tissues]. Ukrainskii Biokhimicheskii Zhurnal, 1970, 42(5):584-8.

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

Mahler DJ; Humoller FL. The influence of serotonin on oxidative metabolism of brain mitochondria. Proceedings of the Society for Experimental Biology and Medicine, 1968 Apr, 127(4):1074-9.

Eur J Pharmacol 1994 Aug 11;261(1-2):25-32. The effect of alpha 2-adrenoceptor antagonists in isolated globally ischemic rat hearts. 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 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.”

据报道,- 2肾上腺素受体拮抗剂育亨宾可保护缺氧心肌。育亨宾还具有其他几种活性,包括5-HT受体拮抗,在该浓度下被发现具有保护作用。“育亨宾(1-10微米)预处理可导致再灌注左心室发育压力的浓度依赖性增加,舒张末期压和乳酸脱氢酶释放降低。”结构相似的化合物rauwolscine (10 microM)对缺血心肌也有保护作用。而idozoxan (0.3 ~ 10 microM)和tolazoline (10 microM)则无保护作用。育亨宾的心脏保护作用被30 microm5 - ht部分逆转。这些结果表明育亨宾的心脏保护作用可能与5-HT受体拮抗作用有关。

Zubovskaia AM. [Effect of serotonin on some pathways of oxidative metabolism in the mitochondria of rabbit heart muscle]. Voprosy Meditsinskoi Khimii, 1968 Mar-Apr, 14(2):152-7.

Warashina Y. [On the effect of serotonin on phosphorylation of rat liver mitochondria]. Hoppe-Seylers Zeitschrift fur Physiologische Chemie, 1967 Feb, 348(2):139-48.

Eur Neuropsychopharmacol 1997 Oct;7 Suppl 3:S323-S328. Prevention of stress-induced morphological and cognitive consequences.. 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. 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. Tianeptine is known to enhance serotonin uptake, and we compared it with fluoxetine, an inhibitor of 5-HT reuptake, as well as with desipramine. Tianeptine treatment (10 mg/kg/day) prevented the stress-induced atrophy of dendrites of CA3 pycamidal neurons, whereas neither fluoxetine (10 mg/kg/day) nor desipramine (10 mg/kg/day) had any effect. Tianeptine treatment also prevented the stress-induced impairment of radial maze learning. Because 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.

人类海马体的萎缩和功能障碍是某些人衰老的一个特征,这种功能障碍预示着以后的痴呆。有理由相信肾上腺糖皮质激素可能导致这些变化,因为库欣综合征和正常衰老期间糖皮质激素水平的升高与人类整个海马结构的萎缩有关,并与短期语言记忆缺陷有关。我们已经在细胞水平上建立了大鼠海马的应激性萎缩模型,并且我们一直在研究潜在的机制,寻找能够阻止萎缩的药物。在大鼠中持续3周的重复约束应激导致海马结构的变化,包括抑制5-HT1A受体结合和CA3锥体神经元树突萎缩,以及对桡臂迷宫任务的初始学习障碍。由于5 -羟色胺是由应激源释放的,并且可能在神经细胞的应激行为中发挥作用,我们研究了促进或抑制5 -羟色胺再摄取的agents的行为。已知噻奈普汀可增强血清素摄取,我们将其与5-HT再摄取抑制剂氟西汀以及地西帕明进行了比较。噻奈普汀(10 mg/kg/天)可防止应激诱导的CA3锥体神经元树突萎缩,而氟西汀(10 mg/kg/天)和地西帕明(10 mg/kg/天)均无作用。噻奈普汀治疗还可预防应激性径向迷宫学习障碍。因为皮质甾酮- CA3树突和应激萎缩也被苯妥英、兴奋性氨基酸释放和行动的抑制剂,这些结果表明,血清素释放的压力或皮质甾酮可能交互前或post-synaptically谷氨酸释放的压力或皮质甾酮,最后的共同途径可能涉及血清素和谷氨酸受体在齿状回苔藓纤维支配的CA3神经元树突上的相互作用。我们讨论了这些发现对治疗认知障碍和老年痴呆症风险的影响。