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