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The Thousand Yard Stare
The Look Of Total Stress
The Problem Of Brain Energy
The Boston Globe, in 2000, wrote:
"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."
"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."
And Dr. Ray Peat, of RayPeat.com, comments:
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.
Thus, we set the stage for Part V of this Depression serries.
As one gets older, biochemical changes occur in cell signaling, receptor sites, neurotransmitter synthesis, bioabsorption, biodelivery, and biotransformation, among numerous other things occur. The elderly are often 'targets' for depression therapy.
But now, many in the prime of life and middle age are also undergoing depression diagnosis at an ever alarming rate. Why? One reason is that there are endocrine disruptors everywhere: In the food we eat, the water we drink, and maybe in aerosols one sprays about the domicile, or the city sprays down sewers and in the air for insect control.
More is being discovered on a regular basis. Many throughout the world are believing the 'drivel' that polyunsaturates are not only good for you; they are necessary for you—actually, the PUFAs are toxic fats and probably most of the 'higher–ups' in the medical/scientific community know this; but, they are controlled with the threat of tenure loss, job loss, and defamation of character if they go against the edible oil industry, as they finance so many studies and grants. The government is lobbied by the latter organization, such that "promises made, gifts exchanged, the mouths kept shut!"
There are many diseases out there, such as diabetes that accelerate aging. This accelerated aging often brings depression with it.
However, with the elderly, and now as in the young and middle aged, due to all the toxic fats, endocrine disruptors and other chemicals in our environment, it appears that the brain may be suffering from lack of using glucose adequately in certain areas, as one ages, thus generating cognitive deficits and Alzheimer's, along with depression. See Coconut Oil and Alzheimer’s Disease.
The Medium Chain Triglycerides (MCT), those oils which burn effectively in the body—also known as 'Machine Oil' to body builders, when the brain uses ineffectively glucose, Dr. Newport finds (See above link), the brain tissues suffer and/or deteriorate. Using 'Machine Oil' gives the brain the fuel it needs to stop its downward spiral. And, with proper diet and supplementation, one may regain much lost function, as in recall ability.
If you're a diabetic, and are not obedient to good control, you could set yourself up for, or may have already, dementia. Science News, May 9, 2009, writes:
It would be a good idea to take MCTs several times daily if a diabetic, we feel, to help guard against loss of brain energy. The MCTs just might do the protection you no longer have when glucose drops too low.
Hypoglycemia Linked To Dementia
Severe Low Blood Sugar Episodes Might Heighten Risk In Later Years
By Nathan Seppa May 9th, 2009; Vol.175 #10 (p. 11)
A single episode of low blood sugar severe enough to require prompt medical attention increases a person’s risk of developing dementia in old age, a study in people with diabetes suggests. More than one bout of hypoglycemia seems to heighten the risk even further, researchers report in the April 15 Journal of the American Medical Association.
While chronically high blood sugar is known to increase the risk of dementia and other health problems, less is understood about the long-term effects of periodic low blood sugar, says study coauthor Rachel Whitmer, an epidemiologist at the Kaiser Permanente Division of Research, in Oakland, Calif.
She and her colleagues analyzed medical records from a Kaiser Permanente registry dating from 1980 to 2002 and identified nearly 17,000 people who had type 2 diabetes but no signs of dementia, mild cognitive impairment or even memory complaints during the time span. The people averaged 65 years of age as of 1994.
The scientists noted any low blood sugar episodes that required a trip to a hospital or other emergency facility. For such treatment, Whitmer says, a patient would have gone beyond just being shaky and weak, as happens with mildly low blood sugar. “These were events where patients may have fainted or passed out or may have been unable to communicate with others — and were brought in,” she says.
The scientists then checked for any dementia diagnoses from 2003 to 2007 in this population and found 1,822 cases.
After accounting for differences in age, weight, race, education, gender and diabetes history, the researchers found that people with one severe low blood sugar episode on their record were 45 percent more likely to have dementia in their later years than were people without any blood sugar crashes on their charts. Those with two or more episodes faced more than double the risk of dementia.
Because the study is observational, it’s not clear whether severe low blood sugar actually contributes directly to dementia risk or whether some people already had unnoticed cognitive impairments that heightened their risk of a blood sugar drop — possibly by mishandling medication, Whitmer says.
But when she and her colleagues looked at data only from the early 1980s — nearly two decades before any dementia diagnosis, and when patients were younger and would have been less likely to have dementia — they found that low blood sugar episodes back then still correlated with slightly higher dementia risk later.
The authors hypothesize that a glucose shortage in brain cells or other biomechanisms might play a role.
“This is a worrisome association,” says endocrinologist Philip Cryer of Washington University in St. Louis. But he cautions that an association doesn’t prove that one factor causes the other. “I wouldn’t want doctors and patients to overreact to this hypoglycemia issue and leave blood sugar levels to run high,” Cryer says.
Type 2 diabetes cases worldwide have risen sevenfold since 1983, says physician David Nathan of Harvard Medical School and Massachusetts General Hospital in Boston, writing in the same JAMA issue. This and other recent studies show that “despite the strides that have been and continue to be made, optimal care of patients with diabetes remains an elusive, albeit critical, goal,” he says.
Tryptophan(e) To Use / To Not Use
Tryptophan is widely used as a tranquilizer; or, as an aid for sleep; or, an aid against depression by non–medical and medical persons. The reason this is probably so is because SSRIs (Serotonin Reuptake Inhibitors) are touted as getting more serotonin across in the synapses for those neurons that use it, and since tryptophan goes to serotonin, it makes sense to the lay person as well as the medical professional to take tryptophan.
Serotonin is considered by the medical establishment to fight against depression. However, there are 'boatloads' of treatment–resistant depressives that do not respond to SSRIs. What's going on here? Perhaps, it has more to do with cell signaling, proper receptor site attachment, or the two to three weeks when SSRIs do work, many now feel it is because of stimulation of gene activity that brings about the right "stuff" that combats depression. The SSRIs have a delayed response time in most to all.
People take tryptophan for rest, to fight depression, and to serve as a tranquilizer. The reason above includes the numerous articles in health publications, the internet sites selling the amino acid, and various magazine publications that give detailed explanations that if one has a deficiency of tryptophan, they will have a deficiency of serotonin. And this generates depression. Included with this is the idea that aggression and suicide can be generated if serotonin is low in the body.
When serotonin is injected into an organism, it does not work against depression immediately either. Something else, it is felt in scientific circles, is going on. What it is, is not exactly known.
Estrogen is said to be extremely good for depressives (women), because it increases serotonin activity in the body. Dr. Ray Peat says in Serotonin, Depression, and Aggression: The Problem of Brain energy, on his website that "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."
For those who want to/do take the amino acid L–Tryptophan to facilitate Serotonin (5–HT; 5–hydroxytryptamine) formation, its metabolism works like this. It is converted to 5–hydroxytryptophan (5–HTP) in brain serotonergic neurons by the enzyme L–tryptophan–5–monooxygenase, commonly known as tryptophan hydroxylase (See flow chart below). Another enzyme involved in the conversion process is aromatic L–amino acid decarboxylase. It is soluble and dependent upon pyridoxal–5'–phosphate, and this latter enzyme now completes the conversion of 5–HTP to 5–HT (serotonin).
It has been shown that the administration of B–6 (pyridoxine, P–5'–P,) increases the rate of synthesis of 5–HT (serotonin), in the monkey brain that reflects the effect of B–6 on the L–amino acid decarboxylase (AADC). Thus, the assumption can be made that pyridoxine supplements—we recommend the whole B–Complex in high potencies, in conditions wherein one demonstrates a possible deficiency of 5–HT.
AADC is present also in catecholaminergic neurons and not only in serotonergic neurons. This tends to demonstrate why so many people have gotten results when they changed their diet and included more animal protein in it and ingested a high potency vitamin capsule with high B–complex. They felt better and had a better outlook on life.
Basic Neurochemistry points out on page 232, "It is possible to raise the content of 5–HT in brain not only by increasing the dietary intake of tryptophan (speaking of foods here in complete high protein), but also by raising the intake of 5–HTP. This procedure, though, results in the formation of 5–HT in cells that would not normally contain it (e.g. catecholaminergic neurons) because of the nonselective nature of AADC."
It appears the author recommends tryptophan as found in foodstuffs; but is cautious about taking the 5–HTP, as found at pharmacies, whole food marts, vitamin shops, etc. There is a reason for this caution.
Because of the immediate above, if one takes 5–HTP, they should take the decarboxylase inhibitor Carbidopa (a prescription drug) which keeps 5–HTP from going to 5–HT (serotonin) in the bloodstream outside of the brain, and all tissues get it. This is not advisable. Carbidopa causes 5–HTP to form 5–HT in the brain, where it should be formed, as in taking tryptophan via the food route—it does not do its transformation in the bloodstream and go to all tissues wherein problems can arise; but, only to the brain.
Problems can result if the Carbidopa is not present. These can be lethal effects, such as coronary artery spasm, abnormal platelet aggregation, flushing and diarrhea; if you have a serotonin secreting tumor you will have problems with fibrosis of the endocardium and valves of the right heart, which can cause heart failure. The same problems may exist for one taking 5–HT on a regular basis. How much heart disease exists today, and these other problems, because most physicians do not know this, and hence, do not warn their patients!
If you take 5–HTP, you want to boost levels in the brain and not the blood. Do it this way:
- Take 50 mg of Carbidopa before each 5–HTP dose. Carbidopa is a prescription drug.
- Limit B–6 supplement to a small dose taken at least 6–hours before or after 5–HTP/Carbidopa dosing.
- Have urinary test to measure for a metabolite of serotonin called 5–hydroxyindoleacetic acid (5–HIAA) on a regular basis. As long as 5–HIAA levels are normal, then 5–HTP intake would be safe.
Note: Catabolic Process (Breakdown of serotonin)
"Monoamine oxidase (MAO), converts serotonin to 5–hydroxy–indoleacetaldehyde, and this product is oxidized by an NAD+ [WebMasters Comment: It would be advisable to take Niacin to facilitate this compound]–dependent aldehyde dehydrogenase to form 5–hydroxyindoleacetic acid (5–HIAA)". — Basic Neurochemistry, Seventh Edition, page 237.
- Those with Cardiovascular disease, Atrial fibrillation, Congestive heart failure, cardiomyopathy, Valvular disease, or Pulmonary hypertension may want to avoid 5–HTP.
- The effects of 5–HTP are individualistic—Some may not experience any blood serotonin increase; whereas others could suffer a lethal serotonin peripheral blood increase or overload.
- These warnings apply only to 5–HTP and not to Tryptophan. Published studies show that tryptophan does not readily convert into serotonin in the blood, but 5–HTP does! Since 5–HTP can convert directly into serotonin while tryptophan has to go through one additional metabolic step which protects against blood serotonin overload (See Chart).
Remington: The Science and Practice of Pharmacy, 21 Edition, writes this about Carbidopa on page 1419:
"Is used to protect levodopa and L–5–hydroxytryptophan, both of which are decarboxylated by aromatic amino acid decarboxylase. It is essential that levodopa and 5–hydroxytryptophan be decarboxylated in the brain to their respective biogenic amine products, dopamine and serotonin (5–hydroxytryptamine [5–HT]), which are the active agents. But in the periphery it is not desirable that these amino acids be decarboxylated, since decarboxylation not only lowers the concentration of aromatic amino acid available to the brain but also raises the concentrations of the amine products in the periphery, which give rise to some of the untoward effects of the aromatic amino acids."
What does all this have to do with depression? Everybody is either treating themselves in addition to seeing their doctor, and one should see the tremendous interplay of why much depression across the world is treatment–resistant. And, without this knowledge above, and in these documents of this series, one could get into serious trouble. Even if you applied these modalities, problems can still occur. But, no one is telling you what to do When There Is No Doctor About. This series just might help, but be aware—problems, big time, may occur. When certain people's delicate chemistry is disturbed, when it is already much disturbed, psychosis can result.
If by chance you increase, for example, dopamine too much, it may be like the following:
"Abuse of stimulants like amphetamine, which releases dopamine, was known to cause psychotic symptoms, especially paranoid delusions, similar to those observed for schizophrenia. Given the antipsychotic effects of these D2 blocking drugs in schizophrenia, the dopamine hypothesis was articulated, in which schizophrenia was proposed to be caused by excessive dopaminergic neurotransmission." — Basic Neuroschience, Seventh Edition, page 877.
As one can see from this, science still does not know what the real cause of schizophrenia is, and as such, medications that control it cause a lot of other problems such that the patient drops out of the treatment. They continue by saying:
"...advances will provide the hope for developing more effective treatments that will probably be unrelated to the dopaminergic system, which has dominated pharmacotherapy of schizophrenia for the last 50 years. Ibid, page 884.
Something About LSD You Don't Probably Know
We do not recommend 'so–called' recreational drugs in any form or fashion! But, you need to know something about this drug, LSD. We give this here so you can see how your government has been lying to you. Remember! LSD in overdoses can/will cause hallucinations...period! It can also cause death! The same goes with other drugs, such as cocaine. They best be avoided under any and all circumstances.
Why does one see so many—who should know better—in the medical and dental profession doing such a thing as cocaine, or whatever drug similar to a dopamine agonist? They are quite often suffering from depression, do not know it, need a feel–good feeling, and the dopamine agonist stimulates more dopamine response. One such action calls for another. And, it is readily available to them for their practice.
It is not cocaine, but the pain killers they can easily get, that often lead to the bigger stuff, such as morphine, cocaine, marijuana, nicotine, and ethanol. The down side is the receptor sites on the nerves become quickly acclimatized to the drug, and therefore Down–Regulate, that is, they decrease in number. Say, whereas they had a ten receptor site response, they quickly acclimatized to the agonist and reduced in number the sites, leaving 8 sites remaining.
Thus, the user of the agonist needs not the same amount as last usuage, but more to make up for the lost two. This means he starts using more of the drug to get more 'umph' out of the ingestion or injection. Then, the site number goes to 5 eventually. And so to get the same response as the first time and second time, he must use more. Then, say, for instance, the site number goes to 4. By this time, you have a 'drug addict'. You can see why! He is Down–Regulating his receptor sites for dopamine (or whatever the agonist is increasing) and thus, in order to get the same results as each succeeding increase in the agonist, the user pumps more into his body. This down–regulation is called; or is, a form of Addiction! He may have down–regulated so much, there is not enough to help with his original quest, and he is in deep depression.
As down–regulation increases, he eventually overdoses and, if found in time, rushed to a hospital and his life may be saved; then 'rehab', possible loss of licenses, etc. But, the big problem is that the overdose could cause cessation of life functions—and he/she dies. They 'croak'!
The physician or dentist has ready access to such drugs before he runs afoul. The tip off is in his actions, or the number of prescriptions he writes for certain patients, if they exist. The computer tracks every prescription and type of medication the medical advisor prescribes. It is surprisingly, in this modern age of computers and tracking, this type of person thinks—probably due to the drugs activing his dopamine pleasure/reward pathway, and he is feeling so good, he/she is not aware of the tracking procedure.
Everything a medical person prescribes is tracked. One main reason is for the drug companies to know who is prescribing, and how much, of their products. Most to many physicians/dentists profess to not be aware this leads to perks to them if they prescribe a certain number, legally, of a drug company's products over others that are still in patent. Programs have been written to entrap doctors who 'over' prescribe a drug or medication to a patient too often. . .
LSD is an antagonist of dopamine, very powerful. This is what was put out to the public. But, if this be so, then why do humans...and we might add, experimental lab rats...like it so much? It gives them a sense of feeling good. A sense of more play, and learning was accelerated. Everything was well–being. It was first said that it causes genetic damage by an agency of the U. S. Government, the National Institutes of Mental Health. Other agencies voiced similar. However, when it was discovered in the 60s', that LSD does not cause genetic damage, all government agencies remained quiet. This irresponsible, and we might add, reprehensible action of the government, caused a drug sub–culture to develop, as most users in colleges across America and elsewhere here, knew that it was not dangerous except for its addiction qualities, and that someone may hallucinate if taking too much or, go into coma and die, or just plain die!
Impairment of behavior occurs at exceedingly high doses. LSD research was stopped before it was proven to have harmful side effects. The truth about LSD was the opposite to what was claimed about it: Powerful antiserotonin agent. It is a powerful dopamine agonist. But, there's more.
This hallucinogenic drug of abuse, LSD, targets certain areas in the brain, and its primary targets are serotonin receptors. The amygdala, as you recall from the last Update in this series, "is critical for associative learning related to reward," writes Basic Neurochemistry, Seventh Edition. When this area circuitry is altered along with others in the brain (anterior cingulate cortex, the orbitofrontal cortex, and the dorsolateral prefrontal cortex) craving is associated with their activation. "Disruption of these circuits (decision–making, judgment, and control of impuse) in addicts may be associated with alterations in dopamine transmission." — Basic Neurochemistry, pages 913–914.
Marina E. Wolf, Chapter 56, writing in Basic Neurochemistry, page 923, says:
"Two categories of hallucinogens can be defined based on chemical structure: the tryptamines, which include LSD, and the phenethylamines,...LSD, the most–potent hallucinogenic drug. Based on structural similarity between tryptamines and serotonin, interactions between LSD and serotonin systems have been suspected since the 1950s. the hallucinogenic properties of LSD are now attributed mainly to its partial agonist effects at 5-HT2A receptors. However, LSD's mechanism still remains puzzling, because its high in vivo potency is not predicted from its receptor affinity or intrinsic activity at known signaling pathways....It is also possible that other monoamine receptors contribute to LSD's actions. At the neuronal systems level, frontal cortex and thalamus are important sites of LSD action.
Note, MOA's are involved with Epinephrine, another native chemical to the body of humans and lower primates. Decreased epinephrine is involved in depression.
It was well–known, as the U.S. Government continued with its 'genetic damage' hypothesis, they were lying. Hence, anything else, whether truthful or not, that came out was considered to be a lie againts drugs. Just a few years back, when tryptophan was taken off the market, most of the sub–culture did not believe them, as many scientists, because they had been caught in a "blatant fraud," according to Dr. Peat, of renowned credibility.
The problem that stems from the Tryptophan fraud generated the feeling to this day, the government cannot be trusted, because they have lied on so many other fronts.
"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." — Dr. Ray Peat (See References)
Serotonin, 5–hydroxytryptamine (5–HT), is classified as an indolealkylamin that was originally identified due to its effects on smooth muscle. It constricts vascular smooth muscle and increases the tone of blood vessels. Blood platelets are a source of this substance. It is a vasoconstrictor factor in the serum. It is released into the blood from the platelets when blood clots. Thus, it was given the name 'Serotonin' for Sera from platelets and Tonic for tone.
Various theories have arisen from discoveries of this substance that links "abnormalities of 5–HT function in the brain to the development of a number of psychiatric disorders, particularly schizophrenia and depression. Psychotherapeutic drugs are now available that are effective in depression, anxiety disorders and schizophrenia, and have potent, and in some cases selective, effects on sertonergic neurons in the brain." — Basic Neurochemistry, Seventh Edition, pages 227–228.
Dr. Ray Peat writes in his newsletter, Serotonin, Depression, and Aggression: The Problem of Brain energy, 2009, "While it is true that the newer antidepressants increase the actions of serotonin, it is not true that this explains their antidepressant action."
It is well–known that serotonin, as well as other amines, such as adrenalin or dopamine, if injected, sometimes relieve depression—but injected serotonin never does that. SSRIs do work on selected receptor sites and do increase the activities of adrenalin or dopamine enough such that changes occur, and these changes in those other amines might explain the mood alteration. However, as patents expire, there is a need to speak of newer generation of drugs better than the old. It has been shown that the old MAO inhibitors that were replaced by the SSRIs were better at controlling mood than the SSRIs. The problem with the old antidepressant drugs (MAOs) is that one had to be careful and not eat aged cheese while on the MAO.
If you are suffering with depression or some other mood disorder that calls for SSRIs, and you need the mood uplifted rapidly, then why not get an injection of serotonin? Or some manner of increasing its activity rapidly? Because, if it were readily available in those forms—and there is a reason it is probably not readily available—you would increase helplessness, sedation, or apathy. This can occur some of the time. Then, decreasing serotonin may effect a cure, if increasing serotonin does not.
Estrogen is in our foods, the water one drinks, and so are estrogen mimetics. It affects us in ways most have never even dreamt of. Estrogen has numerous system interrelated functions with serotonin.
Women, as we have discussed in earlier issues of this Depression Series, are more, very much more, likely to have depression than men. And if one has allergies, their histamine goes up. And estrogen increases histamine and serotonin. The activation immitates that of estrogen.
As you know from reading this issue, mood disorders and serotonin are highly interrelated. However, another problem affecting women more so than men is that of an energy nature. There appear to be more disorders of energy affecting women than men. This relates to cellular respiration (ATP formation—the energy currency of the body) and thyroid dysfunction.
Women also have more Alzheimer's disease, brain disease, and liver disease, than men. Serotonin and estrogen have strong connections toward energetic processes in the latter two diseases: Liver disease and brain disease. What liver disease does is increase the exposure of the brain to serotonin. And from above, you recall that excess serotonin is bad news.
Now only does liver disease increase serotonin exposure to the brain; but, it increases ammonia and histamine too. These three amines are neurotoxic and occur together. Remember Stress? These neurotoxic substances are stress–related. Yet, they play a significant role in regulation and signaling. It appears once more that too much of anything is bad for the body.
It would be an idea to consider, if one suffers from depression, and has concomitant allergies,that one get the allergies cleared up or under good control. However, if allergists become in short–shrift, then consider over the counter allergy medicines and some to store. We consider it advisable to be on MCTs (what we call machine oil; see above) and store some to plenty. Definitely store coconut oil and use it now in your cooking.
Consider, if you are depressive, taking Silymarin, Alpha Lipoic Acid, N–Acetyl L–Cysteine (NAC) for aiding in protecting the liver. Take Super Carnosine to assist against the 'Chess Knight' of free radicals, the hydroxyl radical.
For those of you who take GABA, the inhibitory neurotransmitter, take the amino acid, Taurine with it. You do not want to have a gabaminergic stroke!
"Serotonergic or serotoninergic means 'related to the neurotransmitter serotonin'. A synapse is serotonergic if it uses serotonin as its neurotransmitter. A substance is serotonergic if it produces its effects via interactions with the serotonin system.
"A serotonergic, or serotonergic agent, is any chemical which functions to enhance the effects mediated by serotonin in the central nervous system" — Wikipedia.
Estrogen increases serotonin's action in the CNS. It increases serotonergia. Body temperature is decreased with estrogen and these last two effects, serotonergia and hypothermia, generated by estrogen, explains an observerance of long–standing: Estrogen slows learning. It follows from if serotonin is increased, consolidation of learning is interferred with, as estrogen increases serotonin's action. Hypothermia causes a similar effect.
We have recommended throughout this document supplements to consider. We have suggested supplements for the liver. It is advisible because of liver dysfunction does not alter ammonia and send it on its way out the body. A liver that is fatigued also produces ammonia. This creates torpor, spoken more of later. With torpor, one feels "dull" and "hung over." Ammonia works together (synergizes) with 5–HT (serotonin). This helps generate excitotoxicity—the process whereby a neuron (nerve cell) excites itself to death.
As the Hell that's coming, hits with its full vengence, you want to be alert to signs of danger and target indicators! You do not want to be in a state of torpor and feeling "hung over" and "dull."
This is what this series is trying to help you guard against, amongst other things!
The SSRI made by Lilly generates over 2 billion dollars yearly from Prozac. It appears, according to Dr. Ray Peat's sources, that "Each suicide caused by Prozac would appear to be balanced by several hundred thousand dollars earned by the corporation." (WebMaster's Emphasis)
Experiments have demonstrated the importance of estrogen for animal behavior's aggressiveness! And, as given above, estrogen facilitates serotonin's actions. Some research illustrates that more serotonin in a system; more aggressiveness! Agents that decrease serotonin decrease aggressiveness (Ieni et al., 1985; McMillen, et al., 1987), but, recall the section in this series about Learned Helplessness, very clear research demonstrates serotonin's role played is of extreme significance in Learned Helplessness.
You recall that Learned Helplessness is a condition that is created biologically in an individual; or animal from Stress. The stress is inescapable and when that occurs, animals that would normally swim to safety simply give up and drown after a few minutes of swimming, even though they could make it easily. They cannot overcome the challenges because the mental energy is gone (mitochondrial respiration is not there) or physical energy is gone, as thyroid hormone is down.
The serotonin level is high in Learned Helplessness! Serotonin dominance or excess facilitates in generating this state of Learned Helplessness with the psychological environment around such an animal; or human.
Many people will develop this as they are on SSRIs; or extra tryptophan; or 5–HTP, as the economy spirals downward and Earth changes abound. They will have at such time, unless they have prepared for such events, psychological stressors generated:
- Lack of Outlets.
- Lack of Control.
- Lack of Social Support.
- The Perception That Things Are Worsening
Some of your strongest people are going to go down, because they are not aware of what you have just been reading! And many who are, will go down because they have not put into practice what's in this document and have also not prepared mentally, physically, and spirtually. One of the preceding is not enough!
Multiple Sclerosis (MS) and Alzheimer's disease (AD) appear to have nerve damage contributed by serotonin. Women have a higher incidence of MS than men. It debuts most often in their reproductive years. Physicians in this discipline are well–aware of this. As the myelin tissue deteriorates and brain lesions are formed, there is an association with the ratio of estrogen to progestin.
Mast cells are activated in allergies and release histamine. Estrogen causes mast cells to behave as if they have been activated by allergies, in that the mast cells release histamine and serotonin. These cells that are activated can result in edema of the brain and demyelination of its nerve tissue. As in MS, microscopic blood clots may be and have been associated with MS lesions. The clots, formed from the associated lesions have blood platelets that are associated with them, release neurotoxic serotonin. Therefore, it may be applicable to rub on twice daily, some Progesterone Cream.
"Deficiencies of myelin can result from a multitude of causes, including autoimmunity, viral infections, genetic defects, toxic agents, malnutrition and mechanical trauma, that affects myelin, myelin–forming cells or myelinated neurons." MS is the most common demyelinating disease involving the brain and spinal cord (central nervous system). — Basic Neurochemistry, Seventh Edition, pages 639, 641.
There's a connection in Alzheimer's disease and Multiple Sclerosis. These conditions have in common serotonin in the blood plasma, when serotonin should be concentrated in the blood platelets. SSRIs stop the platelates from retaining and concentrating serotonin and release it to the plasma.SSRIs allow serotonin to remain in the plasma of the blood.
When dopamine is increased in this case, it generates benefits in this disease by possibly serving as a serotonin antagonist, the same way that anti–serotonin drugs relieve symptoms in Parkinson's disease. Taking, if you have Parkinson's, 5–HTP (5–hydroxytrypptophan) from your pharmacy, natural food store, etc., can worsen the disease symptoms.
Dr. Ray Peat, Ph.D., writes:
"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., 1997)."
Bromocriptine, a prescription drug, in use for some time now, "has dopamine–like agonist activity." It has been used successfully with senile depression and similar disorders. —Remington, 21 Edition, page 1418.
"CDP–Choline is a potent supplement shown to enhance cognitive function and brain processes.
"Cytidine 5' Diphosphate Choline is an essential intermediate in the conversion of choline to phosphatidyl-choline. This derivative is a unique form of choline that readily passes into the central nervous system, wherein CDP-choline activates the synthesis of critical components of cellular membranes, boosts levels of neurotransmitters acetylcholine, noradrenaline, and dopamine, and enhances cerebral energy metabolism. CDP-choline's neuro-protective effects indicate that it may be significantly effective in maintaining normal brain function and/or circulation" — New CDP-Choline Assists Cognitive Function From Vitamin Retailer, December 1998, Page 59.
We do not suggest CDP–Choline if you are a bipolar patient.
Faciltating GABA's inhibitory action helps in some movement and mood disorders. This facilitory process comes from allopregnanolone, a neurosteroid, of which progesterone is its precursor. It would make good sense in this case to use progesterone cream for mood and movement disorders.
In 2000, Wu, et al., pointed out from their studies that progesterone has certain actions against serotonin.
Many people take tryptophan and/or melatonin. There are uses for these supplements at times, however, most probably abuse them through excess.
From the above chart, one can see that tryptophan goes through two steps goes to serotonin. The later can then be metabolized (5–hydroxyindoleacetic acid (5–HIAA)) out of the body and found in the urine. The other route in the pineal gland turns 5–HT (serotonin) to melatonin. However, when serotonin is too high in the plasma, and high melatonin is formed, then this is the same condition as found in torpor and hibernation.
The mechanism works in this schematic manner. Mitochondrial respiration (the process of forming ATP, the energy currency of the body) is inhibited with too much serotonin. Nerve cells can become over active, resulting in excitotoxicity, the process where nerve cells are literally excited too death! As given, increased activity of the neuronal cells and the decrease of energy generates this process. 5–HT can cause both of these actions.
Many natural food stores have noted that there are some people who, when taking melatonin for sleep troubles, report feeling "hung over" and "dull" the following day, but they did not know why. This is the Torpor! Now you know why, and the mechanism of the why.
It is likely that many of these people are also taking antidepressants, such as SSRIs, and are having trouble sleeping, hence they decide to try melatonin, only to discover their condition worsens.
"In hibernation animals," writes Dr. Ray Peat, "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 (increased production of 5–HT) 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." (Emphasis by WebMasters)
One immediately sees that 'low' cold, hypothermia causes subtle to overt problems, such as the need for more Thyroid Hormone (TH).
"Hypothermia is a condition in which core temperature drops below that required for normal metabolism and body functions which is defined as 35.0 °C (95.0 °F). Body temperature is usually maintained near a constant level of 36.5–37.5 °C (98–100 °F) through biologic homeostasis or thermoregulation. If exposed to cold and the internal mechanisms are unable to replenish the heat that is being lost, a drop in core temperature occurs. As body temperature decreases, characteristic symptoms occur such as shivering and mental confusion."
During Napoléon Bonaparte's retreat from Russia
in the winter of 1812 many troops suffered from hypothermia.
Prepare reader...prepare....Extremely cold weather and extremely hot weather are coming! Have fats, such as real butter, coconut oil and MCTs on hand, along with TH.
Going Face Down: No Energy:
When everything is running smoothly, glycolysis (the breakdown of glucose to energy, carbon dioxide, and water), lactic acid is formed. Serotonin activates glycolysis. Excess serotonin generates excess glycolytic action with excess lactic acid formation. This excess of lactic acid interferes with mitochrondrial respiration (formation of the energy currency of the body—ATP) and thus lactic acid can cause less efficient energy production.
Generally not appreciated in the medical profession, unless you're a NeuroScientist with heavy background in BioChemistry; or vice versa, is that muscle hyperalgesia ("an increased sensitivity to pain, which may be caused by damage to nociceptors (cutaneous and subcutaneous receptors, usually free nerve endings, specialized for the direction of harmful [noxious] stimuli) or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection" — Wikipedia), Hypertension, and heart failure (Babenko, et al., 2000. As you can see from reading this document, excess serotonin can cause biological adaptation events and some panic reactions.
You do not want this happening when you will need all the energy to get through the Nuclear Economy, the same as a Nuclear Winter — nothing is growing and it is dark and dismal! Stay up by being prepared from what you have been reading from these ChemicalBio Updates for sometime now, coupled with its newsletters.
We have been discussing hypoglycemia, low blood sugar, and that it can figure in dementia, especially if you're a diabetic. If you have an autistic person around you when this all goes down, be advised of the following that these people, especially the autistic children, have a high concentration of serotonin in their platelets and serum. Family members, especially under the conditions that are now developing into a Nuclear Economy, and their relatives all present with serotonin excess in the bloodstream. Members of an autistic family tend, and will eat the same foods then. And to share environmental conditions alike.
There are some studies that show that thyroid hormone helps relieve somewhat, autistic children. If you have such a child, now is the time to consult with your physician and try a small, very small dose, if the tests come back normal for the autistic child or adult. If this works to help the autistic child or adult, then have some in storage.
Also, anti–serotonin drugs would be advisable, after testing the serum for serotonin levels of excess. If this is not feasible, then start on Branched Chained Amino Acids in the powder form. Take it with your 'Beans and Rice.' This is smart thinking even if one has no Depression or Serotonin overloads!
Serotonin, as we have emphasized, tends to lower blood glucose, causing hypoglycemia. If you're a diabetic, taking SSRIs and/or tryptophane, or 5–HT to sleep, etc., you run the risk of causing Dementia—You do not want this at a time you will need all your faculties just to stay alive!
Norepinephrine (noradrenaline) is increased during hypoglycemia and hypothyroidism. Autistic children and adults are shown to have more noradrenaline than normal counterparts. Excess serotonin causing theses changes, hypoglycemia and hypothyroidism would seem to justify in autistic people the use of a thyroid supplement and other antidotes to the syndromes of serotonin excess. We recommend for the patient to check with his doctor as given above and request the weakest dose of Cytomel, which is T3.
Keep this simple schematic in mind: 5–HT (hydroxytryptamine 'serotonin') tends to generate low–blood sugar (hypoglycemia) and this condition decreases T4 from going to T3, the active thyroid hormone!
5–HT → Low–Blood Sugar (Hypoglycemia) → <'s T4 → T3
Overdose With SSRIs and/or 5–HTP (5–hydroxytryptophan):
5–HTP's effects are similar to that of SSRIs (serotonin reuptake inhibitors) and can, on occasion, cause fatal Serotonin Syndrome. Symptoms include consciousness that is altered, the 'shakes' known as
tremors, coordination is poor, seizures, and disturbances of the cardiovascular tree. Anti–serotonin drugs can arrest symptoms considerably and quite often prevents death. If no anti–serotonin drugs are available, use branch chain amino acids (BCCA). However, these may not work effectively as they are used to compete against tryptophan absorption in the small intestine and body cells.
Nevertheless the BCCAs do compete with tryptophan for entry into cells of the body. We recommend athletes use BCCAs as they tend to have some anti–serotonin activity and slow down its entry into the body. Serotonin and tryptophan decreases endurance because serotonin and tryptophan reduce glycogen stores. Keep this in mind when fighting bitter cold and subtropical heat, as you're trying to get out of harm's way.
The Serotonin Syndrome has been reported with St. John's Wort usage as an antidepressant.
As you know from Depression: Part I, "When you eat large amounts of carbohydrates, your body secretes more insulin to lower the high blood sugars that follow from the excessive starch, and here comes the rub. The insulin not only increases protein synthesis, but can also lay down more fat in the fat cells of the body. Insulin still does one thing more—it clears from the blood most of the other 5 amino acids from the transport bus that compete with tryptophane, such that tryptophane now has a free ride practically all to itself to the brain to be converted into serotonin."
Thus, as you can see a large carbohydrate dinner increases the ratio of tryptophan to the competing amino acids (L–Leucine, L–isoleucine, and L–valine (branched chain amino acids), including phenylalanine and methionine). This shift in favor of tryptophan increases the body's homeostasis toward serotonin. An animal study demonstrated that bromocriptine reduces obesity, free fatty acids, and insulin when bromocriptine was used, as it is an antiserotonin drug and dopamin agonist.
Reducing the carbohydrates and increasing the high protein, such as ingestion of a high protein powder, should help improve glucose tolerance and keep serotonin levels normal, When The Hell Breaks in its full rigor and you are eating from your beans and rices, etc. stores.
Serotonin and histamine have their proper uses in the body physiologically. They are a mediator of stress that must be balanced the body's energy systems of cellular respiration (ATP formation), and when not, one suffers with lack of energy and depression can come on. They also suffer from hypothyroidism.
When one uses 5–HTP or tryptophan, or SSRIs, which promote serotonin, as the former two, many consider this not wise.
We spoke about the symptoms of hypothyroidism. Many of these are the same as when excess serotonin is in the body. Thyroid hormone, progesterone, complete animal protein are quite important in protection against Serotonin Syndromes.
Incidently, progesterone, like LSD, can stop serotonergic nerves from firing off. An overdose of progesterone, however, does not cause problems, whereas LSD overdose can cause hallucinations, maybe even death.
Prozac is fluoxetine, which is an SSRI. Dr. Ray Peat says:
"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."
Some Neurochemistry /|
Physiology / Anatomy
We Give Some Of Dr. Ray Peat's Notes and Sources: They are well–worth studying and understanding and for his economically priced Ray Peat's Newletter.
Some Notes and Sources:
*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: “Pharmacodynamics: The antidepressant and antiobsessive-compulsive action of fluoxetine is presumed 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 into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine.”
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.
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 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. [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.”
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, 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. 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.
J Mol Cell Cardiol 1985 Nov;17(11):1055-63. Digitoxin therapy partially restores cardiac catecholamine and brain serotonin metabolism in congestive heart failure. 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 an increase both in serotonergic activity in the posterior hypothalamus and pons-medulla and in cardiac sympathetic tone in the failing cardiomyopathic hamster. 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 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. 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.. 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.+2
Brain Res 2000 Jan 24;853(2):275-81. Duration and distribution of experimental muscle hyperalgesia in humans following combined infusions of serotonin and bradykinin. Babenko V, Svensson P, Graven-Nielsen T, Drewes AM, Jensen TS, Arendt-Nielsen L.
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.
Neuropharmacology 1992 Apr;31(4):323-30. Presynaptic serotonin mechanisms in rats subjected to inescapable shock. 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.
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.
Stroke 1991 Nov;22(11):1448-51. Platelet secretory products may contribute to neuronal injury. 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. 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.
J. Clin Psychopharmacol 1991 Aug; 11(4):277-9. Disseminated intravascular coagulation and acute myoglobinuric renal failure: a consequence of the serotonergic syndrome. Miller F, Friedman R, Tanenbaum J, Griffin A. Letter
Chronobiol Int 2000 Mar;17(2):155-72. 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. Luo S, Luo J, Cincotta AH. “Bromocriptine, a dopamine D2 agonist, inhibits seasonal fattening and improves seasonal insulin resistance in Syrian hamsters.” “Compared with control values, bromocriptine treatment significantly reduced weight gain (14.9 vs. -2.9 g, p < .01) and the areas under the GTT glucose and insulin curves by 29% and 48%, respectively (p < .05). Basal plasma insulin concentration was markedly reduced throughout the day in bromocriptine-treated animals without influencing plasma glucose levels. Bromocriptine reduced the daily peak in FFA by 26% during the late light span (p < .05).” “Thus, bromocriptine-induced resetting of daily patterns of SCN neurotransmitter metabolism is associated with the effects of bromocriptine on attenuation of the obese insulin-resistant and glucose-intolerant condition. A large body of corroborating evidence suggests that such bromocriptine-induced changes in SCN monoamine metabolism may be functional in its effects on metabolism.”
Eur J Pharmacol 1982 Jul 30;81(4):569-76. Actions of serotonin antagonists on dog coronary artery. 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, bromocriptine, lisuride, ergometrine, ketanserin, trazodone, cyproheptadine and pizotifen caused non-competitive antagonism of serotonin concentration-response curves.. 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. Maternal aggression in mice: effects of treatments with PCPA, 5-HTP and 5-HT receptor antagonists. 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, 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. 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 possible role for serotonin in the mediation of maternal aggressive behavior of mice.
Naunyn Schmiedebergs Arch Pharmacol 1987 Apr;335(4):454-64. Effects of gepirone, an aryl-piperazine anxiolytic drug, on aggressive behavior and brain monoaminergic neurotransmission. McMillen BA, Scott SM, Williams HL, Sanghera MK. Gepirone (BMY 13805), a buspirone analog, was used to determine the antianxiety mechanism of the arylpiperazine class of drugs. Because of the weak effects of these drugs on conflict behavior, isolation-induced aggressive mice were used as the antianxiety model. Gepirone, like buspirone, potently inhibited attacks against group housed intruder mice (ED50 = 4.5 mg/kg i.p.) without causing sedation or ataxia. Inhibition of aggression was potentiated by co-administration of 0.25 mg/kg methiothepin or 2.5 mg/kg methysergide. Gepirone had variable effects on dopamine metabolism and reduced 5-hydroxytryptamine (5HT) metabolism about one third after a dose of 2.5 mg/kg. In contrast to buspirone, which markedly increased dopaminergic impulse flow, gepirone inhibited the firing of most cells recorded from the substantia nigra zona compacta in doses of 2.3-10 mg/kg i.v. and the effects were reversible by administration of haloperidol. The common metabolite of buspirone and gepirone, 1-(2-pyrimidinyl)-piperazine, caused increased firing rates only. Gepirone potently inhibited serotonergic impulse flow recorded from the dorsal raphe nucleus (88.3% after 0.04 mg/kg) and this effect was partially reversed by serotonergic antagonists. Both buspirone and gepirone displaced [3H]-5HT from the 5HT1a binding site in the hippocampus with IC50 values of 10 and 58 nM, respectively. Non-alkyl substituted aryl-piperazines displaced [3H]-5HT from both 5HT1a and 5HT1b binding sites. Thus, although gepirone may be a weak postsynaptic 5HT agonist, its primary effect is to decrease 5HT neurotransmission. In support of this conclusion was the observed potentiation of antiaggressive effects by blocking 5HT receptors 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. [Participation of the serotonin-reactive brain structure in certain forms of behavior in golden hamsters]. Popova NK, Bertogaeva VD. 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, while the corticosteroids content of the peripheral blood with the playful behavior experiences no changes. Iprazid and 5-oxytryptophan inhibit the playful activity, 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 not associated with the emotional colouration of the condition, but rather reflect the transition from the somnolence to a highly active behavior.
Biol Psychiatry 1985 Sep;20(9):1023-5 Triiodothyronine-induced reversal of learned helplessness in rats. Martin P, Brochet D, Soubrie P, Simon P.
We Now Reccommend One Review:
The Psychology Of Depression |
- Lack of Outlets.
- Lack of Control.
- Lack of Social Support.
- The Perception That Things Are Worsening
The Depressive Spirit Now Cometh
It will be like Atlanta, burn and slash! Total chaos just around the corner!
... To Be Continued ...
Basic Medical Biochemistry: A Clinical Approach, Marks, D.B., Marks, A.D., Smith, C. M., Lippincott Williams & Wilkins, Pennsylvania, 1996.
Basic Neurochemistry: Molecular, Cellular, and Medical Aspects: Seventh Edition, Editors: Siegel, Albers, Brady, Price, Elsevier Academic Press, 2006.
Biochemistry and Molecular Biology: Third Edition, Elliott, W.H., Elliott, D.C., Oxford University Press. NY; 2005.
Cell And Molecular Biology: Concepts And Experiments. Fourth Edition Karp, Gerald. John Wiley & Sons, 2005.
Instant Notes in Biochemistry, Hames, B.D., Hooper, N.M., & Houghton, J. D., Bios Scientific Publishers, NY, Reprinted 1999.
NeuroScience: Fourth Edition, Editors: Purves, Augustine, Fitzpatrick, et. al., Sinauer Associates, Inc. Sunderland, Massachusetts, U.S.A 2008.
Remington: The Science and Practice of Pharmacy, 21 Edition, Lippincott Williams & Wilkins, 2006.
Stress and Your Body, Transcript Book. Professor Robert Sapolsky, Stanford University. The Great Courses®, Science & Mathematics by The Teaching Company. DVD; 2010.
Peat, Ray, Ph.D., Serotonin, Depression, And Aggression: The Problem of Brain Energy. RayPeat.com, 2009.
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As you use your computer, overtime, it slows down!
If your computer downloads slowly, you need to daily do the Following:
- Defrag your machine.
- Use a Cleaner, such as CCleaner (one can also use their Defragger) to Optimize your computer for better performance. Get them here: http://www.ccleaner.com/. It's Free!
- If you find a download from email coming down very slowly; simply close your computer and reboot. Then restart the download.
- Find out from your ISP how much file storage you have, you need at least 20 MB. Also, go there and clean up used files. The ISP does this for you every 30 or so days. If you receive large files, the ISP may bump them back because "no room at the inn."
You Must Defrag Your Computer Regularly
Clean The Registry and Optimize the Machine Regularly
It Will Run Very Erratic and Quite Slowly!
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