Serotonin Injection Induces A Dramatic Fall In Brain ATP Levels

Mufasa

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This is a study from 1994 by Koren-Schwartzer et al. that is often cited often by Ray Peat. It shows that intraperitoneal serotonin injection (40 mg/kg) causes a dramatic fall in brain ATP levels (24% of normal level). What I don't understand is how the injected serotonin in the peritoneum can have such adverse and immediate effect on the brain, as serotonin does not cross the blood brain barrier. Do you have an idea about this @haidut? As high plasma serotonin is also consistently shown in autism, it seems a valid angle to explore lowering plasma serotonin for autism treatment. I'm not sure what Ray Peat thinks about the calmodulin antagonist that this article mentions.

Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of plasma hemoglobin; the protective action of cal... - PubMed - NCBI
"Plasma serotonin (5-hydroxytryptamine, 5-HT) levels are known to increase in many pathological conditions and diseases. For example, a 15-fold increase in plasma serotonin levels have been demonstrated during cerebrovascular thrombosis (Wester et al., 1992). Elevation of plasma serotonin level by intravenous infusion of this amine into rats, significantly increased blood-brain barrier permeability and reduced cerebral blood flow (Sharma et al., 1990). These findings prompted us to investigate the effects of serotonin on ATP levels and glycolysis in rat brain. Previous experiments in our laboratory have revealed that serotonin exerts a deleterious effect on muscle and skin glucose metabolism, which could be prevented by treatment with calmodulin (CAM) antagonists (Beitner et al., 1982, 1983; Kaplansky and Beitner, 1984). We also found that CaM antagonists are most effective drugs for treatment of skin trauma (Beitner, 1987; Beitner et al., 1989a, b, 1991) and muscle damage (Beitner and Lilling, 1993), where serotonin is known to play a pathogenic role."

"We show here that injection of serotonin to rats induces in brain a dramatic decrease in ATP level, accompanied by stimulation of the activity of cytosolic phosphofructokinase (PFK), the rate-limiting enzyme of glycolysis, and accumulation of lactate. We also show that injection of serotonin causes a marked increase in plasma hemoglobin. All these pathological changes induced by serotonin were prevented by treatment with the CaM antagonists, trifluoperazine (TFP) or thioridazine (TRZ)."

"The experiments presented in Table 1 reveal that injection of serotonin to rats induced a drastic fall in the level of brain ATP (to 24% of normal level), accompanied by an increase in P_i. The levels of Glc-l,6-P:, the potent regulator of carbohydrate metabolism (for reviews, see Beitner, 1979, 1984, 1985, 1990, 1993), were significantly decreased, whereas Fru-2,6-P2 remained unchanged. Lactate content was markedly (more than 3-fold) elevated, suggesting stimulation of glycolysis."

"During these studies, we observed that injection of serotonin causes blood hemolysis. We therefore measured plasma hemoglobin obtained from rats following the injection of serotonin. As shown in Fig. 4, injection of serotonin induced a marked (about 5-fold) increase in plasma hemoglobin. This increase was prevented by treatment with TFP or TRZ. The CaM antagonists alone had no effect on plasma hemoglobin."

"The serotonin-induced changes in ATP, Pi, PFK and glycolysis, as well as the reduction in Glc-1,6-P2, are typical changes which we found to occur in tissue during anoxia (Beitner et al., 1979). Serotonin was reported to induce cerebral arteriolar constriction (Thompson et al., 1984). It also increases blood-brain barrier permeability and reduces regional cerebral blood flow (Olesen, 1985; Sharma et al., 1990). Through these actions, serotonin may induce brain ischemia, which is reflected here by the fall in ATP and the stimulation of anaerobic glycolysis, changes that are characteristic for cerebral ischemia (Sims, 1992). Serotonin has been implicated in the pathogenesis of neuronal damage during ischemia (Globus et al., 1992). Serotonin or ischemia is known to induce accumulations of intracellular calcium which causes cell damage. It was recently found that the calmodulin antagonists, phenothiazines, reduce brain damage after ischemia (Zivin et al., 1989; Yu et al., 1992). Calmodulin antagonists are also cardioprotective in ischemic heart, preserving myocardial ATP (Sargent et al., 1992)."

"An interesting observation is the increase in plasma hemoglobin induced by serotonin (Fig. 4). This increase, which reflects lysed erythrocytes, is compatible with the in vitro experiments, which have shown that exposure of erythrocytes to serotonin increases their osmotic fragility (Kirshtein and Gilboa-Garber, 1975). The increase in plasma hemoglobin may be a useful parameter to measure, in various pathological conditions in which plasma serotonin concentration is increased. The calmodulin antagonists, TFP or TRZ, prevented the serotonin induced elevation in plasma hemoglobin (Fig. 4), suggesting a protective action on erythrocyte membrane against the damaging effect of serotonin. We have also previously found that serotonin induces pathological changes in glucose metabolism in muscle and skin, which were prevented by treatment with calmodulin antagonists (Beitner et al., 1982, 1983; CaM inhibitors antagonize serotonin 1261 Kaplansky and Beitner, 1984). Calmodulin antagonists were also found in our laboratory to be effective drugs in treatment of skin injuries, e.g. burns or frostbite (Beitner, 1987; Beitner et al., 1989a, b, 1991), as well as in treatment of muscle damage (Beitner and Lilling, 1993). It has recently become evident that calmodulin antagonists are a new generation of drugs with broad therapeutic applications (for review, see Mannhold and Timmerman, 1992)."

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Ulysses

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Nice find. The human equivalent is 200-300 mg. Is this a physiological dose?

I'm having a hard time finding information about the total serotonin content of the body, but taking plasma levels, which are typically 100-300 nanograms per milliliter, we have a total plasma content of:

(200 ng/1 mL) * (1000 mL/1 liter) * (1 gram/10^9 nanograms) * (~5 liters of blood) = 10 *10^-4 grams in the blood, or 0.001 grams overall. So, at first blush it would appear that this injection is a huge amount of serotonin. But, it was an intraperitoneal injection, so I'm also not sure about the relevance of the plasma levels. It's hard to find information about the "total" level of serotonin in the body.

For context, how much would 60 mg/day of Prozac raise cerebral serotonin levels?
 
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Mufasa

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Nice find. The human equivalent is 200-300 mg. Is this a physiological dose?

I'm having a hard time finding information about the total serotonin content of the body, but taking plasma levels, which are typically 100-300 nanograms per milliliter, we have a total plasma content of:

(200 ng/1 mL) * (1000 mL/1 liter) * (1 gram/10^9 nanograms) * (~5 liters of blood) = 10 *10^-4 grams in the blood, or 0.001 grams overall. So, at first blush it would appear that this injection is a huge amount of serotonin. But, it was an intraperitoneal injection, so I'm also not sure about the relevance of the plasma levels. It's hard to find information about the "total" level of serotonin in the body.

For context, how much would 60 mg/day of Prozac raise cerebral serotonin levels?

I was wondering the same. I wished they had measured the plasma serotonin concentration before and after injection.
 

haidut

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Nice find. The human equivalent is 200-300 mg. Is this a physiological dose?

I'm having a hard time finding information about the total serotonin content of the body, but taking plasma levels, which are typically 100-300 nanograms per milliliter, we have a total plasma content of:

(200 ng/1 mL) * (1000 mL/1 liter) * (1 gram/10^9 nanograms) * (~5 liters of blood) = 10 *10^-4 grams in the blood, or 0.001 grams overall. So, at first blush it would appear that this injection is a huge amount of serotonin. But, it was an intraperitoneal injection, so I'm also not sure about the relevance of the plasma levels. It's hard to find information about the "total" level of serotonin in the body.

For context, how much would 60 mg/day of Prozac raise cerebral serotonin levels?

It is a high amount but it has been seen to happen naturally in humans, so it is quite possible such levels to occur during severe stress, exhaustive exercise, hypothyroidism, etc.
Great find @Mufasa .

http://www.annclinlabsci.org/content/28/3/167.full.pdf
 

haidut

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Ulysses

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It is a high amount but it has been seen to happen naturally in humans, so it is quite possible such levels to occur during severe stress, exhaustive exercise, hypothyroidism, etc.
Great find @Mufasa .

http://www.annclinlabsci.org/content/28/3/167.full.pdf
Awesome, thanks. This is exactly what I was hoping someone would come back with.

One more question: would the systemic effects of intraperitoneal injection appear faster than those of a plasma injection, or slower? I can see arguments for either.
 

haidut

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Awesome, thanks. This is exactly what I was hoping someone would come back with.

One more question: would the systemic effects of intraperitoneal injection appear faster than those of a plasma injection, or slower? I can see arguments for either.

An IV infusion would usually have faster effects. Since serotonin cannot cross the BBB, it would be the availability of tryptophan that matters the most for brain serotonin levels. However, it has been shown that increased gut serotonin increase brain serotonin levels indirectly, possibly through vagus nerve communication. So, even without systemic presence (e.g. present only in the gut) serotonin can still wreak havoc on the brain.
 
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Mufasa

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However, it has been shown that increased gut serotonin increase brain serotonin levels indirectly, possibly through vagus nerve communication. So, even without systemic presence (e.g. present only in the gut) serotonin can still wreak havoc on the brain.

Yes, this puzzles me the most, that plasma serotonin has such a dramatic effect on the brain in this study. Do you have any evidence that increasing gut serotonin increases brain serotonin? I was thinking that since serotonin increases the permeability of the BBB, it may be able to pass through?
Forced Swimming Increases Serotonin Which Increases The Permeability Of The BBB
 

haidut

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Yes, this puzzles me the most, that plasma serotonin has such a dramatic effect on the brain in this study. Do you have any evidence that increasing gut serotonin increases brain serotonin? I was thinking that since serotonin increases the permeability of the BBB, it may be able to pass through?
Forced Swimming Increases Serotonin Which Increases The Permeability Of The BBB

I saw several studies on this but this was years ago so I have to go look for them. The issue was not only increase BBB permeability. Disturbed digestion seemed to directly affect brain serotonin through nerve signals, which is something Peat has been saying for years.
 
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Mufasa

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I saw several studies on this but this was years ago so I have to go look for them. The issue was not only increase BBB permeability. Disturbed digestion seemed to directly affect brain serotonin through nerve signals, which is something Peat has been saying for years.

Ah that is interesting. This study discusses that serotonin passes the BBB through the serotonin transporter:
Serotonin Crosses The BBB Through The Serotonin Transporter
 

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