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)."
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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