Participation Of Serotonin Research Articles

Linking chronic tryptophan deficiency with impaired bone metabolism and reduced bone accrual in growing rats

There is increasing evidence that serotonin may regulate bone metabolism. However, its role remains to be clarified. Serotonin seems to be either beneficial or detrimental for bone tissues depending on the pharmacological manipulation used. In this study we evaluated the impact of a reduction of serotonergic stores induced by chronic tryptophan (TRP) depletion on various bone parameters in growing rats. For this purpose rats received a TRP-free diet for 60 days. Bone mass, mineral content and density were measured by DXA and by pQCT in the appendicular skeleton. Bone metabolic markers included urinary deoxypyridinoline and serum osteocalcin measurements. IGF-I levels were also evaluated. In TRP-free diet rats, we found a decrease in body weight, a delayed femoral bone growth and bone mineral content as measured by DXA. pQCT analysis showed that these effects were related to a reduction of both cortical and trabecular bone and are associated with a reduction of bone strength. These effects are due to a negative shift in the balance between bone formation and resorption with a significant decrease in bone formation as evidenced by a reduction both in osteocalcin and IGF-I levels. The present data extend our overall knowledge on the participation of serotonin in the regulation of growing bone and could be of interest in studying the impairment of bone growth in depressed subjects under particular condition of rapid bone accrual such as childhood and adolescence.

Role of central dopamine in pain and analgesia

Recent insights have demonstrated a central role for dopaminergic neurotransmission in modulating pain perception and natural analgesia within supraspinal regions, including the basal ganglia, insula, anterior cingulate cortex, thalamus and periaqueductal gray. In addition, while the participation of serotonin and norepinephrine in spinal descending inhibition of pain is well known, a critical role for dopamine in descending inhibition has also been demonstrated. Decreased levels of dopamine likely contribute to the painful symptoms that frequently occur in Parkinson’s disease. Moreover, abnormalities in dopaminergic neurotransmission have been objectively demonstrated in painful clinical conditions, including burning mouth syndrome, fibromyalgia and restless legs syndrome. Evidence from animal models and indirect evidence from pharmaceutical trials also suggest a role for dopamine in chronic regional pain syndrome and painful diabetic neuropathy. Several novel classes of medication with analgesic properties have bearing on dopaminergic activity as evident in the capacity of dopamine antagonists to attenuate their analgesic capacity. An expanded appreciation for the role of dopamine in natural analgesia provides the impetus for further study involving preclinical models and advanced neuroimaging techniques in humans, which may lead to the development of novel therapeutic strategies.

Rikkunshito, an Herbal Medicine, Suppresses Cisplatin-Induced Anorexia in Rats Via 5-HT2 Receptor Antagonism

Chemotherapy with an anticancer agent generally causes gastrointestinal tract disorders such as vomiting and anorexia, but the mechanism remains unclear. Rikkunshito, a kampo preparation, is known to alleviate such adverse reactions. In this study, we attempted to clarify the mechanism. We investigated the decreases of plasma acylated-ghrelin level and food intake caused by cisplatin, serotonin (5-HT), 5-HT agonists, and vagotomy as well as the decrease-suppressing effects of rikkunshito and 5-HT antagonists. In addition, binding affinities of rikkunshito components were determined in receptor-binding assays using 5-HT2B and 5-HT2C receptors. Cisplatin, 5-HT, BW723C86 (5-HT2B-receptor agonist), and m-chlorophenylpiperazine HCl (5-HT2C agonist) markedly decreased plasma acylated-ghrelin levels, although 5-HT3 and 5-HT4 agonists had no effect. In contrast, 5-HT2B and 5-HT2C antagonists suppressed the cisplatin-induced decrease of plasma acylated-ghrelin level and food intake. Administration of rat ghrelin improved the cisplatin-induced decrease in food intake. Vagotomy decreased the plasma acylated-ghrelin level, which was decreased further by cisplatin. Rikkunshito suppressed such cisplatin-induced decreases of plasma acylated-ghrelin level and food intake. The suppressive effect of rikkunshito was blocked by a ghrelin antagonist. Components of rikkunshito, 3,3',4',5,6,7,8-heptamethoxyflavone, hesperidin, and iso-liquiritigenin showed a 5-HT2B-antagonistic effect in vitro, and oral administration of rikkunshito suppressed the cisplatin-induced decrease in the plasma acylated-ghrelin level. The cisplatin-induced decreases of the plasma acylated-ghrelin level and food intake are mediated by 5-HT2B/2C receptors and suppressed by flavonoids in rikkunshito.

Immunohistochemical study of serotonin in lesions of chronic eczema.

Inflammatory mediators participate in the pathogenesis and pathophysiology of skin disease (e.g. eczema). Although some investigators have suggested that serotonin may participate in the eczematous process, there has been little substantial evidence. Our objective was to study further the participation of serotonin in the pathogenesis of chronic eczema. Immunohistochemical techniques were used to study the expression of serotonin in the lesions of patients with chronic eczema. There was a significantly stronger expression of serotonin in the prickle cells, sweat gland cells, sebaceous gland cells, and hair roots of the lesions in patients with chronic eczema. There was no positive expression of serotonin in normal skin. Serotonin is probably important in the pathogenesis of chronic eczema. We demonstrated alterations in the expression of serotonin in chronic eczema lesions, which may in turn provide new insight into the pathogenesis of chronic eczema. Serotonin, along with cytokines, T lymphocytes, B lymphocytes, and macrophages, participates in the immune response and influences the inflammatory process by means of keratinocytes.

Possible Participation of Serotonin in the Peripheral Link of the Defensive Reflex in the Mollusc Lymnaea stagnalis

The contractions of the dorsal longitudinal muscle of the mollusc Lymnaea stagnalis L., which are evoked by electric stimulation of n. cervicalis inferior were studied. It has been shown that an increase of magnesium ion concentration in saline to 10–15 mM decreases reversibly amplitude of the evoked contractions. Application of serotonin produced a dual effect: at concentrations of 2 × 10−5–10−6 M, it enhanced muscle contractions, whereas at concentrations above 10-5 M, on the contrary, decreased them. The inhibitory effect of the serotonin antagonist mianserin on the evoked contraction amplitude increased with elevation of its concentrations in the studied range (from 10−5 to 10−3 M). The enhancing effect of serotonin on muscle contractions was blocked either by previous mianserin application or its application on the background of the already acting serotonin. A participation of serotoninergic mechanisms in the control of the contractile function of the studied muscle is suggested.

Transport and Metabolism of Serotonin in the Human Placenta from Normal and Severely Pre-Eclamptic Pregnancies

We have attempted to elucidate the possible participation of serotonin as an etiological factor in pre-eclampsia. The transport of serotonin into vesicles from the maternal-facing brush border membrane was measured, as well as the metabolism induced by monoamine oxidase (MAO) in placental homogenate obtained from normal-term and severely pre-eclamptic placentas. Kinetic analysis of serotonin uptake by the placental brush border membrane of the syncytiotrophoblast between normally pregnant and severely pre-eclamptic subjects showed no significant difference (similar Vmax and Km values). However, the metabolism of serotonin was significantly higher in placental homogenate from normal pregnancies than in placentas from severely pre-eclamptic pregnancies. These findings suggest that the higher plasma-free serotonin levels observed in severe pre-eclampsia are mainly due to a reduction in MAO-A activity and not limited by the rate of serotonin uptake into the cells.

Mast cell degranulation induces delayed rectal allodynia in rats: role of histamine and 5-HT.

Visceral hypersensitivity is a common feature of functional bowel disorders, where an increased number of mast cells have often been described. Thus, we investigated the effect of an experimental mast cell degranulation induced by BrX-537A on somatic (tail heating) and visceral (rectal distension) sensitivity in rats and the involvement of histamine and/or serotonin on this last response. After BrX-537A administration, the latency of tail withdrawal reflex was shortened within the 2- to 8-hr period. Moreover, BrX-537A reduced the distension volume threshold from 0.8 ml to 0.4 ml inducing allodynia, from 6 to 12 hr after its administration. This effect was suppressed by doxantrazole (mast cell stabilizing agent) and WAY 100635 (5-HT1A receptor antagonist), and reproduced by 5-HTP (5-HT precursor) and 8-OH-DPAT (5-HT1A receptor agonist). However, neither granisetron (5-HT3 receptor antagonist) nor H1, H2, or H3 histamine receptor antagonists modified the BrX-537A-induced allodynia. Consequently, mast cell degranulation initiates a delayed somatic and visceral allodynia, with the participation of serotonin, through 5-HT1A receptor activation, on the visceral response.

Participation of Serotonin in Capsaicin-Induced Mouse Ear Edema

We investigated the involvement of serotonin (5-HT) in mouse ear edema induced by topical application of capsaicin (250 μg/ear). Application of capsaicin to the ear caused degranulation of mast cells in skin connective tissue. Capsaicin-induced ear edema was significantly inhibited by preadministration of 5-HT2 receptor antagonists such as ketanserin (2 mg/kg, i.v.) and LY 53857 (1 mg/kg, i.v.), but not 5-HT1-, 5-HT3- and 5-HT4-receptor antagonists. Intradermal injection of a-methyl 5-HT (5-HT2-receptor agonist) and 5-HT into ear skin produced edema formation more potently than 8-OH-DPAT (5-HT1A agonist) and 2-methyl 5-HT (5-HT3 agonist). 5-HT2 antagonists markedly suppressed the edema response to 5-HT and its receptor agonists, whereas any antagonist for 5-HT1, 5-HT3 and 5-HT4-receptors had no effect. Furthermore, 5-HT2-receptor antagonists partly prevented ear edema in response to substance P (SP), a putative mediator of capsaicin-induced edema, and compound 48/80, a releaser of vasoactive amines from mast cells. These results suggest that 5-HT released from mast cells is partly involved in the development of capsaicin-induced mouse ear edema via 5-HT2 receptors in the ear skin.

Evidence for 5-HT 2 receptor involvement in the stimulation of preovulatory LH and prolactin release and ovulation in normal cycling rats

The participation of serotonin (5-HT) in the control of LH secretion and ovulation has been reported in numerous pharmacological experiments, although the results have been contradictory. In this study to determine the physiological involvement of 5-HT 2 receptors in the control of preovulatory LH and prolactin (PRL) release and ovulation, ketanserin (KET), a selective 5-HT 2 receptor antagonist, was administered to normal cycling rats. Oral administration of KET at 10 mg/kg BW between 0900h and 1300h on the day of proestrus completely blocked ovulation, while the administration after 1500h did not. The ovulation was confirmed 2 days after treatment with KET. There was no consistent effect on the number of ova ovulated. Co-administration of KET with 5-methoxy-N, N-dimethyltryptamine (5-MeDMT), a 5-HT agonist, at a dose of 2 mg/ kg BW ip reversed KET-induced inhibition of ovulation. The highest rate (89%) of reversal was obtained by co-administration at 1500h. KET administered at 1100h completely blocked the preovulatory surge of LH and PRL observed in control animals at 1800h. The present study suggests that 5-HT stimulates preovulatory LH and PRL surge and ovulation via 5-HT 2 receptor under physiological conditions and that the effect of 5-HT depends on the critical period and the 24-hour periodicity.

Blood serotonergic mechanisms in type 2 (non-insulin-dependent) diabetes mellitus

Serotonin (5-hydroxytryptamine, 5HT) is believed to play a role in vasospasm and increased platelet aggregability that in turn could contribute to atherosclerosis. The present study was designed to evaluate a possible participation of serotonin in the development of vascular complications in diabetes mellitus. Whole blood and plasma serotonin, the platelet uptake and release of the amine and serotonin-induced platelet aggregation were studied in 32 patients with Type 2 diabetes. The patients were divided into three groups according to the presence and advancement of retinopathy. Mean levels of blood serotonin content were significantly lower in diabetic patients. The concentration of the amine in the plasma was markedly increased in diabetes. It was correlated with vascular changes of the retina. We established that platelets from diabetic patients took up less serotonin when compared to the control group. Concomitantly enhanced spontaneous release of 5HT from platelets was observed. The platelets of diabetic patients showed increased response to serotonin. There was a relation between serotonin-induced aggregation and the presence of retinopathy. These results suggest that serotonin may be involved in the pathogenesis of diabetic vasculopathy.

Regulation of corticotropin-releasing factor secretion from Leydig cells by serotonin.

CRF is produced in the Leydig cells and acts as a negative autocrine regulator of Leydig cell function. To clarify the hormonal control of CRF secretion by Leydig cells, we evaluated the participation of serotonin (5HT) and serotonin agonists in the release of CRF from Leydig cells and their effects on hCG-induced cAMP generation and steroidogenesis. Serotonin stimulated CRF secretion up to 4-fold above basal levels and inhibited basal and hCG-stimulated cAMP generation and testosterone production (ID50, 1 nM). The inhibitory action of 5HT was prevented by a CRF antibody and the alpha-helical CRF-(9-41) antagonist. The selective 5HT2 receptor agonist (+-)1-[2,5-dimethoxy-4-iodophyryl]2-amino propane hydrochloride (DOI) also stimulated CRF secretion and inhibited hCG-stimulated cAMP generation and testosterone production to control levels (ID50, 7 microM). Serotonergic 5HT1A, 5HT1B/1C, 5HT1D, and 5HT3/5HT2 agonists were less effective inhibitors of hCG-stimulated cAMP and testosterone production, while agonists for the 5HT3 receptor had no effect. [125I]DOI binding studies in Leydig cells demonstrated two sets of receptors with Kd values in the nanomolar and micromolar range, with low and high capacities, respectively. The low affinity site differed from that of brain receptors (Kd, 4.2 nM) and displayed higher binding capacity (50-fold). The selective 5HT2 receptor antagonist ketanserin prevented CRF stimulation and blocked the inhibitory actions of 5HT and DOI, while the alpha 1-adrenergic antagonist prazosin had no effect. Also, treatment of cells with ketanserin increased sensitivity to hCG and raised maximal cAMP and testosterone production. 5HT was a more effective stimulus than hCG in stimulating CRF secretion, and gonadotropin-induced CRF release was inhibited by ketanserin. Inhibitory effects of exogenous CRF were demonstrable after blockade of 5HT action by ketanserin. The inhibitory actions of 5HT were unaffected by pertussis and cholera toxins and were reversed by the addition of 8-bromo-cAMP. These results demonstrate that 5HT acts on 5HT2 receptors in Leydig cells that are distinct from those in the brain to stimulate CRF secretion through a pertussis toxin-insensitive G-protein. This action of 5HT is predominantly mediated by the low affinity 5HT2-binding site and requires full occupancy for maximal CRF stimulation, indicating the absence of spare receptors. 5HT-stimulated CRF inhibits basal and hCG-induced cAMP generation and steroidogenesis. Furthermore, 5HT mediates the stimulatory action of LH/hCG on CRF secretion from Leydig cells and, thus, participates in a negative autoregulatory loop to limit the testosterone response to the gonadotropic stimulus.

Serotonergic effects on carbonic anhydrase activity in the choroid plexus

The carbonic anhydrase (CA) activities in the choroid plexus of dogs were investigated by electron microscopy, and the effects of 5-hydroxytryptophan (5-HTP) on them were examined to elucidate the participation of serotonin in the production of cerebrospinal fluid. The reaction products yielded by the method employed proved to be CA activity by elimination tests using acetazolamide (Diamox). Following administration of 5-HTP, the CA activities fell to 43.3% of the control value, that is, approximately 56% of the CA activities in the choroid plexus were affected by serotonin. When tetrabenazine (TBZ) was administered, the CA activities in the choroid plexus decreased to 22.4% of the control value. These results suggest that the CA activity in the choroid plexus is remarkably suppressed when nervous control of the choroid plexus is disturbed by the administration of a monoamine denervator such as TBZ. The present data indicate that the serotonergic inhibitory effect on the CA activity in the choroid plexus may be less predominant than that of TBZ and acetazolamide.

Participation of serotonin and substance P in the action of cholecystokinin on colonic motility

Cholecystokinin (CCK) has a potent stimulatory effect on gastrointestinal motility. The mechanism of CCK-generated contractions in the colon is unknown. We explored the possibility that CCK-mediated contractions in the guinea pig colon occur via a serotonin and/or substance P pathway. In the circular layer, octapeptide of CCK (CCK-8) had no effect under basal conditions, but after treatment with tetrodotoxin the peptide generated dose-dependent contractions (ED50 6 X 10(-8) M). In the longitudinal layer, CCK-8 produced dose-related contractions (ED50 6 X 10(-9) M) blocked by tetrodotoxin and markedly inhibited by the substance P antagonist, Spantide. The effect of substance P was not significantly antagonized by tetrodotoxin but was markedly attenuated by Spantide. Serotonin produced dose-dependent contractions in the longitudinal layer (ED50 4 X 10(-8) M). Desensitization to serotonin antagonized the action of CCK-8 but had no effect on substance P-mediated contractions. Pretreatment with the serotonin antagonist mianserin inhibited CCK-8- but not substance P-generated contractions. In contrast, the stimulatory effect of serotonin was antagonized by Spantide. These studies suggest that in the circular layer of the guinea pig colon CCK-8 has no effect under basal conditions, but after removal of tonic inhibition, the peptide produced a direct stimulatory effect. In contrast, CCK-8 generated contractions in guinea pig colon longitudinal layer, mediated by a pathway involving serotonin and substance P.

Mechanisms of serotonin involvement in conditioned reflex consolidation.

1. Intrahippocampal injection of 5 μg serotonin into rats immediately after defensive conditioning leads to the development of retrograde amnesia. Injection of the same dose of serotonin inhibits incorporation of [3H]leucine into hippocampal proteins. An increase in the dose of serotonin injected to 10 μg has no effect on consolidation of conditioned reflexes once formed or on protein synthesis in the hippocampus. 2. Addition of serotonin to the incubation medium containing surviving hippocampal slices leads to a decrease in the incorporation of [14C]leucine and an increase in the incorporation of [3H]fucose into total proteins of the hippocampal slices. The most profound inhibition of incorporation of [14C]leucine into hippocampal proteins is observed by the action of maximal and minimal serotonin concentrations. 3. These results suggest that the participation of serotonin in the consolidation process is connected with its regulatory role in protein metabolism in the hippocampus.

Participation of Serotonin in Thyrotropin Release. II. Evidence for the Action of Serotonin on the Phasic Release of Thyrotropin*

During a 12-h light 12-h dark schedule (lights off at 1900 h), male Sprague-Dawley rats show a circadian rhythm of plasma TSH with a zenith near midday. The participation of serotonin (5HT) in the phasic release of TSH was studied using both pharmacological and surgical-stereotaxical approaches. Animals treated with parachlorophenylalanine methyl ester (pCPA), an inhibitor of 5HT synthesis (one or two injections of 250 mg/kg each) showed a reduction or a disappearance of the diurnal peak of TSH, respectively. Additional treatment by 5-hydroxytryptophan, a precursor of 5HT, completely, restored the diurnal TSH peak. Treatment with 5,6-dihydroxytryptamine creatine sulfate, a neurotoxin which selectively destroys 5HT terminals, also induced alterations of the diurnal peak of TSH. There were no major modifications observed in the low nocturnal levels of TSH in rats treated with pCPA, 5-hydroxytryptophan, or 5,6-dihydroxytryptamine. The major serotoninergic innervation of the hypothalamus originates from the raphe dorsalis or centralis; destruction of these two nuclei caused a quasiabolition of the diurnal TSH peak (only a low amplitude TSH circadian rhythm persisted). Hypothalamic 5HT content was measured in the majority of these experiments; the greatest depletions (near 90%) were observed after two injections of pCPA or in rats bearing raphe lesions. We conclude that the diurnal peak of TSH, observed during the physiological circadian rhythm, is serotoninergic dependent.

Participation of serotonin in thyrotropin release. I. Evidence for the action of serotonin on thyrotropin releasing hormone release.

Injection of serotonin (5-HT) into the third ventricle of the rat resulted in a rapid increase of serum TSH; a significant effect was observed 5 min after injection, whereas the maximal effect appeared 10 min after the injection of 1 microgram 5-HT. This stimulating effect of 5-HT was completely prevented by pretreatment with cyproheptadine, a blocker of 5-HT receptors, whereas fluphenazine, a dopamine receptor blocker, was unable to block it. Third venticle injection of 5-HT in rats bearing anterior hypothalamic lesions (which did not affect the suprachiasmatic nucleus or the medio-basal hypothalamus) also induced an increase of serum TSH similar to that observed in normal rats despite the fact that these animals show a lower basal TSH. In vitro, the addition of 5-HT to an incubation medium containing one hemi-anterior pituitary did not modify medium TSH, whereas 5-HT addition induced an increase of medium TSH in the system containing one hemi-anterior pituitary and two hypothalami. We conclude that 5-HT acts on TSH function probably through a stimulation of TRH release.

Participation of serotonin in the phasic release of luteinizing hormone. II. Effects of lesions of serotonin-containing pathways in the central nervous system.

Circadian LH variations were measured in castrated, estradiol-implanted female rats bearing lesions of the raphe nuclei, in which most serotonin (5-HT) containing ascending projections originate, or mediopontine transections interrupting such projections before they enter the hypothalamus. Previous data indicated that pharmacological blockade of 5-HT biosynthesis abolishes the rhythmic pattern of LH secretion; the present study was intended to check whether surgical depletion of hypothalamic 5-HT had a similar effect and whether such abolition could be correlated with hypothalamic or forebrain endogenous concentrations of the amine and of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA). Maximal inhibition of hypothalamic 5-HT and 5-HIAA concentrations were obtained after complete basal mediopontine transections and after lesions of the medial and the dorsal raphe nuclei; under these conditions, the daily variations in plasma LH were reduced by more than 70%. Smaller lesions, even when they completely destroyed the medial raphe, were much less effective. A good correlation was observed between the amplitude of the LH cycle and the extent of hypothalamic, but not of forebrain, 5-HT and 5-HIAA depletion. However, and in contrast to the results of pharmacological 5-HT inhibition, the cyclic pattern of LH secretion could not be totally abolished by any of these surgical procedures. It is concluded that the dorsal raphe contributes to the regulation of rhythmic LH secretion in castrated female rats bearing estradiol implants by modulating the amplitude of this circadian cycle rather than by generating the rhythmic pattern itself.

Inhibitory role of the serotoninergic system in hypoglycaemia-induced growth hormone release in the dog.

The effect of functional activation of the serotoninergic system on base line plasma growth hormone (GH) levels and the participation of serotonin (5-HT) in the GH response evoked by insulin-induced hypoglycaemia were studied in the unanaesthetized dog with the aid of a specific and sensitive homologous radioimmunoassay method. In 4 dogs, intravenous injection of insulin (0.4 IU/kg iv) or infusion of L-tryptophan (TP, 2.0 g over 30 min) showed the latter stimulus to be by far less potent in eliciting growth hormone (cGH) release. Intravenous injection of L-5-hydroxytryptophan (5-HTP, 10 mg/kg iv) in 5 dogs induced a clear-cut rise in cGH, but was accompanied by striking side effects. In 9 dogs, administration of p-chlorophenylalanine (PCPA, 100 mg/kg po daily × 5 days), an inhibitor of 5-HT synthesis, did not modify base line cGH and glucose levels, caused a marked decrease of blood 5-HT and resulted in a magnification of the insulin-induced cGH release. In 8 dogs, similarly treated with PCPA, administration of 5-HTP (10 mg/kg iv), 10 min before the hypoglycaemic stimulus, blunted the GH secretory response to the latter. Chronic feeding of a TP-deficient diet in 5 dogs, was accompanied by a progressive decrease of total and "free" plasma TP, no significant changes in base line cGH and blood glucose levels and a GH response to the insulin stimulus (0.2 IU/kg iv) almost super-imposable to that elicitable in the same animals under normal conditions. TP infusion (2.0 g over 30 min) in 3 TP-deficient dogs, induced a striking reduction of the hypoglycaemia-induced GH release. Collectively, this study suggests that 5-HT does not have a noticeable effect on base line plasma cGH levels but exerts an inhibitory role in hypoglycaemia-induced cGH release.

The influence of apomorphine and tricyclic antidepressant drugs on the level of serotonin and its metabolite in rat brain

Brain levels of serotonin and 5-hydroxyindoleacetic acid were measured in rats after combined treatment with apomorphine and tricyclic antidepressants. The apomorphine-induced elevation of 5-hydroxyindoleacetic acid was prevented by tertiary but not by secondary antidepressants. The results are discussed in relation to the possible participation of serotonin in the mechanism of action of apomorphine.

Studies on the change of fibrinolytic enzyme system due to electric shock. Studies on renal hematuria fibrinolytic enzyme system in blood, urine and kidney tissue

Serotonin is considered a kind of shock-producing substances and its physiological and Pharmacological properties have gradually been elucidated by many investigators since its discovery by Rapport in 1948.Using rabbits, investigations were carried out on the participation of Serotonin in producing renal hematuria which may be explained by Reilly's phenomenon, as well as, on the effect of Serotonin on the fibrinolytic enzyme system in vivo, and the effect of an anti-serotonin agent, Cyproheptadine (Periactin: Nippon Merck-Banyu), on the renal hematuria and the fibrinolytic enzyme system.1) Serotonin, immediately after an intravenous injection, increased plasminogen or proactivator in the blood transiently. While, it showed almost no influence on the fibrinolytic enzyme system in urine, and it did not induce hematuria. There was no increase in the urinary excretion of 5-HIAA (by the method of Sjoerdsma et al.).2) In the case of Reilly's phenomenon, there was no urinary excretion of 5-HIAA.3) In the renal hematuria caused by Reilly's phenomenon, Serotonin showed a slight inhibitory tendency by the retrograde infusion in the renal pelvis. Its effect on the fibrinolytic enzyme system in the blood was complicated.4) Periactin inhibited the renal hematuria caused by Reilly's phenomenon, and also inhibited the fibrinolyic effect of urine. By administration of Periactin, moreover, the increase of plasminogen or proactivator in the blood was inhibited and the mucous membrane of the renal pelvis acquired fibrinolytic ability.