Behavioral depression in pigeons following L-tryptophan administration

Since elevations of serotonin (5-HT) content in brain have been related to the behavioral depression which follows administration of 5-hydroxytryptophan (5-HTP) to pigeons emitting a food-reinforced learned response, injections of L-tryptophan (100, 200, and 300 mg/kg I.M.), which is partially metabolized to 5-HT, were given to pigeons working on the same behavioral schedule. Qualitatively similar, but shorter, periods of disrupted behavior followed. As is also the case with 5-HTP, pretreatment with 50 mg/kg iproniazid, a monoamine oxidase inhibitor, increases the duration of behavioral depression following L-tryptophan. Pretreatment with 10 mg/kg Lilly 110140, a new highly selective inhibitor for uptake of 5-HT into synaptosomes, also enhanced L-tryptophan induced depression. Initial neurochemical studies indicate that the elevated levels of 5-HT in the telencephalon after an injection of L-tryptophan follow the time course of the depressed behavior. These data support the suggestion that the release of 5-HT plays a role in certain types of behavioral depression.     

Schistosoma mansoni: effects of serotonin and serotonin receptor antagonists on motility and length of primary sporocysts in vitro

The effects of serotonin (5-hydroxytryptamine; 5-HT) on in vitro transformed primary sporocysts of Schistosoma mansoni were investigated. Serotonin treatment significantly increased parasite motility (percentage of motile sporocysts) and length at concentrations as low as 1 microM. These effects were mimicked by the 5-HT agonist tryptamine, albeit with 10- to 100-fold less potency. The effects of 10 microM 5-HT on sporocyst motility were observed within 15 min posttreatment and on parasite length by 6 h posttreatment, and both effects were stable for up to 48 h. Receptor antagonists with varying affinities for defined vertebrate neurotransmitter receptor subtypes were examined for their effects on parasite behavior in the absence and presence of 10 microM 5-HT. In the absence of 5-HT, only methiothepin significantly inhibited normal parasite growth after 48 h of incubation. In the presence of 10 microM 5-HT, the serotonin receptor antagonists mianserin, ketanserin (both at 100 microM), and methiothepin (at 10 microM) significantly inhibited 5-HT-induced lengthening of primary sporocysts, while 3-tropanyl-indole-3-carboxylate and chlorpromazine had no significant effect. The effects of these same drugs on parasite motility were also examined. In the absence of 5-HT, 10 microM chlorpromazine increased parasite motility, while the other antagonists had no effect. When sporocysts were treated with 10 microM 5-HT for 2 h in the continued presence of antagonist, 100 microM mianserin, ketanserin, 3-tropanyl-indole-3-carboxylate, and 10 microM methiothepin inhibited 5-HT induced increases in parasite motility, while 10 microM chlorpromazine had no effect. These results show that primary sporocysts of S. mansoni exhibit behavioral responses to serotonin much like adult stages of this parasite. Furthermore, these responses appear to be mediated via receptors with pharmacological similarities to those previously described in adult worms.     

Effect of serotonin on the basal and gonadotrophin-releasing hormone-induced release of luteinizing hormone from rat pituitary glands in vitro

The effect of serotonin (5-HT) on the basal and gonadotrophin-releasing hormone (GnRH)-stimulated release of luteinizing hormone (LH) was studied in rat adenohypophysis in vitro. Anterior pituitary glands from ovariectomized rats were incubated for 1h in the presence of different doses of 5-HT (0.01 to 3 mumol/l). Serotonin added to the culture medium slightly dimished the basal release of LH and markedly inhibited the release of LH induced by GnRH. Responsiveness to GnRH (3 nmol/l) was significantly reduced, in a dose-dependent manner, by the simultaneous treatment of glands with 5-HT. Maximal inhibition to 65% of the response obtained with GnRH alone, was attained with 1 mumol/l 5-HT. The EC50 value was estimated to be about 1.9 X 10(-7) M. The inhibitory effect of 5-HT was evident within 30 min of incubation. Furthermore, 5-HT appear to exert a short-lasting action, since the rate of basal and GnRH-induced release of LH was reduced during the first hour of incubation, but after 2h the suppressive effects of 5-HT were no longer apparent. Methysergide, a serotonin receptor blocking agent, partially antagonized the inhibitory effect of 5-HT on LH release, either basal or GnRH-stimulated. This suggests that a receptor-mediated component may be involved in the mechanism of 5-HT action. The present results indicate that 5-HT can affect the release of LH by acting directly at the pituitary gland level.     

Effects of L-Tryptophan on Indoleamines and Catecholamines in Discrete Brain Regions of Wild Type and Lurcher Mutant Mice

The biochemical parameters of the serotoninergic system were examined in wild type mice and Lurcher mutants after chronic treatment (40 days) with the serotonin (5-HT) precursor L-tryptophan (50 mg/kg; i.p.). Tissue contents in 5-HT, dopamine and noradrenaline, as well as some of their metabolites, were measured in frontal cortex, neostriatum, thalamus, brainstem, cerebellum and spinal cord by high-performance liquid chromatography. The tissue levels were used as a biochemical index of the function of the monoamine innervations in this animal model of cerebellar ataxia. The results show that Lurcher mutants retain higher concentrations of L-tryptophan and total indoleamines, but that 5-HT is probably stored in a non-releasable compartment. In the particular case of the hypoplastic cerebellum, the reorganization of 5-HT nerve terminals leads to an accrued indoleamine synthesis, indicating that the Lurcher mutants can accumulate 5-HT, but do not utilize it efficiently in synaptic transmission.     

Ovine Pineal Indoles: Effects of l-Tryptophan or l-5-Hydroxytryptophan Administration

L-5-Hydroxytryptophan (L-5-HTP) (20 or 200 mg/kg i.p.) but not L-tryptophan (500 mg/kg i.p.) loading substantially increases serum melatonin in sheep. In the present study we examined the effects of these compounds on pineal serotonin and six serotonin metabolites. L-Tryptophan failed to increase 5-hydroxytryptamine (5-HT; serotonin) or any of its metabolites despite a five-fold increase in pineal tryptophan. In contrast, L-5-HTP loading produced a marked increase in pineal 5-HT and its metabolites, including N-acetylserotonin (NAS) and melatonin, indicating that an increased synthesis of melatonin is responsible for the increased serum melatonin concentration after loading with this precursor. No change in pineal indoleamine N-acetyltransferase (NAT) activity was seen. These results are consistent with the suggestion that, during daytime in the sheep, 5-HT availability may limit the production of melatonin.     

Localization of serotonin in the hypothalamus and the mesencephalon of the guinea-pig

Summary The distribution of serotonin in the hypothalamus and the mesencephalon of guinea-pigs pretreated with both pargyline and L-tryptophan was investigated immunohistochemically using monoclonal antibodies to 5-HT. 5-HT-positive fibers and varicosities appeared distributed throughout the hypothalamus. Some areas showed a greater density of immunoreactivity: the suprachiasmatic nucleus, the region of the supraoptic crest, the area of the medial forebrain bundle, the ventral part of the nucleus ventromedialis, the median eminence and the ventral part of the mammillary bodies. 5-HT nerve fibers were also scattered in the posterior lobe of the pituitary. An extensive supraependymal plexus of immunoreactive axons was observed in most ventricular regions. No 5-HT positive cell bodies were present in the hypothalamus of the guinea-pig under our experimental conditions, whereas an intense serotonin immunoreactivity was detected in perikarya of the brain stem. 5-HT cell bodies were found predominantly in the raphe region including the nucleus raphe dorsalis and raphe medianus, nucleus interpeduncularis, reticular formation and dorsal area of the medial lemniscus.     

Effect of acute administration of L-tryptophan on the release of 5-HT in rat hippocampus in relation to serotoninergic neuronal activity: an in vivo microdialysis study.

Here we have used the brain microdialysis method to test the effect of the 5-HT precursor L-tryptophan on 5-HT release. The release of endogenous 5-HT was measured in ventral hippocampus of the anesthetized rat both under basal conditions and when serotoninergic neuronal activity was raised by electrical stimulation of the dorsal raphe nucleus (DRN). Low frequency electrical stimulation of the DRN evoked a frequency-dependent (2-10 Hz) release of hippocampal 5-HT. The electrically evoked release of 5-HT was markedly enhanced by pretreatment with L-tryptophan (50 and 100 mg/kg i.p.). The effect of L-tryptophan on evoked release of 5-HT was dose-related, detectable at low (2 Hz) stimulation frequencies, and became stronger as the stimulation frequency increased. L-Tryptophan (10, 50 and 100 mg/kg i.p.) had no effect on basal output of 5-HT. We conclude from these findings that elevation of 5-HT precursor availability increases 5-HT release in hippocampus in vivo under conditions of increased serotoninergic neuronal activity.     

Morphofunctional characteristics of serotonin-like neurons in the hypothalamus of rats in ontogeny

An attempt has been made to reveal 5-HT immunopositive (IP) neurones in the hypothalamus of intact foetuses (18th day of gestation) and neonatal (9-day) rats under normal conditions and after their treatment with drugs involved into 5-HT metabolism or into regulation of its uptake by serotoninergic neurones. 5-HTIP cells were not observed in intact animals as well as after L-tryptophan treatment, whereas two large colonies of these neurones were found in the anterio-lateral hypothalamus and dorsomedial nucleus after subsequent injections of monoamine oxidase inhibitor, pargyline, and amino acid precursor of 5-HT synthesis, L-tryptophan. Significantly less intensive reaction was observed after injections of another precursor of 5-HT synthesis, 5-hydroxytryptophan, or pargyline only. Immunostaining evoked by pargyline or L-tryptophan can be prevented by preliminary injections of fluoxetine, a specific inhibitor of 5-HT uptake by serotoninergic neurones. These data suggest that the immunostaining of hypothalamic neurones is due to their capacity to take up specifically 5-HT from the environment rather than to its intraneuronal synthesis from L-tryptophan. However, 5-HT synthesis from 5-hydroxytryptophan in the same cells may also take place. The uptake of extracellular 5-HT by catecholaminergic neurones is absent, since nomifensine, a specific inhibitor of this uptake, does not affect immunostaining.     

Effect of 8-hydroxy-2-(di-n-propylamino)-tetralin on the tryptophan-induced increase in 5-hydroxytryptophan accumulation in rat brain

The injection of 8-hydroxy-2-(di-n-propylamino)-tetralin [8-OH-DPAT]reduced 5-hydroxytryptophan accumulation in vivo in rat cerebral cortex, hypothalamus and brainstem. Brain tryptophan levels were unaffected. Dose-related increases in 5-hydroxytryptophan accumulation produced by single injections of L-tryptophan (0, 25, 75 mg/kg ip) were substantially diminished by pretreatment with 8-OH-DPAT. The drug did not affect the tryptophan-induced increments in brain tryptophan level. Since 8-OH-DPAT is known to reduce the activity of serotonin neurons in vivo, these results suggest that when serotonin neurons are relatively inactive, the ability of an injection of tryptophan to stimulate serotonin synthesis is greatly attenuated.     

Effect of orally administered l-tryptophan on serotonin,melatonin, and the innate immune response in the rat

To assess the effects of external administration of L-tryptophan on the synthesis of serotonin and melatonin as well as on the immune function of Wistar rats, 300 mg of the amino acid were administered through an oral cannula either during daylight (08:00) or at night (20:00) for 5 days. Brain, plasma, and peritoneal macrophage samples were collected 4 h after the administration. The accumulation of 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition was used to measure the rate of tryptophan hydroxylation in vivo. Circulating melatonin levels were determined by radioimmunoassay, and the phagocytic activity of macrophages was measured by counting, under oil-immersion phase-contrast microscopy, the number of particles ingested. The results showed a diurnal increase (p < 0.05) in the brain 5-HTP, serotonin (5-hydroxytryptamine, 5-HT), and 5-hydroxyindolacetic acid (5-HIAA) of the animals which had received tryptophan at 08:00 and were killed 4 h later. In the animals which received tryptophan during the dark period, the 5-HT declined but the 5-HT/5-HIAA ratio remained unchanged. There was also a significant increase (p < 0.05) in nocturnal circulating melatonin levels and in the innate immune response of the peritoneal macrophages in the animals which had received tryptophan at 20:00. The results indicated that the synthesis of serotonin and melatonin, as well as the innate immune response, can be modulated by oral ingestion of tryptophan.     

Inhibition of FAAH,TRPV1, and COX2 by NSAID–serotonin conjugates

Serotonin was linked by amidation to the carboxylic acid groups of a series of structurally diverse NSAIDs. The resulting NSAID–serotonin conjugates were tested in vitro for their ability to inhibit FAAH, TRPV1, and COX2. Ibuprofen-5-HT and Flurbiprofen-5-HT inhibited all three targets with approximately the same potency as N-arachidonoyl serotonin (AA-5-HT), while Fenoprofen-5-HT and Naproxen-5-HT showed activity as dual inhibitors of TRPV1 and COX2.     

Serotonin-induced enhancement of vasopressin and oxytocin secretion in rat neurohypophyseal tissue culture

The effects of serotonin (5-hydroxytryptamine; 5-HT) on vasopressin (VP) and oxytocin (OT) secretion were studied in 13-14-day cultures of isolated rat neurohypophyseal (NH) tissue. The VP and OT contents of the supernatant were determined by radioimmunoassay after a 1 or 2 h incubation. Significantly increased levels of VP and OT production were detected in the tissue culture media following 5-HT administration, depending on the 5-HT dose. The elevation of NH hormone secretion could be partially blocked by previous administration of the 5-HT antagonist ketanserin or metergoline. WAY-100635 did not influence the increased VP secretion induced by 5-HT, but the elevated OT production was prevented by WAY-100635 before 5-HT administration. The application of WAY-100635, ketanserin or metergoline, after 5-HT administration proved ineffective. The results indicate that NH hormone release is influenced directly by the serotonergic system. The serotonergic control of VP and OT secretion from the NH tissue in rats can occur at the level of the posterior pituitary.     

Synthesis and Pharmacology of the enantiomers of the potential atypical antipsychotic agents 5-OMe-BPAT and 5-OMe-(2,6-di-OMe)-BPAT.

The optically pure enantiomers of the potential atypical antipsychotic agents 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]tetralin (5-OMe-BPAT, 5) and 5-methoxy-2-{N-[2-(2,6-dimethoxy)benzamidoethyl]-N-n-propylamino}t etralin [5-OMe-(2,6-di-OMe)-BPAT, 6] were synthesized and evaluated for their in vitro binding affinities at alpha1-, alpha2-, and beta-adrenergic, muscarinic, dopamine D1, D2A, and D3, and serotonin 5-HT1A and 5-HT2 receptors. In addition, their intrinsic efficacies at serotonin 5-HT1A receptors were established in vitro. (S)- and (R)-5 had high affinities for dopamine D2A, D3, and serotonin 5-HT1A receptors, moderate affinities for alpha1-adrenergic and serotonin 5-HT2 receptors, and no affinity (Ki > 1000 nM) for the other receptor subtypes. (S)- and (R)-6 had lower affinities for the dopamine D2A and the serotonin 5-HT1A receptor, compared to (S)- and (R)-5, and hence showed some selectivity for the dopamine D3 receptor. The interactions with the receptors were stereospecific, since the serotonin 5-HT1A receptor preferred the (S)-enantiomers, while the dopamine D2A and D3 receptors preferred the (R)-enantiomers of 5 and 6. The intrinsic efficacies at the serotonin 5-HT1A receptor were established by measuring their ability to inhibit VIP-induced cAMP production in GH4ZD10 cells expressing serotonin 5-HT1A receptors. Both enantiomers of 5 behaved as full serotonin 5-HT1A receptor agonists in this assay, while both enantiomers of 6 behaved as weak partial agonists. The potential antipsychotic properties of (S)- and (R)-5 were evaluated by establishing their ability to inhibit d-amphetamine-induced locomotor activity in rats, while their propensity to induce extrapyramidal side-effects (EPS) in man was evaluated by determining their ability to induce catalepsy in rats. Whereas (R)-5 was capable of blocking d-amphetamine-induced locomotor activity, indicative of dopamine D2 receptor antagonism, (S)-5 even enhanced the effect of d-amphetamine, suggesting that this compound has dopamine D2 receptor-stimulating properties. Since both enantiomers also were devoid of cataleptogenic activity, they are interesting candidates for further exploring the dopamine D2/serotonin 5-HT1A hypothesis of atypical antipsychotic drug action.     

Effect of different environmental temperatures on the serotonin concentration and turnover in the brain stem of a hibernator.

The serotonin (5-HT) and 5-hydroxyindoleacttic acid (5-HIAA) levels and 5-HT turnover were studies in the brain stem of warm- (+30 degrees C) and cold- (+6 degrees C) acclimated golden hamsters, exposed for 3 hours to temperatures of +6 degrees C, +30 degrees C and +37 degrees C, respectively. In war-acclimated hamsters kept under conditions the 5-HT level in the brain did not change significantly during the year. The 5-HIAA level was slightly higher in the winter. The 5-HT turnover varied within limits of 0.071 to 0.180 mug/g/hour-1. Three hours' exposure of warm-acclimated golden hamsters to cold (6 degrees C) increased the concentrations of 5-HT and 5-HIAA and the 5-HT turnover in the brain. After long-term adaptation to cold (6 degrees C) the 5-HT level, and the 5-HT turnover returned to the original level. Three hours' exposure of golden hamsters to higher environmental temperatures (warm-acclimated individuals to 37 degrees C and cold-acclimated individuals to 30 degrees C) also increased the 5-HT turnover. The concentrations of 5-HT and 5-HIAA increased in cold-acclimated golden hamsters exposed to 30 degrees C and was not changed in warm-acclimated ones, exposed to 37 degrees C. Although the elevated temperatures induce greater changes in serotonin metabolism than lowered temperatures, the serotonin pathways in the brain do not seem to be affected by short-term temperature changes specifically. The findings are rather indicative that changes in 5-HT turnover may be the primary reaction to stressful conditions.     

Immunocytochemical Distribution of 5-HT (Serotonin) in the Nervous System of the Gastrotrich Turbanella cornuta

The 5-HT (serotonin) distribution in the nervous system of the macrodasyoid gastrotrich Turbanella cornuta was studied using immunocytochemical methods. Positive immunoreaction was found in two pairs of neurons. The neurons of one pair had processes which extended peripherally to the surface of the body. Central processes of both pairs entered the brain commissure and proceeded into the longitudinal cords. Unlike other acoelomate worms studied so far, the Platyhelminthes and the Nematoda, in this gastrotrich no 5-HT positive perikarya or processes were present in the pharynx innervation, and no positive neurons sent processes directly to the nerve cords     

A comparative study of serotonin metabolism in helminths and their hosts]

Studies have been made on the content of the main metabolite of serotonin, namely 5-hydroxyindoleacetic acid in parasitic worms from various classes. It was shown that 5-hydroxyindoleacetic acid level is lower than that of serotonin, which is taken as an indication of low catabolism of serotonin in worms. This tendency was observed in helminths from different taxonomic, ecological and age groups invading media with both low and high levels of serotonin metabolism.     

The occurrence, synthesis and metabolism of 5-hydroxytryptamine and 5-hydroxytryptophan in the cestode Hymenolepis diminuta: a high performance liquid chromatographic study

The biosynthesis and metabolism of 5-hydroxytryptamine (serotonin; 5-HT) in the cestode Hymenolepis diminuta was investigated by High Performance Liquid Chromatography (HPLC). Incubation of intact H. diminuta in [3H]tryptophan resulted in substantial radioactivity recovered in 5-HT, 5-hydroxytryptophan (5-HTP), and 5-hydroxyindoleacetic acid (5-HIAA). Furthermore, the tissue levels of 5-HT and 5-HTP, as determined by HPLC with electrochemical detection, were significantly depressed when the animals were deprived of tryptophan. On the other hand, the tissue levels of 5-HTP were significantly increased following incubation with the 5-HTP decarboxylase inhibitor m-hydroxybenzylhydrazine. The synthesis and metabolism of 5-HT are discussed in the light of 5-HT as a physiological transmitter in H. diminuta.     

Sites of serotonin uptake in epithelia of the developing mouse palate, oral cavity, and face: possible role in morphogenesis

With the method of whole mouse embryo culture, together with immunocytochemistry with an antiserum to serotonin (5-HT), sites of 5-HT uptake were found to be transiently expressed in the epithelia of the developing palate, tongue, nasal septum, and maxillary and mandibular prominences during the period of active morphogenesis (embryonic days 12-14; or E12-14). These sites had the ability to take up 5-HT when added to the culture medium in the presence of the MAO inhibitor nialamide and an antioxiant, L-cysteine (NC), and could also be seen after exposure of embryos to the 5-HT precursor L-tryptophan (L-TRP) + NC. These sites were also visible after culturing embryos without any additives, which may have been due to the presence of L-TRP in one component of the culture medium (DMEM) or to 5-HT itself, which is present in relatively high amounts in fetal calf serum. At E12-13, the appearance of 5-HT immunoreactivity (IR) at these sites after treatment with 5-HT + NC was blocked by the 5-HT uptake inhibitor fluoxetine, providing further evidence that these are true sites of 5-HT uptake. However, fluoxetine did not completely block the appearance of these sites in E14 embryos after 5-HT + NC or L-TRP + NC although it was effective with NC alone. This finding could mean that at E14 5-HT uptake into these sites occurs by mechanisms not completely blocked by fluoxetine or that there is some limited capacity for 5-HT synthesis. Taken together with results from previous studies where 1) 5-HT has been reported to stimulate palatal shelf reorientation and palatal mesenchyme cell motility in vitro [Wee et al., J Embryol Exp Morphol 53:75-90, 1979; Zimmerman et al., J Craniofac Genet Dev Biol 3:371-385, 1983] and 2) long-term culturing of mouse embryos in the presence of 5-HT or fluoxetine has been shown to cause malformations of the craniofacial region (Lauder, Thomas, and Sadler, in preparation), the results of the present study suggest that 5-HT could act as a developmental signal in the palate, oral cavity, and face during the period of active morphogenesis.     

Effects of sex factors and hemispheric localization on the involvement of serotonin from the frontal cortex, striatum, and nucleus accumbens into the processing of novel and repeatedly presented information in rats

The effects of novel or relevant (a single exposure to experimental chamber) and irrelevant (20 exposures to experimental chamber) stimuli on the levels of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the frontal cortex, striatum, and nucleus accumbens in the left and right hemispheres were studied in male and female rats. It was found that 5-HT and 5-HIAA contents in the frontal cortex changed in response to neither relevant nor irrelevant stimuli. However, there were hemispheric difference in 5-HT and 5-HIAA in the frontal cortex of intact animals. The level of 5-HT in males and the level of 5-HIAA in females were higher in the left frontal cortex. In females, the level of 5-HIAA in the left striatum decreased in response to the novel stimulus. Sex differences in: a) 5-HT metabolism (increase in the level of 5-HIAA in males and increase in 5-HT in females) and b) lateralization (the striatal 5-HT metabolism in males changed bilaterally and only in the left hemisphere in females) were observed in reactions to irrelevant stimuli. Both in male and female rats, serotonin content in the nucleus accumbens changed only in response to the irrelevant stimuli. The 5-HT level increased in the left and right hemispheres independently of sex, but hemispheric difference was revealed only in females, in which the serotonin level was higher in the left nucleus accumbens. It is concluded that serotonergic neurotransmitter mechanisms are involved in hemispheric and sex differences in selective attention.     

Role of Ca(2+) and protein kinase C in the serotonin (5-HT) transport in human platelets

Accumulation of serotonin (5-HT) into human platelets was not affected by the presence of the extra-cellular calcium chelator EGTA, while decreased by platelet incubation with the membrane permeant chelator BAPTA-AM. Serotonin uptake also diminished upon platelet exposure to EGTA/thapsigargin or EGTA/ionomycin which increased the cytosolic [Ca(2+)] to levels lower than those inducing secretion of dense granules. The latter inhibition depended in part on changes of intra-granular pH, since the accumulation of acridine orange, which is driven into the dense granules by the intra-granular acid pH gradient, was slightly decreased in the presence of EGTA/thapsigargin. These compounds also inhibited the 5-HT uptake in platelets pre-incubated with reserpine and bafilomycin that prevent 5-HT from entering into the dense granules. Inhibitors of protease, protein phosphatase, Na(+)/H(+) exchanger or ciclo-oxygenase activities did not modify the serotonin accumulation. Addition of EGTA/thapsigargin to reserpine-treated, [(14)C]5-HT-loaded, platelets caused an imipramine-insensitive release of labelled serotonin. This release was reduced by both BAPTA-AM or protein kinase C inhibitor bisindoylmaleimide (GF). The latter compound, either alone or together with EGTA/thapsigargin, inhibited the 5-HT accumulation in reserpine-treated platelets. It is concluded that both cytosolic [Ca(2+)] and protein kinase C are involved in the regulation of the plasma membrane 5-HT transport.