Comparative experimental study of antiemetic action of latranum in radiation-induced vomiting and vomiting caused by apomorphine

The experiments on dogs showed that Latranum, a selective blocker of serotonin 5-HT3-receptors, has a moderate capacity to modify emetic reaction caused by dophamin-stimulating action of Apomorphinum. These results, taking in account of our preliminary experimental data obtained by a model of early radiation-induced emetic reactions, show that the high antiemetic effect of Latranum may affect another mechanisms of the initiation of early radiation-inducing vomiting which do not connect immediately with the chemoreceptor trigger zone.     

An experimental study of the role of a blockade of serotonin 5-HT3 receptors and dopamine D2 receptors in the mechanism of the occurrence of early radiation vomiting in monkeys

The experiments with M. fasciculata monkeys exposed to 137Cs gamma-radiation with a dose of 6.9 Gy showed that Latranum, a blocker of serotonin 5-HT3 receptors, is a more efficient antiemetic than Dimetphramidum, a D2 dophamin lytic. This is suggested by fewer animals with emetic reaction of by less severe vomiting in case they have any. The results agree well with a hypothesis that serotonin receptors are dominant in the chemoreceptor trigger zone of monkeys.     

The involvement of brain 5-HT(1A)-receptors in genetically determined aggressive behavior

The hypothesis was tested that one of the critical mechanisms underlying genetically determined aggressiveness involves brain serotonin 5-HT(1A)-receptors. The expression of 5-HT(1A)-receptor mRNA in brain structures and functional correlate for 5-HT(1A)-receptors identified as 8-OH-DPAT-induced hypothermia were studied in Norway rats bred over the course of 59 generations for the low and high affective (defensive) aggressiveness with respect to man and in highly aggressive (offensive) MAO A-knockout mice (Tg8 strain). Considerable differences between the aggressive and the nonaggressive animals were shown. Agonist of 5-HT(1A)-receptor 8-OH-DPAT (0.5 mg/kg for rats and 2.0 mg/kg for mice, i.p.) produced a distinct hypothermic reaction in nonaggressive rats and mice and did not affect significantly the body temperature in aggressive animals. In aggressive rats, a significant reduction of the expression of 5-HT(1A)-receptor mRNA was found in the midbrain. In Tg8 mice, 5-HT(1A)-receptor mRNA level was increased in the frontal cortex and amygdala and not changed in the hypothalamus and the midbrain. The results provide support for the idea that brain 5-HT(1A)-receptors contribute to the genetically determined individual differences in aggressiveness.     

Impact of serotonin 1A receptors in the kappa-opioid immunosuppression

The data obtained indicate that rimorphin (0.1 mg/kg), a specific kappa-agonist, evoked a significant inhibition of the immune response in CBA mice. Pretreatment of the animals with 8-OH-DPAT (0.1 mg/kg), a selective serotonin (5-HT) agonist, activating presynaptic 5-HT(1A) receptors, or WAY-100635 (1.0 mg/kg), a selective 5-HT(1A) receptors blocker of postsynaptic 5-HTIA receptors, prevents kappa-opioid effect. The present data indicate that kappa-opioid-induced immunosuppression is due to the involvement of the 5-HT-ergic mechanisms that are modulated via pre- and postsynaptic 5-HT(1A) receptors.     

In vivo evaluation of 5-hydroxytryptamine stimulation of the testes in the fiddler crab,Uca pugilator: A presumed action on the neuroendocrine system

1. Male fiddler crabs, Uca pugilator, received injections of 5-hydroxytryptamine (5-HT, serotonin). The crabs showed dose-dependent testicular development.2. Like 5-HT, the 5-HT releaser fenfluramine and the 5-HT potentiator fluoxetine induced testicular maturation also, but the 5-HT receptor blocker LY-53857 did not.3. The data support the hypothesis that 5-HT exerts this stimulatory effect on the testes indirectly, by triggering release of gonad-stimulating hormone.     

The effect of the domestication of Norway rats and silver foxes on the serotonin S1A- and S2-receptors of the brain]

The specific radioligand binding of serotonin 5-HT1A and 5-HT2 receptors was determined in the frontal cortex and in the hypothalamus of Norway rats and silver foxes. Aggressive wild rats and silver foxes and animals selected for many generations for nonaggressive behavior towards man (domestication) were compared. The binding of the 5-HT1A receptors was found to be significantly higher in domesticated Norway rats and lower in domesticated foxes than in aggressive animals. The specific binding of the 5-HT2 receptors was found to be similar in aggressive and domesticated animals, both in rats and foxes. The data obtained indicate the involvement of 5-HT1A receptors in the hypothalamus into the process of domestication.     

Effect of activation of serotonin 5-HT1A-receptors on the immune response in mice of the ASC strain with depressive-like behavior

Selective activation of serotonin 5-HT(1A)-receptors produced different effects on immunological reactivity in mice of ASC strain with genetic predisposition to depressive-like behavior, and parental CBA and AKR strains displaying no depressive reactions. Administration of 5-HT(1A)-receptors agonist 8-OH-DPAT at low dose (0.1 mg/kg) affecting upon presynaptic receptors resulted in immunostimulation in CBA mice and did not change the immune response level in mice of ASC strain. Activation of postsynaptic 5-HT(1A)-receptors with higher dose of 8-OH-DPAT (1.0 mg/kg) caused immunosuppression in CBA and AKR strains while under the same conditions the immune response of ASC mice was increased. Decrease the immune reactions in ASC mice was observed only after application of 8-OHDPAT at dose of 5 mg/kg. The changes of functional activity of pre- and postsynaptic 5-HT(1A)-receptors under a high predisposition to depressive-like behavior providing different effects of this receptor activation on immune function are discussed.     

Contributions of raphe-cortical and thalamocortical axons to the transient somatotopic pattern of serotonin immunoreactivity in rat cortex

Two experiments were carried out to evaluate the relative contributions of thalamocortical and raphe-cortical fibers to the transient somatotopically organized pattern of serotonin (5-HT) immunoreactivity that appears in the primary somatosensory cortex (SI) of rats during the first 2 weeks of life. In the first experiment, the specific 5-HT uptake inhibitors, fluoxetine and paroxetine, were administered systemically, animals were killed 3, 6, or 12 h later, and cortices evaluated for 5-HT immunoreactivity. Fluoxetine treatment had no appreciable effect on the density of 5-HT immunoreactivity in the cortex. Paroxetine treatment caused a reduction in 5-HT immunoreactivity which was maximal 6 h after administration. Examination of the cortices of these animals revealed a loss of very fine dust-like 5-HT immunoreactivity, but a vibrissae-related pattern remained visible in thicker fibers. In a second experiment, raphe-cortical fibers were destroyed by systemic administration of 5,7-dihydroxytryptamine on the day of birth. Six days after this manipulation, 5-HT was applied directly to the cortex in vivo and the animals were then killed and cortices processed to demonstrate 5-HT immunoreactivity. The cortices of these rats revealed a fine dust-like immunoreactivity organized in a somatotopic pattern, but only very few 5-HT-positive axons. The results of these experiments suggest that both raphe-cortical axons and thalamocortical fibers contribute to the patterned 5-HT immunoreactivity observed in SI of perinatal rats.     

Hypotensive activity of serotonin antagonists; correlation with alpha 1-adrenoceptor and serotonin receptor blockade

For a series of 12 serotonin antagonists, largely varying in potency, the decrease in diastolic pressure was determined after intravenous injection into pentobarbitone-anaesthetized normotensive rats. The hypotensive activity of these antagonists was correlated with their affinity for alpha 1-adrenoceptors, established by [3H]prazosin radioligand displacement, and the 5-HT2 serotonergic receptor, determined by inhibition of specific [3H]mianserin binding. The radioligand binding assays were performed since they correspond to the in vivo antagonistic potencies of the antagonists at alpha 1--and 5-HT2-receptors, respectively. A close correlation (r = 0.963) was found between the affinity for alpha 1-adrenoceptors and hypotensive activity. On the other hand, a negative correlation of lower statistical quality (r = -0.808) existed between the affinity for 5-HT2-receptors and the depressor potency. In this series of 12 compounds, the new antihypertensive drug ketanserin is included for which it has been speculated that it lowers blood pressure by virtue of its serotonin antagonistic activity. The results of the present study, however, point towards alpha 1-adrenolytic potency as an important mechanism in the hypotensive action of the drug.     

Influence of human B-casomorphin-7 on specific binding of 3H-spiperone to the 5-HT2-receptors of rat brain frontal cortex

Using radio-receptor analysis, it has been demonstrated that human beta-casomorphin-7 (Tyr-Pro-Phe-Val-Glu-Pro-Ile) displaces 3H-spiperone from 5-HT2-receptors of rat brain frontal cortex. IC50 of human beta-casomorphin-7 was 8 microM. These data suggest that one of the mechanisms of neurotropic action of beta-casomorphin-7 is might be associated with its influence on the serotoninergic system.     

Thyroid hormone plasmatic levels in rats treated with serotonin in acute and chronic way

Many experiments show that serotonin (5-HT) controls thyroidal function at hypothalamic level, inhibiting the TRH secretion. The majority of experiments are done in an acute way, consisting of a single serotonin dose injected intraperitoneally (ip) or intracerebroventricularly (ic) with the effect registered after a short time (usually 1 h) as in normal environmental conditions similar to the TSH stimulation test, that consists of transfer of the experimental animals from 30°C to 4°C for 30 min, thus inducing stimulation of the hypothalamus-hypophysis-thyroid axis. The aim of the present research was to study the correlation between 5-HT and the thyroidal function, measuring plasmatic thyroid hormone levels in rats ip treated in chronic (injected daily for 10 days with different doses of 5-HT), and in acute way (after 1 h from a single 2.0 mg/kg bw 5-HT dose) in normal environmental conditions to evidence the serotonin site action activity outside the blood-brain barrier. The results of the chronic experiment show an inhibitory effect of 5-HT, on T3 and T4 plasmatic level, only when it is injected at medium doses (0.2 and 0.4 mg/kg bw for T3, and 0.2 for T4), while the results of the acute experiment do not evidence any modification. These results show that in normal environmental conditions the outside 5-HT site action is active only when the 5-HT is injected chronically at defined doses, probably for a down-regulation phenomenon.     

Diurnal Variation in the Function of Serotonin Terminals in the Rat Hypothalamus

The high-affinity binding of [3H]imipramine is associated with the serotonin (5-hydroxytryptamine; 5-HT) transporter in the brain and in platelets. In the rat hypothalamus it has been reported that the density of these sites is increased in the dark period of the day, and this could result in an alteration in the release of 5-HT. The electrically evoked release of [3H]5-HT was thus studied in preloaded hypothalamic slices prepared from rats kept under 12:12 h light/dark or dark/light schedules. The fractional release of [3H]5-HT evoked by electrical stimulation, but not by the 5-HT releasing agent fenfluramine, was significantly decreased during the dark period when compared with the light period. The effects of the 5-HT reuptake blocker citalopram, of the two 5-HT autoreceptor agonists 5-methoxytryptamine and RU 24969, and of the 5-HT autoreceptor antagonist methiothepin on the release of [3H]5-HT were the same in both groups of rats. In conclusion, the release of [3H]5-HT from prelabelled rat hypothalamic slices is decreased during the dark period of the day. This modification is not reflected by changes in the effects of citalopram, an inhibitor of 5-HT reuptake, to modify the overflow of [3H]5-HT. The sensitivity and efficacy of agonists of the 5-HT autoreceptor are the same during the light and dark periods of the day.     

Evidence that serotonin reuptake modulators increase the density of serotonin innervation in the forebrain

The mechanism of action of commonly used antidepressants remains an issue of debate. In the experiments reported here we studied the effects of three representative compounds, the selective serotonin reuptake inhibitor fluoxetine, the selective serotonin reuptake enhancer tianeptine and the selective norepinephrine reuptake inhibitor desipramine on the structure of central serotonin pathways after a 4-week administration. We found that the serotonin modulators fluoxetine and tianeptine, but not desipramine, increase the density of 5-HT and serotonin transporter (SERT)-immunoreactive axons in the neocortical layer IV and certain forebrain limbic areas, such as piriform cortex and the shell region of nucleus accumbens. These changes were noted in the absence of a significant effect of serotonin antidepressants on the expression of tryptophan hydroxylase (TPH-2), i.e. the rate-limiting enzyme for 5-HT biosynthesis and of SERT at the mRNA level. In addition, we found that anterogradely filled terminal axons from injections of biotinylated dextran amine into the dorsal raphe showed significantly more branching in animals treated with fluoxetine compared with animals treated with liposyn vehicle. Our findings suggest that antidepressants may exert very selective structural effects on their cognate monoamine systems in normal animals and raise the possibility that neurotrophic mechanisms may play a role in their clinical efficacy.     

The role of the glycoprotein gp130 in serotonin mediator system in mouse brain

Glycoprotein gp130 is involved in signaling out of significant cytokine receptors as interleukin-6 (IL-6), leukemia inhibitory factor and ciliary neurotrophic factor, which play critical role in immunity, inflammation and neurogenesis. IL-6 and brain neurotransmitter serotonin are involved in the mechanism of depression. The aim of this work was to investigat the role of protein gp130 in the regulation of expression of genes, coding the key enzyme of serotonin synthesis--tryptophan hydroxylase 2 (TPH2), 5-HT-transporter, 5-HT(1A)- and 5-HT(2A)-receptors of serotonin. The study was carried out on adult mouse males of AKR and congenic AKR.CBA-D13Mit76 strains, created by transfer of the fragment of chromosome 13 containing the gene coding gp130 protein from CBA/Lac strain to the genome of AKR/J strain. Decreased expression of 5-HT(1A) - 5-HT(2A)-receptor genes in hippocampus midbrain and TPH2 gene in midbrain in AKR.CBA-D13Mit76 mice compared with AKR mice were shown. Activation of nonspecific immunity by bacterial endotoxin lipopolysaccharide (LPS) administration did not affect the genes expression in AKR mice, but increased 5-HT(2A)-receptor expression in midbrain and decreased 5-HT(1A)-receptor expression in cortex in AKR.CBA-D13Mit76 mice. The results indicate: 1) the participation of gp130 in the regulation of TPH2, 5-HT(1A)- and 5-HT(2A)-receptor genes and 2) association of this protein in the genetically determined sensitivity to LPS.     

Stimulation of adenylate cyclase in the heart of Aplysia californica by biogenic amines

The effects of serotonin (5-HT), dopamine (DA), several peptides including FMRFamide and arginine vasotocin, the diterpene forskolin and Ca2+ were examined on adenylate cyclase in a particulate fraction from hearts of Aplysia californica. Enzyme activity was stimulated 6-7-fold by 5-HT (EC50, 1 microM) in the presence of GTP. Several 5-HT analogs particularly 5-methoxytryptamine and 5-methoxy-N-N-dimethyltryptamine were also active. The stimulatory action of 5-HT was antagonized by the 5-HT receptor blockers methergoline and metitepine and by the DA receptor blocker chlorpromazine. Dopamine had weak stimulatory action (EC50, 10 microM) and an efficacy relative to that of 5-HT of 0.3. The action of DA was antagonized by chloropromazine and metitepine. Several peptides including FMRFamide and arginine vasotocin had no effect on adenylate cyclase when tested over the concentration range 0.1-100 microM. The enzyme was stimulated 6-fold by the diterpene forskolin (EC50, 2 microM). 5-HT-stimulated activity was strongly inhibited by Ca2+. Calmodulin had no action on the enzyme in the presence of Ca2+.     

The effects of glycogen synthase kinase-3beta in serotonin neurons

Glycogen synthase kinase-3 (GSK3) is a constitutively active protein kinase in brain. Increasing evidence has shown that GSK3 acts as a modulator in the serotonin neurotransmission system, including direct interaction with serotonin 1B (5-HT1B) receptors in a highly selective manner and prominent modulating effect on 5-HT1B receptor activity. In this study, we utilized the serotonin neuron-selective GSK3β knockout (snGSK3β-KO) mice to test if GSK3β in serotonin neurons selectively modulates 5-HT1B autoreceptor activity and function. The snGSK3β-KO mice were generated by crossbreeding GSK3β-floxed mice and ePet1-Cre mice. These mice had normal growth and physiological characteristics, similar numbers of tryptophan hydroxylase-2 (TpH2)-expressing serotonin neurons, and the same brain serotonin content as in littermate wild type mice. However, the expression of GSK3β in snGSK3β-KO mice was diminished in TpH2-expressing serotonin neurons. Compared to littermate wild type mice, snGSK3β-KO mice had a reduced response to the 5-HT1B receptor agonist anpirtoline in the regulation of serotonergic neuron firing, cAMP production, and serotonin release, whereas these animals displayed a normal response to the 5-HT1A receptor agonist 8-OH-DPAT. The effect of anpirtoline on the horizontal, center, and vertical activities in the open field test was differentially affected by GSK3β depletion in serotonin neurons, wherein vertical activity, but not horizontal activity, was significantly altered in snGSK3β-KO mice. In addition, there was an enhanced anti-immobility response to anpirtoline in the tail suspension test in snGSK3β-KO mice. Therefore, results of this study demonstrated a serotonin neuron-targeting function of GSK3β by regulating 5-HT1B autoreceptors, which impacts serotonergic neuron firing, serotonin release, and serotonin-regulated behaviors.     

Endogenous Release of Neuronal Serotonin and 5-Hydroxyindoleacetic Acid in the Caudate-Putamen of the Rat as Revealed by Intracerebral Dialysis Coupled to High-Performance Liquid Chromatography with Fluorimetric Detection

Extracellular levels of endogenous serotonin (5-HT) and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were measured in the caudate-putamen of anesthetized and awake rats using intracerebral microdialysis coupled to HPLC with fluorimetric detection. A dialysis probe (of the loop type) was perfused with Ringer solution at 2 microliters/min, and samples collected every 30 or 60 min. Basal indole levels were followed for up to 4 days in both intact and 5,7-dihydroxytryptamine (5,7-DHT) lesioned animals. Immediately after the probe implantation, the striatal 5-HT levels were about 10 times higher than the steady-state levels that were reached after 7-8 h of perfusion. The steady-state baseline levels, which amounted to 22.5 fmol/30 min sampling time, remained stable for 4 days. In 5,7-DHT-denervated animals, the steady-state levels of 5-HT, measured during the second day after probe implantation, were below the limit of detection (less than 10 fmol/60 min). However, during the first 6 h post-implantation, the 5-HT output was as high as in intact animals, which suggests that the high 5-HT levels recovered in association with probe implantation were blood-derived. As a consequence, all other experiments were started after a delay of at least 12 h after implantation of the dialysis probe. In awake, freely moving animals, the steady-state 5-HT levels were about 60% higher than in halothane-anesthetized animals, whereas 5-HIAA was unaffected by anesthesia. KCl (60 and 100 mM) added to the perfusion fluid produced a sharp increase in 5-HT output that was eight-fold at the 60 mM concentration and 21-fold at the 100 mM concentration. In contrast, 5-HIAA output dropped by 43 and 54%, respectively. In 5,7-DHT-lesioned animals, the KCl-evoked (100 mM) release represented less than 5% of the peak values obtained for the intact striata. Omission of Ca2+ from the perfusion fluid resulted in a 70% reduction in baseline 5-HT output, whereas the 5-HIAA levels remained unchanged. High concentrations of tetrodotoxin (TTX) added to the perfusion medium (5-50 microM) resulted in quite variable results. At a lower concentration (1 microM), however, TTX produced a 50% reduction in baseline 5-HT release, whereas the 5-HIAA output remained unchanged. The 5-HT reuptake blocker, indalpine, increased the extracellular levels of 5-HT sixfold when added to the perfusion medium (1 microM), and threefold when given intraperitoneally (5 mg/kg). By contrast, the 5-HIAA level remained unaffected during indalpine infusion.(ABSTRACT TRUNCATED AT 400 WORDS)     

The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity

In recent years the role of the area postrema in the emetic reflex has been predominant and the involvement of the abdominal visceral innervation has tended to be overlooked. This paper attempts to redress the balance reflex by reviewing aspects of the existing literature and complementing this with original studies from the ferret. In view of the widespread use of the ferret in studies of emesis and particularly in the characterization of the antiemetic actions of 5-HT3 receptor antagonist, the opportunity is taken to assess the suitability of this species for studies of emesis. It is concluded that the ferret is sensitive to a wide range of emetic stimuli including intragastric irritants, opiate and dopamine receptor agonists, many cytotoxic drugs, and radiation. For several stimuli it is more sensitive than other species and for radiation on the basis of its ED100 it appears to be the most sensitive of the laboratory animals studied. Using electrical stimulation of the central end of the dorsal vagal trunk in the abdomen in conscious and anaesthetized animals, the vagal afferents were shown to be capable of eliciting emesis. Using lesioning studies an involvement of the vagus in the emetic response to a number of cytotoxic drugs (e.g., cisplatinum, cyclophosphamide, mustine) and radiation was demonstrated, although the magnitude of the effect varied with the different stimuli. An attempt is made to reconcile these observations with previous studies of area postrema ablation. The problems of interpreting the effects of nerve lesions are critically discussed in light of preliminary evidence presented here that there may be a degree of plasticity in the emetic pathway following such lesions. The range of antiemetic effects of 5-HT3 receptor antagonists is reviewed and an attempt is made to identify the site(s) at which these agents act. Results are presented that suggest a link between the vagus and 5-HT3 receptor antagonism. These studies are discussed together with others and lead us to propose that (in the ferret) 5-HT3 receptor antagonists have their main antiemetic effect by acting on vagal afferent terminals in the wall of the upper gut with an additional minor site either in the nucleus tractus solitarius or presynaptically on the vagal afferent terminals in the medulla where binding sites for 5-HT3 receptor ligands have recently been demonstrated in this species.     

Serotonin enhances beta-endorphin secretion to lower plasma glucose in streptozotocin-induced diabetic rats

Although serotonin, serotonin uptake inhibitors and serotonin precursors (including tryptophan or 5-hydroxytryptophan) are known to have hypoglycemic action in rodents or human, it is not clear whether serotonin has hypoglycemic effect in streptozotocin-induced diabetic rats (STZ-diabetic rats). The aim of this study was to investigate the action of serotonin in regulating the plasma glucose STZ-diabetic rats. Plasma glucose, insulin, beta-endorphin and adrenaline were assessed after intraperitoneal administration of serotonin. Serotonin produced hypoglycemic effects without altering plasma insulin and adrenaline levels but increasing beta-endorphin level in STZ-diabetic rats. The glycogen content in soleus muscle was increased at 90 min after application of serotonin (0.3 mg/kg) in STZ-diabetic rats. Dihydroergotamine (non-selective 5-HT receptor blocker) and pimozide (5-HT(7) receptor blocker) abolished the hypoglycemic effect of serotonin in STZ-diabetic rats. Serotonin-induced hypoglycemic effect in association with the increase of beta-endorphin release was abolished in bilaterally adrenalectomized STZ-diabetic rats. In isolated adrenal gland of STZ-diabetic rats, the increase of beta-endorphin secretion in response to serotonin was reduced by either dihydroergotamine or pimozide. Pretreatment with naloxone (1.0 mg/kg, i.p.) prevented serotonin-induced plasma glucose lowering effect in STZ-diabetic rats. The results demonstrated that serotonin may activate 5-HT(7) receptor on rat adrenal gland to enhance of beta-endorphin secretion, which then stimulates the opioid receptor to increase peripheral glucose utilization, resulting in decreased plasma glucose levels in STZ-diabetic rats.     

Halothane induces vesicular and carrier-mediated release of [3H]serotonin from rat brain cortical slices

The serotonergic system may play a role during general anesthesia but the effect of the volatile anesthetic halothane on the release of serotonin (5-HT) is not fully understood. Rat brain cortical slices were labeled with [3H]5-HT to investigate the effects of halothane on the release of this neurotransmitter from the central nervous system. Halothane induced an increase on the release of [3H]5-HT that was dependent on incubation time and anesthetic concentration (0.006, 0.012, 0.024, 0.036, 0.048 and 0.072 mM). This effect was independent of extracellular calcium and was not affected by tetrodotoxin (blocker of voltage dependent Na+ channels). In contrast, the halothane-evoked [3H]5-HT release was reduced by BAPTA-AM, a membrane-permeable BAPTA analog that chelates intracellular Ca2+. The anesthetic-induced [3H]5-HT release depends on the ryanodine-sensitive intracellular calcium store since it was blocked by dantrolene and azumolene (inhibitors of the calcium-release through ryanodine receptors) but was not affected by aminoethoxydiphenylborate (2-APB), an inhibitor of inositol 1,4,5-triphosphate receptor. The [3H]5-HT release induced by halothane comes mainly from the vesicular pool since it was reduced in about 70% by reserpine, a blocker of vesicular monoamine transporter. The halothane-evoked release of [3H]5-HT release is reduced by fluoxetine, an inhibitor of 5-HT uptake, and the volatile agent also decreased the uptake of [3H]5-HT into rat brain cortical slices. Moreover, a decrease on halothane-induced release of [3H]5-HT was also observed when the brain cortical slices were incubated at low temperature, which is known to interfere with the carrier-mediated release of the neurotransmitter. Ouabain, a Na+/K+ ATPase pump inhibitor, which induces 5-HT release through reverse transport, also decreased [3H]5-HT release induced by halothane, confirming the involvement of a carrier-mediated release of the neurotransmitter in the presence of halothane. In conclusion, these data suggest that halothane induces vesicular and carrier-mediated release of [3H]5-HT in rat brain cortical slices.