Effects Of 5HT Research Articles

Differential modulatory actions of serotonin in Aplysia sensory neurons: implications for development and learning

We have addressed whether mechanisms of adult plasticity reflect conserved forms of developmental processes by comparing the effects of serotonin (5HT) in juvenile and adult Aplysia sensory neurons. We show that the effects of 5HT can be dissociated into two functional classes which (i) contribute differentially to short- and long-term synaptic plasticity in adults and (ii) emerge differentially during development. We propose a model in which one class of mechanism mediates structural changes early in development and is retained in the adult to subserve long-term memory, while the second class develops late and contributes only to short-term memory in the adult.

Heterologous sensitization of adenylate cyclase activity by serotonin in the rat cerebral cortex

In vitro exposure of rat cerebrocortical slices to μM concentrations of serotonin (5HT) results in an increased response of adenylate cyclase to isoproterenol (ISO). No change in the affinity of the β-adrenoceptor toward the agonist was found after 5HT exposure when measuring ISO displacement of [ 3H]CGP 12177 binding. A similar increase of adenylate cyclase response was also found when using VIP as a stimulatory agent. The dose-response curve of adenylate cyclase to the GTP analogue, GppNHp, was modified by 5HT, which promotes a significantly higher maximal response without altering the potency of GppNHp. Forskolin-stimulated adenylate cyclase activity was not affected by 5HT. Serotonergic 5HT 2 receptors are involved in the sensitization of adenylate cyclase to GppNHp, since the selective 5HT 2 antagonist ketanserin inhibits the effect of 5HT, whereas the 5HT 2 agonist DOI mimics 5HT. The involvement of 5HT 2 receptor-coupled activation of protein kinase C is also demonstrated: direct protein kinase C activators such as phorbol esters and s,n-dioctanoylglycerol behave in the same manner as 5HT, while the protein kinase C inhibitor CGP 41251 prevents 5HT from increasing adenylate cyclase responsiveness to GppNHp. Moreover, in vitro exposure of cortical slices to 5HT results in reduced inhibition of adenylate cyclase by somatostatin. Since no change was observed at the receptor level and in the direct stimulation of the catalytic subunit of the enzyme, we propose that 5HT might accomplish the sensitization of adenylate cyclase through protein kinase C by inactivating the inhibitory coupling protein Gi and facilitating the interaction of the exogenous GppNHp with the stimulatory coupling protein Gs.

Effects of serotonin on rat ileocolonic transit and fluid transfer in vivo: possible mechanisms of action.

The aim was to investigate the action of serotonin (5HT) on function of the ileocolonic junction (ICJ) in vivo. In anaesthetised rats, models were developed to study the effects of intra-aortic (ia) serotonin on ileocolonic and colonic transit, and the effects on transit of a number of 5HT receptor antagonists. In the first series of experiments, a bolus of saline labelled with 99mTc DTPA was instilled 20 cm proximal to the ICJ and transit was assessed three hours later by the geometric centre of the spread of isotope. In the second series, similar techniques were used on the postcaecal colon and transit assessed two hours later. In the third series of experiments, the effects of ia 5HT on ileal net fluid flux was evaluated by standard perfusion experiments with 14C polyethylene glycol (PEG) 4000 as a non-absorbable marker in rat plasma-like electrolyte solution. Compared with ia saline, 5HT accelerated ICJ transit significantly (p < 0.05). This acceleration was comparable with the effect of ia bethanechol. The effects of 5HT on ICJ transit were inhibited by the intraperitoneal (ip) infusion of atropine, the 5HT receptor antagonists, methysergide, ketanserin, zacopride, and the 5HT4 agonist, SC53116. Methysergide, zacopride, and SC53116 given with ia 5HT slowed ICJ transit to rates below those of ia saline alone. When these same agents were given together with ia saline, the ICJ transit was not significantly altered. Serotonin, at the dose that accelerated ICJ transit, did not significantly alter colonic transit or ileal fluid transport. In conclusion, 5HT is a potent pharmacological stimulant of transit across the rat ICJ in vivo; the action of 5HT is mediated partly through muscarinic neurones and several 5HT receptor subtypes.

Blockage of nicotinic acetylcholine receptors by 5-hydroxytryptamine.

The action of 5-hydroxytryptamine (5HT) on nicotinic acetylcholine receptor (nAChR) channels was investigated in mouse myotubes, human cloned TE671/RD cells, and Xenopus laevis oocytes. The decay of the ACh-activated whole-cell currents was reversibly accelerated in the presence of 5HT (10(-5) to 10(-3) M), in a dose-dependent manner. 5HT also reduced the size and accelerated the decay of currents elicited by ACh in Xenopus oocytes injected with mRNA extracted from C2 myotubes or Torpedo electroplaques, or oocytes injected with cloned mouse muscle AChR subunit mRNAs. The effect of 5HT was promptly reversed after washout, or by depolarizing the oocyte beyond -10 mV. In patch-clamp recordings from myotubes, bath-application of 5HT did not exert an indirect influence on the ACh-activated channels within the patch membrane. In contrast, when the patch membrane was exposed to 5HT (10(-6) M), ACh unit responses appeared as bursts of short pulses. It is concluded that the regulation of ACh responses by 5HT results from a fast noncompetitive blocking action of nAChR-channels. These results show that ligand-gated channels, activated by their specific neurotransmitter, may be regulated by a different neurotransmitter through a direct action on the receptor molecule.

Meiosis reinitiation in surf clam oocytes is mediated via a 5-hydroxytryptamine5 serotonin membrane receptor and a vitelline envelope-associated high affinity binding site.

The neurohormone serotonin (5-hydroxytryptamine, 5HT) triggers meiosis reinitiation in prophase-arrested oocytes of Spisula solidissima. The original pharmacological profile of this response prompted us to examine whether it involved a novel type of 5HT receptor. In order to characterize these putative receptors, we performed [3H]5HT binding assays. Given the complexity of oocyte surface architecture, [3H]5HT-specific binding was measured in both plasma membrane and vitelline envelope fractions. Our data reveal the existence of a single class of 5HT-specific binding sites in each fraction. These binding sites appear distinct by their kinetic properties: 1) plasma membrane binding sites are of lower affinity but are more numerous than vitelline envelope sites; 2) [3H]5HT binding is more rapid in membrane fraction. The pharmacological profiles of both binding sites were defined in competition experiments by using sixteen 5HT-related and unrelated compounds. Both membrane and vitelline envelope sites displayed novel profiles. However, only the pharmacological profile determined for the plasma membrane sites corresponds to that observed for 5HT-induced meiosis reinitiation. These new 5HT5 binding sites are therefore the physiological receptors that mediate the effects of 5HT in Spisula oocytes. The putative role of vitelline envelope sites is discussed.

Modulation of swimming rhythmicity by 5-hydroxytryptamine during post-embryonic development in Xenopus laevis.

During the first 24 h of post-embryonic development in Xenopus laevis, a rapid change in the neural activity underlying swimming occurs in which the duration of ventral root discharge on each cycle increases from a single compound impulse to discrete bursts of activity. Moreover, this change in motor output progresses rostrocaudally, suggesting that it could result from the influence of a descending neural pathway upon the spinal rhythm-generating circuitry during early post-embryonic development. To begin to examine whether serotonergic neurons of brainstem raphe nuclei might have a role in this swimming development, we have studied the effects of 5-hydroxytryptamine (5HT) on fictive swimming in embryonic and larval animals. As previously demonstrated for other vertebrate locomotor rhythms, we find that bath-applied 5HT enhances the duration of motor activity on each cycle of larval fictive swimming. In addition, our results show that the sensitivity of the swimming rhythm to exogenous 5HT follows a strict rostrocaudal gradient. In young embryos (stages 32-36) 5HT does not affect the duration of ventral root impulses per cycle; by the time of hatching (stage 37/38), rostral but not caudal discharge is enhanced, and by stage 42 (24 h post-hatching) 5HT can increase motor burst durations along most of the length of the animal. These reversible changes induced by bath-applied 5HT closely resemble the normal rostrocaudal development of burst discharge during swimming in animals some 12 h older.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of FMRFamide, 5-hydroxytryptamine and phorbol esters on the heart of the mussel Geukensia demissa.

The ventricle of the mussel Geukensia demissa is inhibited by 5-hydroxytryptamine and excited by the molluscan neuropeptide FMRFamide. Supra-threshold doses of amide result in marked positive chronotropy and inotropy within 5-15 s. 5-Hydroxytryptamine at 10(-8) M produces diastolic arrest within 10 s. A 1-min exposure to FMRFamide (5 x 10(-8) M) results in a small increase in the cytoplasmic levels of adenosine 3',5'-cyclic monophosphate; shorter or longer exposures have no effect. The cAMP content of ventricles incubated in 5 x 10(-8) M 5-hydroxytryptamine for 1 min decreases by 2.3 pmol/mg protein; longer or shorter incubations have no effect. Treatment with forskolin results in 3- or 4-fold increases in adenosine 3',5'-cyclic monophosphate, but forskolin has no effect on the mechanical activity of the ventricle. The levels of inositol monophosphate, inositol 1,4-diphosphate, and inositol 1,4,5-triphosphate in tissues exposed to 5-hydroxytryptamine are not different from levels in control tissues. FMRFamide decreases the levels of these phosphoinositides by 50% or more. Lower concentrations of phorbol 12,13-diacetate (10(-8) to 10(-7) M) and phorbol 12-myristate,13-acetate (10(-6) M) cause positive chronotropy in the isolated ventricle; higher concentrations induce systolic arrest. These results suggest that the effects of 5HT on the ventricle are not mediated by adenosine 3',5'-cyclic monophosphate or inositol 1,4,5-triphosphate. The effects of FMRFamide may involve a decrease in inositol 1,4,5-triphosphate. The effects of amide may involve a decrease in inositol 1,4,5-triphosphate. The response of the ventricles to phorbol esters suggest that protein kinase C may be involved in the regulation of cardiac contractility.

Handling of 5-hydroxytryptamine by platelets in migraine.

There is little dispute that a link exists between 5-hydroxytryptamine (5HT) and migraine but the exact mechanism of an attack has yet to be established. The handling of 5HT by the platelet is regarded as a simple model of the handling of 5HT by nerve terminals. If differences are seen in how the platelets from migraineurs handle 5HT compared to those from a control population, it is possible that a similar difference exists in the nerve terminal. The Haemostatometer allows the rapid and simultaneous in vitro assessment of platelet function (shear-induced haemostasis), coagulation and thrombolysis from non anticoagulated blood samples. In this study, a baseline comparison of haemostasis was made on 20 migraineurs between attacks and 20 controls. No differences were found in the results from each of the two groups. 5 microM of 5HT was then added to blood taken from 10 migraineurs and 10 controls and the recordings were repeated. Again, no differences were found between the results from the two groups. In blood taken from both migraineurs and controls, the effect of 5HT was to significantly enhance clotting time and clot lysis. No effect was seen on primary aggregation. The possible reasons for and significance of these findings is discussed.

Handling of 5-Hydroxytryptamine by Platelets in Migraine

SYNOPSIS There is little dispute that a link exists between 5-hydroxytryptamine (5HT) and migraine exists but the exact mechanism of an attack has yet to be established. The handling of 5HT by the platelet is regarded as a simple model of the handling of 5HT by nerve terminals. If differences are seen in how the platelets from migraineurs handle 5HT compared to those from a control population, it is possible that a similar difference exists in the nerve terminal. The Haemostatometer allows the rapid and simultaneous in vitro assessment of platelet function (shear-induced haemostasis), coagulation and thrombolysis from non anticoagulated blood samples. In this study, a baseline comparison of haemostasis was made on 20 migraineurs between attacks and 20 controls. No differences were found in the results from each of the two groups. 5μM of 5HT was then added to blood taken from 10 migraineurs and 10 controls and the recordings were repeated. Again, no differences were found between the results from the two groups. In blood taken from both migraineurs and controls, the effect of 5HT was to significantly enhance clotting time and clot lysis. No effect was seen on primary aggregation. The possible reasons for and significance of these findings is discussed.

Constrictive Effect of Serotonin on Visible Renal Arteries

Serotonin (5HT) has been implicated in the pathogenesis of several arterial disorders. Experimental intrarenal infusion of 5HT has produced initial decreases, and later sustained increases in total renal blood flow in the dog, and flow limiting renal artery spasm in other species. We assessed renal angiographic responses to 5HT infused into one renal artery of nine dogs before and after treatment with indomethacin (I). On blinded assessment of arteriograms, 5HT-induced narrowing was detected (p less than 0.001), and the effect was accentuated by I (p less than 0.001). Ketanserin (K), a 5HT-2 receptor antagonist, reversed the arteriographic vasoconstrictor effect of 5HT in five I-treated dogs (p less than 0.05). Linear cortical defects and decreased contrast intensity were seen in the nephrogram phase during 5HT infusion after I. This appearance resembled the arteriographic findings in hemorrhagic shock, suggesting profound impairment of renal cortical perfusion. This study suggests that 5HT constricts visible renal arteries via interaction with the 5HT-2 receptor, and that this in vivo effect is modified by arterial synthesis of vasodilator prostaglandins in the anesthetized dog.

Interaction between Serotonin and Other Regulators of Aldosterone Secretion in Rat Adrenal Glomerulosa Cells

Although serotonin (5HT) is a recognized stimulator of aldosterone secretion in vivo and in vitro, its physiological role as a regulator of mineralocorticoid secretion and its mechanism of action in the adrenal glomerulosa have not been elucidated. To address these questions we studied the interaction of 5HT with other aldosterone regulators in isolated rat adrenal glomerulosa cells. 5HT stimulated aldosterone production 14-fold, with an ED50 of 20 +/- 5 nM, and stimulation was maximal at 0.8 microM. The stimulation of aldosterone production by 5HT was accompanied by a 5-fold increase in cAMP production, with an ED50 of 1 microM. Threshold levels of 5HT (1 nM) potentiated the effect of submaximal concentrations of angiotensin-II (AII), decreasing the ED50 from 1.3 to 0.46 nM and increasing the maximum response in an additive manner. In contrast, the stimulatory effect of 5HT was purely additive to that of submaximal ACTH concentrations. 5HT had no effect on aldosterone secretion stimulated by maximal ACTH concentrations, despite full additivity on cAMP accumulation. Stimulations of steroidogenesis by potassium and 5HT were fully additive at submaximal concentrations, but only partially additive at-maximal levels. To determine the mechanism of the synergistic effects of AII and 5HT, we analyzed the interaction of both stimuli on cAMP accumulation, intracellular calcium, and inositol phosphate formation. Consistent with the inhibitory effect of AII on adenylate cyclase, in the presence of AII the stimulation of cAMP by 5HT was reduced by 18 +/- 3%. 5HT alone had no effect on cytosolic calcium, but significantly enhanced the peak and later phases of the AII-stimulated increase (P less than 0.005). This effect of 5HT was due to calcium influx and not to release from intracellular pools, as shown by suppression of the potentiation in the absence of extracellular calcium and the lack of effect of 5HT on basal or AII-stimulated inositol phosphate formation. The ability of low concentrations of 5HT to potentiate the stimulatory effect of AII on aldosterone secretion suggests that under some physiological conditions, 5HT may play a role in regulating the adrenal sensitivity to AII.

Tachyphylaxis to the Local Effect of 5HT, Infused into a Peripheral Vein

Tachyphylaxis to the Local Effect of 5HT, Infused into a Peripheral Vein

In vivo exposure to hyperoxia increases airway responsiveness in rats. Demonstration in vivo and in vitro.

Studies regarding O2-induced lung injury have concentrated on damage to alveolar structures and pulmonary vasculature without consideration of alterations that may be occurring in airways. This study was undertaken to determine the effects of in vivo hyperoxic exposure on airway responses to excitatory stimuli in intact, anesthetized rats and in intrapulmonary bronchi isolated from hyperoxia-exposed rats. Using lung conductance (G1) as an index of bronchoconstriction, intravenously administered 5-hydroxytryptamine (5HT) elicited greater bronchoconstrictor responses in anesthetized, mechanically ventilated rats that had been exposed to 85% O2 for 7 days rather than to air. Further, airways of hyperoxia-exposed rats were more sensitive to the effects of intravenously administered 5HT as evidenced by the lower log dose of 5HT required to decrease G1 30%. Cylindrical segments of intrapulmonary bronchi isolated from hyperoxia-exposed rats were more responsive to the contractile effects of 5HT and electrical field stimulation. However, no differences in responsiveness to bethanechol or KCl were observed between the two groups. The log concentration of 5HT and the log frequency of electrical field stimulation that elicited half-maximal responses were smaller in bronchi isolated from hyperoxia-exposed animals, indicating an increase in sensitivity of the airways to these stimuli. These results suggest that prolonged exposure to greater than ambient levels of O2 can alter airway function; however, the mechanism responsible for these changes remains to be determined.

Chapter 26 Serotonin receptor subtypes and the modulation of pain transmission

Publisher Summary This chapter describes the serotonin receptor subtypes and discusses the modulation of pain transmission. Three major subtypes of the serotonin 5-hydroxytryptamine (5HT) receptor have been identified: 5HT 1 , 5HT 2 , and 5HT 3 . The subtypes have different anatomical distributions that are important for understanding the unique effect each receptor subtype has on primary afferent and central pain transmission. The chapter reviews data on all three major 5HT receptor subtypes focusing on 5HT 1 receptors. 5HT resulted in muscle contractions by a direct action on 5HT receptors located on smooth muscle, an action preferentially antagonized by phenoxybenzamine (dibenzyline) and therefore referred to as the D-receptor. 5HT produces muscle contraction by an indirect effect on cholinergic ganglionic neurons innervating the guinea pig ileum; an effect of 5HT preferentially antagonized by morphine (M-receptors). Intradermal administration of 5HT mimics the effects of mechanical or chemical insult in man, including vasodilation (flare response), edema formation, and the perception of pain.

Actions of serotonin recorded intracellularly in rat dorsal lateral septal neurons.

The actions of serotonin (5HT) on passive and active membrane properties of neurons in the rat dorsal lateral septal nucleus (LSN) were studied by using intracellular recordings in transverse, septal slices. Superfusion with 10 microM 5HT induced a hyperpolarization of the membrane in almost all neurons tested in the dorsolateral part of the LSN. The hyperpolarization was accompanied by a decrease in membrane resistance. These effects of 5HT persisted in a low-Ca2+/high-Mg2+-containing medium or medium with tetrodotoxin, indicating a post-synaptic site of action for 5HT. The reversal potential for the hyperpolarizing effect was ca. -95 mV. If the extracellular K+-concentration was raised, the reversal potential became less negative. These data suggest that 5HT hyperpolarizes LSN neurons by increasing a K+-conductance. Spontaneous, synaptically evoked action potentials and action potentials induced in LSN neurons by a depolarizing current step typically display a fast Na+-spike with a subsequent K+-afterhyperpolarization, followed by a much slower Ca2+-dependent afterdepolarization. The amplitude of the K+-afterhyperpolarization was decreased by 5HT, while at the same time the afterdepolarization became more pronounced. The Ca2+-spike of LSN neurons was not affected by 5HT. Synaptic responses that were evoked in LSN neurons by stimulation of the dorsal part of the LSN consisted of a fast EPSP or spike, followed by a Cl(-)-dependent fast IPSP and a K+-dependent late IPSP. Of these synaptic responses, 5HT suppressed particularly the late IPSP. The present data indicate that 5HT affects the conductance for active and passive K+-channels in LSN neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasoactive Amines Directly Modify Endothelial Cells to Affect Polymorphonuclear Leukocyte Diapedesis In Vitro

Bovine aortic endothelial cells were cultured on the basement membrane surface of amnionic membrane and used as a substrate for polymorphonuclear leukocyte (PMN) diapedesis in vitro. Norepinephrine (NE), serotonin (5HT), or phalloidin treatment of the endothelial cells (ECs) reduces, whereas histamine or cytochalasin B increases, the number of PMNs migrating across the ECs and amnionic membrane. In contrast, amine treatment of PMNs or acellular amnionic membrane does not alter PMN diapedesis or chemotaxis. The NE and histamine effects are blocked by appropriate receptor antagonists, but the 5HT effect is not. All the agents' effects are also reversible. Qualitatively similar effects on EC permeability to Evan's blue-labeled albumin occur with all agents; however, PMN adhesion to ECs is not affected. Previously, we reported that NE and 5HT increase stress fiber numbers and decrease EC permeability to macromolecules in vitro, whereas histamine has the opposite effects, and that NE and 5HT eliminate the erythrocyte extravasation associated with thrombocytopenia in vivo. In this study, we propose that these vasoactive amines also alter PMN diapedesis in vitro through a direct effect on the EC, in part due to alterations in the EC cytoskeleton.

Vasoactive amines directly modify endothelial cells to affect polymorphonuclear leukocyte diapedesis in vitro

Bovine aortic endothelial cells were cultured on the basement membrane surface of amnionic membrane and used as a substrate for polymorphonuclear leukocyte (PMN) diapedesis in vitro. Norepinephrine (NE), serotonin (5HT), or phalloidin treatment of the endothelial cells (ECs) reduces, whereas histamine or cytochalasin B increases, the number of PMNs migrating across the ECs and amnionic membrane. In contrast, amine treatment of PMNs or acellular amnionic membrane does not alter PMN diapedesis or chemotaxis. The NE and histamine effects are blocked by appropriate receptor antagonists, but the 5HT effect is not. All the agents' effects are also reversible. Qualitatively similar effects on EC permeability to Evan's blue-labeled albumin occur with all agents; however, PMN adhesion to ECs is not affected. Previously, we reported that NE and 5HT increase stress fiber numbers and decrease EC permeability to macromolecules in vitro, whereas histamine has the opposite effects, and that NE and 5HT eliminate the erythrocyte extravasation associated with thrombocytopenia in vivo. In this study, we propose that these vasoactive amines also alter PMN diapedesis in vitro through a direct effect on the EC, in part due to alterations in the EC cytoskeleton.

Effect of the 5HT 2 antagonist ritanserin on food intake and on 5HT-induced anorexia in the rat

The present study investigated the effect on the rat's eating behavior of the new selective 5HT 2 antagonist ritanserin. The results obtained indicate that: (a) single subcutaneous (SC) injection of ritanserin, at doses between 0.1 and 1 mg/kg b.wt., neither elicits food intake in sated rats, nor increases the intake induced by food deprivation; (b) subchronic SC treatment (15 days) with 0.1 mg/kg does not increase food intake nor body weight gain; (c) subchronic SC treatment with high doses, 1 or 10 mg/kg, produces small and transient increases in food intake without affecting body weight gain. When ritanserin was tested for its ability to block the anorectic effect of exogenous 5HT, it inhibited the effect of intraperitoneal (IP) 5HT, but proved to be completely inactive versus the effect of 5HT injected into the hypothalamic paraventricular nucleus, which is highly sensitive to this effect of 5HT. This last finding suggests that the anorectic action of central endogenous 5HT is also not blocked by ritanserin, thus proposing a reasonable explanation for the absence of orexigenic effect following its administration. Moreover, it suggests that in rats the hypothalamic receptors mediating the effect of 5HT on eating behavior are different from the 5HT 2 of the frontal cortex which have been shown to be completely blocked by ritanserin under the experimental conditions employed in our study.

Evidence for serotonin (5HT) binding sites on murine lymphocytes

The binding of 3H-labeled serotonin (or 5-hydroxytryptamine: 5HT) to mouse lymphocytes was investigated. It was shown to be highly specific, time-dependent, saturable and partly reversible. Saturation analysis demonstrated a Kd of 198 nM and B max of 3.53 nM. We studied receptor specificity by using different types of serotonin antagonists, and numerous other substances. Serotonin was found to be the most effective drug among those tested in inhibiting the binding of 3H-5HT, having an IC 50 of 194 nM. The fact that 5 HTP, a 5HT precursor, had no inhibitory capacity indicted the high specificity of these 5HT binding sites. Dopamine was somewhat able to competitively inhibit 5HT fixation ( IC 50 = 27,000 nM ), whereas norepinephrine and histamine had no effect. Lastly, we investigated the cellularspecificity of this binding, and observed that nonmacrophage peritoneal cells extensively bound serotonin under the same conditions as spleen cells. This is the first direct demonstratin of 5-hydroxytryptamine receptors on mouse lymphocytes. The presence of these binding sites can contribute to the understanding of the suppressive effect of 5HT on mouse immunoreactivity.

Serotonin and the renal blood supply: Role of prostaglandins and the 5HT-2 receptor

Serotonin (5HT) has been reported to increase, to decrease, or not to change renal blood flow. We postulated that prostaglandin release in response to 5HT acted as a confusing variable, and tested the hypothesis by comparing infusions of serotonin and angiotensin into one renal artery of 14 anesthetized dogs before and after indomethacin administration. Renal blood flow (Q, by EM flow-meter) responses to 5HT were routinely biphasic, an initial sharp decrease followed by a gradual increase which stabilized well above baseline at three to six minutes. Indomethacin, 1 to 2 mg/kg, did not alter the acute Q decrement induced by 5HT but abolished the increase in Q at three to six minutes (P less than 0.001). Instead, sustained vasoconstriction became apparent. Ketanserin reversed the sustained vasoconstrictor effect of 5HT in indomethacin-treated dogs, leading to striking, serotonin-induced vasodilatation. The latter vasodilatation in turn was inhibited by methysergide. Four independent elements, two promoting vasoconstriction and two vasodilatation, are suggested. One vasodilator response is abolished by prostaglandin synthetase inhibition and the other by methysergide, a complex 5HT receptor blocker. The sustained vasoconstrictor response is blocked by ketanserin, suggesting an action on the 5HT-2 receptor. The initial, transient vasoconstrictor response is resistant to the blockers employed. These complex interactions may account for the variability in reported responses of the renal blood supply to serotonin.