Effects of the 5-HT3 antagonist GR38032F (ondansetron) on benzodiazepine withdrawal in rats

Effects of the 5-HT3 receptor antagonist GR38032F (ondansetron) on chlordiazepoxide withdrawal were assessed in rats which received chlordiazepoxide b.i.d. for 21 days at doses up to 40 mg/kg per injection. Withdrawal signs recorded were: body weight and food intake, which fell and then recovered over 9 days. Saline or GR38032F (1.0, 0.1 or 0.01 mg/kg) were administered b.i.d. during withdrawal. Clear withdrawal signs were seen in rats treated with saline after chronic chlordiazepoxide. However, GR38032F at 0.1 mg/kg reduced the severity of withdrawal. At 0.01 mg/kg GR38032F shortened withdrawal duration, but did not diminish peak withdrawal signs. At 1.0 mg/kg GR38032F, did not attenuate withdrawal signs at all. GR38032F (0.01-1.0 mg/kg) had no effect on ad lib food intake, therefore the attenuation of withdrawal was probably not simply due to stimulation of appetite. These data support recent claims that GR38032F attenuates benzodiazepine withdrawal, and they indicate that this effect shows an inverted U-shaped dose-response curve.     

Effects of chronic administration of ondansetron (GR38032F), a selective 5-HT3 receptor antagonist,on monoamine metabolism in mesolimbic and nigrostriatal dopaminergic neurons and on striatal D2-receptor binding

The effects of chronic administration of the selective 5-HT₃ receptor antagonist ondansetron (GR38032F) on dopamine (DA) and 5-hydrotryptamine (5-HT) metabolism in the major ascending dopaminergic neurons and on striatal D2-receptor binding characteristics were investigated. The metabolism of 5-HT was also studied in a number of other brain areas. Chronic ondansetron (0.2 mg/kg/day and 1.0 mg/kg/day SC for 16 days) did not change DA or 5-HT metabolism in the nigrostriatal or mesolimbic dopaminergic areas, although the larger dose of ondansetron slightly and statistically significantly reduced basal concentrations of DA and 5-HT in the nucleus caudatus. D2-receptor binding characteristics were not affected in the caudateputamen. Ondansetron did not change 5-HT metabolism in the nucleus raphé dorsalis, amygdala, hippocampus or in habenula. It is concluded that chronic administration of ondansetron does not change DA or 5-HT metabolism in the major ascending dopaminergic neurons. This suggest that unlike chronic D2-receptor blockade, chronic blockade of central 5-HT₃ receptors does not result in a similar reduction in the activity of nigrostriatal and mesolimbic dopaminergic neurons.     

Pharmacological properties of GR38032F, a novel antagonist at 5-HT3 receptors.

1. This paper describes the pharmacology of the novel 5-hydroxytryptamine3 (5-HT3) receptor antagonist GR38032F. 2. On the isolated vagus nerve and superior cervical ganglion of the rat, R,S-GR38032F behaved as a reversible competitive antagonist of 5-HT-induced depolarization with pKB values of 8.61 +/- 0.08 (n = 19) and 8.13 +/- 0.07 (n = 16), respectively. The resolved R- and S-isomers of GR38032F were approximately equipotent as 5-HT antagonists on the rat vagus nerve: the pKB values were 8.95 +/- 0.05 (n = 16) and 8.63 +/- 0.08 (n = 17), respectively. R,S-GR38032F was also an effective antagonist of 5-HT on the rabbit isolated vagus nerve: in this case the pKB value was 9.40 +/- 0.14 (n = 4). 3. On the rabbit isolated heart, low concentrations of R,S-GR38032F (3 X 10(-11)-1 X 10(-9) M) antagonized the positive chronotropic effect of 5-HT and 2-methyl-5-hydroxytryptamine (2-methyl-5-HT). However, the effects of the compound did not appear consistent with simple reversible competition. 4. On the longitudinal smooth muscle of the guinea-pig ileum, R,S-GR38032F caused concentration-dependent parallel rightward displacement of the 2-methyl-5-HT concentration-contraction response curve; in contrast, a portion of the response to 5-HT appeared resistant to R,S-GR38032F. pKB values estimated from the effects of the compound against 2-methyl-5-HT or the inhibitable portion of the response to 5-HT were 7.31 +/- 0.06 (n = 8) and 7.33 +/- 0.13 (n = 8), respectively. Against 2-methyl-5-HT, R-GR38032F seemed more potent (pKB 7.20 +/- 0.10; n = 6) than S-GR38032F (pKB 6.30 +/- 0.05; n = 6). 5. R,S-GR38032F is highly selective for 5-HT3 receptors, and at concentrations of 3 X 10(-6)-3 X 10(-5) M, had negligible agonist or antagonist activity on other 5-HT or non-5-HT receptor-containing tissues on which it was tested. 6. The potency and duration of action of R,S-GR38032F in blocking 5-HT3 receptors in vivo were assessed by measuring its ability to antagonize the bradycardic response to 5-HT or 2-methyl-5-HT administered intravenously (i.v.) to anaesthetized animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

The potential anxiolytic activity of GR38032F, a 5-HT3-receptor antagonist.

1. The highly selective 5-HT3-receptor antagonist, GR38032F, has been tested in five animal models predictive for anxiolytic activity. 2. In the social interaction test in the rat and in a light/dark exploration test in the mouse, GR38032F dose-dependently released suppressed behaviour without modifying locomotor activity. 3. In the cynomolgus monkey and the marmoset, GR38032F reduced anxiety-related symptoms without causing sedation. In the marmoset, the effects were clearly dose-related. 4. GR38032F did not have any detectable activity in the water-lick conflict test in the rat. 5. We conclude that GR38032F is potentially a very potent anxiolytic agent without sedative, anticonvulsant or hypnotic activity.     

Effects of acute GR38032F (odansetron), a 5-HT3 receptor antagonist, on dopamine and serotonin metabolism in mesolimbic and nigrostriatal dopaminergic neurons

The acute administration of GR38032F, a selective 5-HT3 receptor antagonist, did not change the concentrations of dopamine (DA) or 5-hydroxytryptamine (5-HT) or their deaminated metabolites in nucleus caudatus, nucleus accumbens or substantia nigra. Pretreatment with GR38032F failed to modify the haloperidol-induced activation of DA turnover. It is concluded that the blockade of central 5-HT3 receptors by GR38032F under these experimental conditions does not result in alternations in metabolism of DA or 5-HT in major ascending dopaminergic areas.     

The effects of ondansetron (GR38032F) in rats and mice treated subchronically with diazepam

Using rat and mouse models of aversive behaviour, we have further investigated the properties of the 5-HT3 receptor antagonist ondansetron (GR38032F) that are relevant to its proposed use as an anxiolytic agent. Tolerance to the disinhibitory properties of diazepam was readily demonstrated in the social interaction test in the rat, but did not occur after subchronic treatment with ondansetron. In both the light/dark exploration test in mice and the social interaction test in rats, withdrawal from subchronic treatment with diazepam increased behavioural suppression, whereas this was not observed with ondansetron. The behavioural suppression and weight loss induced by either the withdrawal of diazepam or the administration of the benzodiazepine receptor antagonist, flumazenil, in animals treated subchronically with diazepam, was prevented or antagonised by diazepam or ondansetron. Buspirone was ineffective. It is concluded that, in rats and mice, tolerance to the disinhibitory effects of ondansetron does not occur, that withdrawal from subchronic treatment with ondansetron is not associated with any behavioural disturbances and that ondansetron is highly effective in preventing the behavioural suppression and weight loss following withdrawal from subchronic diazepam treatment. These data suggest that ondansetron may have major therapeutic advantages over currently available anxiolytic agents, particularly in patients who have previously received prolonged benzodiazepine therapy.     

GR38032F, a serotonin 5-HT3 antagonist, fails to alter cocaine self-administration in rats.

Recent data have supported a role for serotonin (5-HT) in the self-administration of cocaine by laboratory rats. More specifically, it has been suggested that 5-HT3 receptor antagonists may be useful in the treatment of drug abuse. To assess this possibility, we compared the effects of the 5-HT3 antagonist, GR38032F, with the dopamine D2 receptor blocker, haloperidol, on the intravenous self-administration of cocaine (0.5 mg/kg/infusion) in rats. The serotonin antagonist (0.01, 0.1 or 1.0 mg/kg, IP) failed to alter self-administration (0.5 mg/kg/infusion). In contrast, haloperidol (0.125 mg/kg, IP) increased responding for cocaine (0.5 mg/kg/infusion), and shifted the dose-response curve for cocaine self-administration to the right. These data fail to support a role for the serotonin 5-HT3 receptor system in the reinforcing properties of this psychostimulant. Rather, the 5-HT1 or 5-HT2 receptors may be the critical subtype.     

The GABA(A) receptor antagonist picrotoxin inhibits 5-hydroxytryptamine type 3A receptors

For a number of years it has been known that the CNS convulsant picrotoxin inhibits the GABA(A) receptor, an anion-selective member of the ligand-gated ion channel (LGIC) superfamily. PTX also inhibits other anion-selective LGIC members, such as GABA(C), glycine and glutamate-gated Cl(-) channels. In the present report, we tested the ability of picrotoxin to inhibit cation-selective 5-HT(3A) receptors. Murine 5-HT(3A) receptors were expressed in HEK293 cells, and functionally evaluated using whole-cell patch clamp recording. Picrotoxin inhibited 5-HT-gated currents in a concentration-dependent manner, with an IC(50) of approximately 30 microM. Moreover, the blockade by PTX was non-competitive and use-facilitated. Pentylenetetrazole and U-93631, ligands that act at a domain similar to that of picrotoxin in GABA(A) receptors, also inhibited the 5-HT(3A) receptor. For each ligand tested, its potency was 5-10 fold lower than typically observed in GABA(A) receptors. Our results demonstrate that, in addition to being a relatively non-selective inhibitor of anionic LGICs, picrotoxin also inhibits the cation-selective 5-HT(3A) receptor. Moreover, the fact that both PTZ and U-93631 similarly inhibit the 5-HT(3A) receptor is consistent with the suggestion that the site of picrotoxin action in this receptor may be comparable to that in anion-selective LGICs.     

The effect of GR38032F, novel 5-HT3-receptor antagonist on gastric emptying in the guinea-pig.

The effects of GR38032F a novel, selective and potent 5-hydroxytryptamine (5-HT3)-receptor antagonist on gastric emptying in the guinea-pig were investigated and compared to those of metoclopramide and haloperidol. Both GR38032F and metoclopramide increased gastric emptying in a dose-dependent manner. In contrast, haloperidol was ineffective. GR38032F was about 200 times more potent than metoclopramide in enhancing gastric emptying over the 2 h period studied.     

Effects of a selective thromboxane receptor antagonist (GR32191B) and of glyceryl trinitrate on bleeding time in man

1. GR32191B is a potent and selective thromboxane receptor antagonist. Glyceryl trinitrate (GTN) also inhibits platelet function in vitro. Both have been reported to prolong bleeding time. Since they may be used together in patients with coronary artery disease, we have investigated the possibility of an interaction between them. 2. Twenty-four healthy male volunteers were treated with GR32191B using a double-blind placebo-controlled crossover design. Bleeding times were determined before and after GR32191B or placebo and during co-administration of GTN. Plasma GR32191B concentration was measured. Platelet aggregation in response to adenosine diphosphate and to a thromboxane mimetic, U46619, was measured ex vivo. Urinary excretion of thromboxane (TX)B2 and 2,3-dinor-TXB2 was determined in 24 h urine samples. 3. Twelve hours after GR32191B (80 mg; p.o.), the plasma concentration was 36.6 +/- 2.7 nM (mean +/- s.e. mean) and bleeding time was increased by 66%. Ninety minutes after a second dose (40 mg; p.o.) the plasma concentration was 431.9 +/- 23.6 nM but bleeding time was not further prolonged. 4. Responses of platelets to U46619 were selectively antagonised following GR32191B. Urinary excretion rates of TXB2 and 2,3-dinor TXB2 were similar after treatment with GR32191B or placebo. 5. GTN (1 mg sub-lingually) had no significant effect on bleeding time 90-100 min following either placebo or GR32191B. 6. We conclude that GR32191B, in a dose that causes profound yet specific blockade of thromboxane receptors, causes only a modest prolongation of bleeding time that is unaffected by a therapeutic dose of GTN. This may prove advantageous when GR32191B is used in patients with ischaemic heart disease.     

The effect on motion sickness and oculomotor function of GR 38032F, a 5-HT3-receptor antagonist with anti-emetic properties.

1. The 5-hydroxytryptamine (5-HT3) receptor antagonist, GR 38032F, which possesses potent anti-emetic properties in vomiting induced by cancer chemotherapeutic drugs, has been tested to determine its value in the prophylaxis of motion sickness induced by cross-coupled stimulation. The double-blind trial compared GR 38032F with both a placebo (lactose) and with hyoscine. In addition, studies of ocular pursuit and saccadic eye movements were carried out following the administration of each drug. 2. The prophylactic effect of GR 38032F on motion-induced nausea was indistinguishable from that of placebo, whereas following hyoscine subjects showed a highly significant (P less than 0.001) increase in tolerance to cross-coupled stimulation. Tests of oculomotor function showed no effect on saccadic eye movement from either drug. However, both drugs produced a significant (P less than 0.05) though small reduction in eye velocity gain during pursuit eye movement. 3. These findings suggest that the 5-HT3 receptor is not involved in the neural pathways that bring about motion sickness, but that it may have a role in the control of ocular pursuit. The absence of an anti-motion sickness effect from a drug that is effective in the treatment of vomiting induced by cancer chemotherapy serves to emphasize that different neural mechanisms are involved in the generation of motion sickness.     

Blockade of the flare response to intradermal 5-hydroxytryptamine in man by MDL 72.222, a selective antagonist at neuronal 5-hydroxytryptamine receptors

Summary MDL 72.222 is a potent and selective antagonist of excitatory neuronal 5-hydroxytryptamine (5-HT) receptors which has been shown to provide symptomatic benefit in migraine. In the present study, the effects of MDL 72.222 on the flare response to intradermal injection of 5-HT (10^–5, 4×10^–5 and 1.6×10^–4 mol/l) have been examined in six healthy male volunteers using a double-blind, placebo-controlled, randomized, crossover design. The study consisted of two sessions separated by at least 5 days. Comparison of within and between day responses to 5-HT indicated good reproducibility. Significant attenuation of the flare response to 5-HT, 10^–5 and 4×10^–5 mol/l was observed following a slow (4 min) i.v. injection of MDL 72.222, 20 mg. No significant change was observed for the 1.6×10^–4 mol/l dose. The investigator was able to guess with a high degree of accuracy the sequence of MDL 72.222 and placebo (100% correct) and the order of 5-HT dose administration (70% correct), providing further evidence of the reproducibility and sensitivity of the method. MDL 72.222 was well tolerated. Thus, a dose of MDL 72.222 previously shown to provide symptomatic relief in migraine attenuates the flare response to intradermal 5-HT in the human forearm. The observation strengthens the view that the beneficial effects of MDL 72.222 in migraine result from blockade of the sensory neuronal stimulant effects of 5-HT and implies a role for 5-HT in the pain production of the acute attack.     

Long-term blockade of the expression of cocaine sensitization by ondansetron, a 5-HT(3) receptor antagonist

Intermittent cocaine administration induces sensitization (reverse tolerance) to its behavioral effects. The mechanism(s) mediating sensitization is not clear, however, previous research has implicated 5-HT(3) receptors in the expression of sensitization. The present experiment evaluated the ability of the 5-HT(3) receptor antagonist, ondansetron, administered during withdrawal from chronic intermittent cocaine administration, to block the expression of sensitization. Rats were pretreated for 14 days by daily subcutaneous injections of either 40 mg/kg cocaine or 0.9% saline. During the first 5 days of withdrawal from this pretreatment regimen, all rats received a daily subcutaneous injection of 0-1.0 mg/kg ondansetron. On days 7, 14 or 28 of withdrawal from the cocaine pretreatment, the rats received a 15.0-mg/kg cocaine challenge. Ambulatory behavior was automatically recorded for 60 min. Ondansetron had no significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron blocked the expression of sensitization at all withdrawal times. We thus report that it is possible to permanently block the expression of sensitization once it has developed by administering a 5-HT(3) receptor antagonist.     

Effects of the 5-HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain.

1 The ability of the selective 5-HT3 receptor antagonist GR38032F to reduce raised mesolimbic dopaminergic activity was studied in behavioural experiments in the rat and marmoset. 2 GR38032F injected into the nucleus accumbens (0.01-1 ng) or peripherally (0.01-1 mg kg-1 i.p.) inhibited the locomotor hyperactivity caused by the acute intra-accumbens injection of amphetamine (10 micrograms) in the rat. Similar treatments with sulpiride and fluphenazine also inhibited the amphetamine-induced hyperactivity. 3 The peripheral administration of GR38032F (0.001-0.1 mg kg-1 i.p., b.d.) during a 13 day period of dopamine infusion (25 micrograms 24 h-1) into the nucleus accumbens of the rat reduced the dopamine-induced hyperactivity response to control (vehicle infused) levels. Locomotor activity remained at control levels after discontinuing the dopamine/GR38032F treatment regimen. 4 The hyperactivity caused by the infusion of dopamine into the rat nucleus accumbens was also inhibited by fluphenazine (0.01-0.05 mg kg-1 i.p., b.d.), but locomotor activity was suppressed to levels below control values and a rebound hyperactivity occurred after discontinuation of the dopamine/fluphenazine treatment regimen. 5 The discontinuation of a concomitant 13 day intra-accumbens infusion of dopamine with haloperidol, 0.01 mg kg-1 i.p.t.d.s., caused a rebound hyperactivity. This hyperactivity was suppressed by GR38032F (0.001-0.1 mg kg-1 i.p.). 6 The unilateral infusion of dopamine (25 micrograms 24 h-1, 13 days) into the left amygdala of rats having right hemispheric dominance (as measured in a turn preference test) caused locomotor hyperactivity. Intraperitoneal administration of GR38032F (0.1-100 micrograms kg-1) or fluphenazine (0.025-0.1 mg kg-1), and the intra-amygdaloid injection of GR38032F (0.1-100 ng) or fluphenazine (25-500 pg), either into the infused or non-infused side, inhibited the dopamine-induced locomotor hyperactivity. 7 Marmosets receiving bilaterial infusions of dopamine (25 micrograms 24 h-1 for 13 days) into the nucleus accumbens also exhibited increased locomotor activity, GR38032F (0.1-1.0 micrograms kg-1 t.d.s.), reduced the hyperactivity to control levels with no rebound hyperactivity following the discontinuation of the dopamine/GR38032F treatment regimen. Fluphenazine (0.01-2.5 mg kg-1 i.p., t.d.s.) also inhibited the hyperactivity, but locomotor activity was reduced to values below control levels and a rebound hyperactivity followed the discontinuation of the dopamine/fluphenazine treatment.(ABSTRACT TRUNCATED AT 400 WORDS)     

N-Chloroacetyl 5-methoxytryptamine (isamide): a selective antagonist of 5-hydroxytryptamine in the rat uterus

Isamide, the N-chloroacetyl derivative of 5-methoxytryptamine, produced a dose-dependent competitive blockade of uterine contractions in vitro induced by 5-HT. The pA₂ value for the 5-HT-isamide interaction was 4.42. The blockade was short-lasting and reversible; after recovery, a dose-dependent increase in the uterine sensitivity to 5-HT was found. The blockade proved to be selective to the 5-HT receptor. The simultaneous application of 5-HT plus isamide partially prevented the 5-HT-induced auto blockade phenomenon. In addition, isamide did not affect the contractile responses of the uterus to oxytocin or bradykinin or the contractile effects of the rat vas deferens to adrenaline.     

Pharmacology of a novel selective 5-hydroxytryptamine1B receptor antagonist, AR-A000002

The terminal 5-HT_1B autoreceptors have attracted great pharmacological interest since they are potential targets for compounds modifying serotonergic neurotransmission. In the present work the in vivo biochemical properties of AR-A000002 ((R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide), a novel selective 5-HT_1B receptor antagonist, are reported.The effects of AR-A000002 on: 5-HT metabolism was measured as the ratio between 5-HIAA and 5-HT concentrations in different brain regions; 5-HT synthesis was measured as the accumulation of 5-HTP after inhibition of the aromatic amino acid decarboxylase activity with m-hydroxybenzylhydrazine (NSD1015); 5-HT release was measured using the microdialysis technique. 5-HT, 5-HIAA and 5-HTP concentrations were analyzed using high power liquid chromatography (HPLC) with electrochemical detection. AR-A000002 significantly enhanced 5-HT metabolism (5-HIAA/5-HT ratio) and 5-HT synthesis in guinea pig brain in the dose range 0.9–18 mg/kg s.c. (ED₅₀=1 mg/kg s.c. in the four brain regions examined) with maximal effect seen after 2–4 h. AR-A000002 (9 mg/kg s.c.) significantly increased the extracellular concentrations of 5-HT and 5-HIAA by 20% in the guinea pig frontal cortex, measured with the in vivo microdialysis technique in freely moving guinea pigs. AR-A000002 (9 mg/kg s.c.) in combination with the 5-HT uptake inhibitor citalopram (5 mg/kg s.c.) increased the extracellular 5-HT concentration in guinea pig frontal cortex from 250 to 400% of the basal level. Citalopram alone decreased the extracellular 5-HIAA levels to 70% of the basal value. AR-A000002 counteracted the citalopram-induced decrease in 5-HIAA. Since the basal level of extracellular 5-HIAA was 160 times higher than that of 5-HT the 20% increase in 5-HIAA concentrations indicates that only a few percent of the exocytotically released 5-HT from the nerve terminals reached the extracellular space when the re-uptake mechanism was intact. The results also show that the terminal 5-HT_1B autoreceptors are tonically activated under drug-free as well as citalopram conditions. The increase in plasma level of cortisol after AR-A000002 administration may indicate stimulation of post-synaptic 5-HT receptors. AR-A000002 also blocked 5-HT_1B agonist-induced (CP-135,807) decrease in 5-HT metabolism and hypothermia (ED₅₀=1 mg/kg s.c.), thus indicating competition between these two drugs.It is concluded that AR-A000002 is a 5-HT_1B receptor antagonist that enhances the serotonergic neurotransmission in guinea pig brain.     

Antinociception in rat by sarpogrelate, a selective 5-HT(2A) receptor antagonist, is peripheral

The antinociceptive effect of sarpogrelate, a new selective 5-hydroxytriptamine (5-HT)(2A) receptor antagonist, in the formalin test was examined in rats. Sarpogrelate was administered intraperitoneally, locally (subcutaneously at the formalin test site) or intrathecally 10 min before formalin injection. Intraperitoneal (1-100 mg/kg) and local (0.01-1 mg) administration of sarpogrelate suppressed flinching behavior in both phases 1 (0-9 min) and 2 (10-60 min) in a dose-dependent manner. Intraperitoneal (100 mg/kg) and local (1 mg) injection 7 min after formalin injection reduced phase 2 flinches to the same degree as with the pre-treatment. Intrathecal administration (1-100 microg) showed no antinociceptive action, and facilitated phase 2 flinches at 10 microg. The plasma concentration of sarpogrelate after local administration of 1 mg was lower than after intraperitoneal administration of 10 mg/kg, although local administration produced more potent antinociception. The data imply that the antinociceptive effect of sarpogrelate results mainly from an action at peripheral sites.     

γ-Mangostin, a novel type of 5-hydroxytryptamine 2A receptor antagonist

γ-Mangostin, purified from the fruit hull of the medicinal plant Garcinia mangostana caused a parallel rightwards shift of the concentration/response curve for the contraction elicited by 5-hydroxytryptamine (5-HT) in the rabbit aorta (pA₂ = 8.2) without affecting the contractile responses to KCl, phenylephrine (α₁) or histamine (H₁). The perfusion pressure response of rat coronary artery to 5-HT (5-HT_2A) was reduced concentration dependently by γ-mangostin (IC₅₀ = 0.32 μM). 5-HT amplified, ADP-induced aggregation of rabbit platelets (5-HT_2A) was inhibited by γ-mangostin (IC₅₀ = 0.29 μM), whereas that induced by thrombin was not affected, nor did γ-mangostin affect 5-HT-induced contraction of the guinea-pig ileum (5-HT₃)in the presence of 5-HT₁, 5-HT₂ and 5-HT₄ receptor antagonists. Furthermore, 5-HT-induced contraction of the rat fundus (5-HT_2B) and 5-HT-induced relaxation of the rabbit aorta in the presence of ketanserin (5-HT₁) and carbachol-induced contraction of the guinea-pig ileum (muscarinic M₃) were not affected by γ-mangostin (5 μM). γ-Mangostin inhibited [³H]spiperone binding to cultured rat aortic myocytes (IC₅₀ = 3.5 nM). The K _d for [³H]spiperone binding was increased by γ-mangostin (3 nM) from 11.7 to 27.4 nM without affecting B _max. These results suggest that γ-mangostin is a novel competitive antagonist, free from a nitrogen atom, for the 5-HT_2A receptors in vascular smooth muscles and platelets. Received: 10 June 1997 / Accepted: 11 September 1997