Similar effects of diazepam and the 5-HT3 receptor antagonist ICS 205-930 on place aversion conditioning

The anti-anxiety effect of diazepam and the antagonist of 5-HT3 receptors, ICS 205-930, was studied with a conditioned place aversion test design. The results showed that when one of two distinctive and previously preferred compartments was associated with an inescapable footshock, the control animals avoided that compartment in the post-conditioning test. Both diazepam (1-4 mg/kg i.p.) and ICS 205-930 (0.125-1.0 mg/kg i.p.), given before the post-conditioning test, increased in a dose-dependent manner the amount of time spent by the animals in the compartment conditioned to footshock. The results support the view that central 5-HT3 receptors may be involved in the control of anxiety.     

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.     

5-HT 3 receptor antagonist ICS 205-930 alters the discriminative effects of ethanol

The ability of a selective 5-hydroxytryptamine (5-HT(3)) receptor antagonist, ICS 205-930 (3-tropanyl-indole-1-carboxylate, tropisetron), to block the discriminative stimulus effects of ethanol was investigated in rats that were trained to discriminate ethanol (1.25 g/kg ip) from saline with food as the reinforcement. Prior administration of ICS 205-930, at the dose of 0.01 mg/kg, significantly decreased ethanol's discriminative stimulus effect at ED(75) dose of ethanol, while higher doses of ICS 205-930 (10 and 17 mg/kg) showed enhancement of ethanol's discriminative effects at ED(0), ED(25), and ED(50) doses of ethanol. Under conditions where ICS 205-930 (10, 17 mg/kg) was tested alone, rats responded exclusively on the saline-appropriate lever. These effects occurred without significantly altering response rates or blood ethanol concentrations. The results suggest that the 5-HT(3) antagonist ICS 205-930 at lower concentration decreases, and at higher concentration enhances the discriminative stimulus effects associated with a lower to moderate dose of ethanol.     

5-HT3 antagonist ICS 205-930 enhances naltrexone's effects on ethanol intake

Opioid receptor antagonist naltrexone has shown some efficacy in decreasing ethanol consumption in humans. However, naltrexone treatment is not always efficacious and produces several aversive effects such as nausea, anxiety and weight loss. Serotonin-3 (5-HT3) receptor antagonists also modulate some of the behavioral effects of alcohol and may decrease alcohol consumption. We examined the effects of the combination of 5-HT3 receptor antagonist ICS 205-930 ((3-tropanyl-indole-1-carboxylate, tropisetron) and naltrexone on ethanol and food intake in Sprague-Dawley rats. Both naltrexone (0.56-10 mg/kg) and ICS 205-930 (5.6 mg/kg), when administered intraperitoneally 30 min before the scheduled 3-h access to ethanol, significantly suppressed ethanol intake. Naltrexone (1 mg/kg) when given in combination with ICS 205-930 (5.6 mg/kg) was significantly more efficacious in suppressing ethanol intake in comparison with naltrexone (1 mg/kg) administered alone. The drug combination did not affect the food intake. These data suggest that 5-HT3 receptor antagonist ICS 205-930 may be used as an effective adjunct for pharmacotherapy of alcoholism.     

Inhibition of the 5-HT-induced cardiogenic hypertensive chemoreflex by the selective 5-HT3 receptor antagonist ICS 205-930

Summary We investigated the effect of ICS 205-930 [(3-tropanyl)-1H-indole-3-carboxylic acid ester], a selective antagonist at 5-HT₃ receptors, on the cardiogenic hypertensive chemoreflex in the anaesthetized dog. The reflex was elicited by injection of 5-HT (12.5–1600 g) into the left cardiac ventricle and consisted of a dose-dependent systemic hypertension associated with a decrease in heart rate. ICS 205-930 (10, 30, and 100 g/kg i.v.) caused a displacement to the right of both the dose-response curves of 5-HT-induced blood pressure increase and heart rate reduction. Its blocking effects upon the action of 5-HT could be surmounted by increasing the dose of the agonist. The selective 5-HT₂ receptor antagonist, ketanserin (0.1 mg/kg i.v.) and the combined 5-HT₁ and 5-HT₂ receptor antagonist, methiothepin (0.1 mg/kg i.v.) had no influence on the hypertensive reflex. When the reflex was elicited by the ganglionic stimulant, 1,1-dimethyl-4-phenyl-piperazinium (DMPP; 100–1600 g), ICS 205-930 had no blocking effect. The results suggest that the 5-HT-induced cardiogenic hypertensive chemoreflex is mediated by 5-HT₃ receptors. Send offprint requests to H. Berthold at the above address     

Behavioural effects in gerbils of the 5-HT3 receptor antagonists, BRL 43694 and ICS 205-930, under circumstances of high and low light intensity

The 5-HT3 receptor antagonists, BRL 43694 and ICS 205-930, were each given for 21 days in the drinking fluid at 1.3 mg/l (120 micrograms/kg daily), to Mongolian gerbils, while the controls received tap water to drink. Effects of the treatments in reducing aversion to a brightly lit environment were assessed on behaviour during social encounters with an unfamiliar untreated resident, under bright white light and in a two-compartment black and white test box, after 12-16 days of treatment. Effects on behaviour under dim red illumination, when encountering unfamiliar untreated residents, were examined after 17-19 days. Behaviour during social encounters was recorded by ethological procedures. During encounters under bright white light, the frequency and duration of the social element "attend" were increased by BRL 43694 and ICS 205-930 and the frequency of "nose" was increased by BRL 43694. In the light-dark box, BRL 43694, though not ICS 205-930, reduced the time spent in the dark compartment. Under dim red light, BRL 43694 and ICS 205-930 increased the occurrence of the social elements, "sniff", "follow" and "sniff chin", suggesting increased sensitivity to olfactory stimuli. Increases of social investigation were associated with compensatory changes to non-social behaviour. It is suggested that 5-HT3 receptor antagonists may, on the one hand, increase sensitivity to social stimuli under dim red illumination and, on the other hand, show an apparent anxiolytic potential, associated with increase of other elements of social investigation under the more aversive test conditions of bright white light.     

Effects of the 5-HT3 antagonist ICS 205-930 on benzodiazepine withdrawal signs in rats

Effects of the 5-HT3 antagonist ICS 205-930 on chlordiazepoxide (CDP) withdrawal were assessed in rats treated for 21 days with doses of CDP up to 40mg/kg/day (b.i.d.). Withdrawal signs recorded were body weight and 24h food intake, which both fell during withdrawal and then recovered. ICS 205-930 (0.001-1.0mg/kg) was administered b.i.d. during withdrawal. At no dose over the wide range tested did ICS 205-930 reduce withdrawal signs. These data contrast with published findings with the 5-HT3 antagonist ondanestron, some of which indicated that ondansetron completely alleviated the "anxiogenic" suppression of exploratory behaviour observed during benzodiazepine (BZ) withdrawal. Possible reasons for these differing findings are discussed. Collectively, these findings suggest that 5-HT3 antagonists may have limited utility in the clinical treatment of BZ withdrawal.     

Attenuation of defensive analgesia in male mice by 5-HT3 receptor antagonists, ICS 205-930, MDL 72222, MDL 73147EF and MDL 72699.

Recent studies have shown that non-opioid defensive analgesia in male mice is potently inhibited by the 5-HT3 receptor antagonist, ondansetron. The present series of experiments was conducted to further explore the involvement of 5-HT3 receptor mechanisms in this particular form of adaptive inhibition of pain. The drug ICS 205-930 significantly attenuated the reaction at 1.25-2.5 micrograms/kg, with smaller and larger doses being ineffective. Both MDL 72222 and MDL 73147EF produced flat dose-response curves, with significant inhibition of defensive analgesia at minimum effective doses of less than or equal to 10 and 300 micrograms/kg, respectively. Although MDL 72699, the quaternary salt of MDL 72222, also inhibited the reaction, this effect was seen at comparatively large doses (0.5-1.0 mg/kg) only. None of the compounds tested had significant intrinsic effects of tail-flick latencies, over the dose ranges tested. These findings indicate that 5-HT3 receptor mechanisms may have an important modulatory role in certain forms of "stress" analgesia. Data are discussed in relation to the consistent profile of partial inhibition produced by 5-HT3 receptor antagonists in this model.     

Inhibition of cholera toxin-induced intestinal secretion by the 5-HT3 receptor antagonist ICS 205–930

Summary The secretory effect of cholera toxin on the gut has been ascribed to the activation of submucosal 5-hydroxytryptamine receptors by 5-hydroxytryptamine released from the enterochromaffin cells. The hypothesis that neuronally located 5-HT₃ receptors are involved in cholera toxin-induced diarrhoea has now been tested. Intestinal secretion was stimulated in mice by oral administration of pure cholera toxin and the effects of ICS 205-930, a potent and selective antagonist at 5-HT₃ receptors, and of ketanserin, a compound that blocks 5-HT₂ receptors, were investigated.Oral administration of cholera toxin resulted in a significant accumulation of fluid in the intestine. Pretreatment of the animals with ICS 205–930 partly prevented this effect and a maximal reduction of about 50% was achieved with doses of 0.3 mg/kg i. p. and higher. Ketanserin had only minimal effects up to a high dose of 1 mg/kg i. p. when a 20% reduction of fluid accumulation was seen. The data support the view that activation of 5-HT3 receptors plays a major role in the secretory effect of cholera toxin in the gut.     

Effect of the selective 5-HT3 receptor antagonists ICS 205-930 and MDL 72222 on 5-HTP-induced head shaking and behavioral symptoms induced by 5-methoxy-N,N,dimethyltryptamine in rats: comparison with some other 5-HT receptor antagonists

The effect of the selective 5-HT₃ receptor antagonists ICS 205-930 and MDL 72222 on head shaking behavior induced by l-5-HTP and behavioral symptoms induced with 5-methoxy-N,N,-dimethyltryptamine (5-MeODMT) in rats was evaluated. Both drugs dose-dependently reduced l-5-HTP-induced head shaking but were at least 600 times less potent than pirenperone and ketanserin and at least 50 times less potent than methysergide. ICS 205-930 and MDL 72222 were more than 1000 times less potent than pirenperone or methysergide and 100 times less potent than ketanserin in blocking 5-MeODMT-induced forepaw treading and tremor. Since it appears that head shakes induced by l-5-HTP are mediated by 5-HT₂ receptors, these data suggest that ICS 205-930 and MDL 72222 do not significantly interact with 5-HT₂ receptors in the brain. Furthermore, the data suggest that ICS 205-930 and MDL 72222 lack appreciable antagonistic activity at the 5-HT receptor(s) mediating those behavioral effects induced by 5-MeODMT.     

Effects of the 5-HT3 receptor antagonist ICS 205-930 on fat-delayed gastric emptying and antral motor activity.

1. The selective 5-HT3 receptor antagonist, ICS 205-930 (Sandoz), has been reported to have potent effects on gastric smooth muscle in vivo and to enhance gastric emptying in animals and in man. 2. This study investigated the effects of ICS 205-930 on fat-delayed gastric emptying of a semisolid meal and antral motor activity in humans. 3. Twelve healthy men participated in each of three studies in which 10 or 20 mg of ICS 205-930 or placebo were infused i.v. in a random double-blind fashion. Gastric emptying and antral motor activity were studied scintigraphically. 4. Gastric emptying was not altered after 10 mg but slower after 20 mg of ICS 205-930 than after placebo. Emptying after 20 mg of ICS 205-930 was significantly slower than after 10 mg of ICS 205-930. 5. Antral contraction amplitude was slightly lower after 20 mg of ICS 205-930 than after placebo, whereas the effects of 10 mg ICS 205-930 did not differ from those of placebo. 6. The results suggest that the investigated doses of ICS 205-930 have only slight effects on gastric motor activity of healthy young men, with 20 mg reducing the rate of emptying.     

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)     

Enhancement of Memory Retrieval and Attenuation of Scopolamine-Induced Amnesia Following Administration of 5-HT3 Antagonist ICS 205-930

Abstract: Experimental evidence suggests an important role of serotonin in the process of learning and memory. The present study investigated the effect of 5HT₃-receptor antagonist (ICS 205-930) on retrieval of a previously learned aversive habit in the mouse. The effect of ICS 205-930 on scopolamine (3 mg/kg) induced amnesia was also studied. ICS 205-930 (1, 10 & 100 μg/kg) produced a dose-dependent increase in latency to cross into the dark chamber. The scopolamine induced memory impairment was significantly attenuated by ICS 205-930 (10 μg/kg). These results suggest that memory deficits may be susceptible to attenuation with non-cholinergic treatments.     

Enhancement of memory retrieval and attenuation of scopolamine-induced amnesia following administration of 5-HT3 antagonist ICS 205-930.

Experimental evidence suggests an important role of serotonin in the process of learning and memory. The present study investigated the effect of 5HT3-receptor antagonist (ICS 205-930) on retrieval of a previously learned aversive habit in the mouse. The effect of ICS 205-930 on scopolamine (3 mg/kg) induced amnesia was also studied. ICS 205-930 (1, 10 & 100 micrograms/kg) produced a dose-dependent increase in latency to cross into the dark chamber. The scopolamine induced memory impairment was significantly attenuated by ICS 205-930 (10 micrograms/kg). These results suggest that memory deficits may be susceptible to attenuation with non-cholinergic treatments.     

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.     

Characterisation of 5-HT3 recognition sites in membranes of NG 108-15 neuroblastoma-glioma cells with [3H]ICS 205-930

1. The binding characteristics of [3H]ICS 205-930, a potent and selective 5-hydroxytryptamine 5-HT3 receptor antagonist, were investigated in membranes prepared from murine neuroblastoma-glioma NG 108-15 cells. 2. [3H]ICS 205-930 bound rapidly, reversibly and stereoselectively to a homogeneous population of high affinity recognition sites: Bmax = 58 +/- 3 fmol/mg protein, pKD = 9.01 +/- 0.08 (n = 11). Non linear regression and Scatchard analysis of saturation data suggested the existence of a single class of [3H]ICS 205-930 recognition sites on NG 108-15 cells. The binding was rapid, stable and reversible. The affinity of [3H]ICS 205-930 determined in kinetic studies was in agreement with that obtained under equilibrium conditions. 3. Competition studies performed with a variety of agonists and antagonists also suggested the presence of a homogeneous population of [3H]ICS 205-930 recognition sites. All competition curves were steep and monophasic and were best fit by a 1 receptor site model. [3H]ICS 205-930 binding sites displayed the pharmacological profile of a 5-HT3 receptor. Potent 5-HT3 receptor antagonists showed nanomolar affinities for [3H]ICS 205-930 binding sites with the following rank order of potency: SDZ 206-830 greater than ICS 205-930 greater than SDZ 206-792 greater than BRL 43694 greater than quipazine greater than BRL 24924 greater than SDZ 210-204 greater than MDL 72222 greater than SDZ 210-205. Metoclopramide, mCP and mianserin showed submicromolar affinity.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of ICS 205-930, a 5-HT antagonist, on arrhythmias and catecholamine release during canine myocardial ischaemia and reperfusion

The effects of ICS 205-930 [3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester), an antagonist of 5-HT at neuronal M receptors, were examined in anaesthetised greyhounds subject to acute coronary artery occlusion and reperfusion. Intravenous administration of 0.3 or 2.0 mg kg-1 of ICS 205-930 did not significantly alter haemodynamics or blood gases. The higher dose had marked antiarrhythmic activity. The total number of ischaemia-induced extrasystoles was reduced to 167 +/- 64 compared with 467 +/- 99 in controls. Ventricular fibrillation induced by reperfusion after 40 min of ischaemia was also significantly reduced from 80 to 33%. Immediately following release of the coronary artery occlusion significant increases in plasma noradrenaline and dopamine concentrations were detected in local coronary venous blood draining from the ischaemic area in control dogs. This catecholamine release was also evident in the dogs which received 2 mg kg-1 ICS 205-930 but was less marked. Thus the antiarrhythmic activity of ICS 205-930 may be related to antagonism of detrimental effects of 5-HT, such as the ability to facilitate the release of noradrenaline from sympathetic nerve terminals in the heart, although other mechanisms may be involved.     

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.