The 5 -HT3 receptor antagonists, granisetron and ondansetron, do not affect cocaine-induced shifts in intra-cranial self-stimulation thresholds

The effects of the 5-HT( 3) receptor antagonists, granisetron and ondansetron, were investigated on behaviour maintained by intracranial self-stimulation (ICSS). Rats, implanted with bipolar electrodes in the lateral hypothalamus, were trained to lever press on a continuous reinforcement schedule for positively reinforcing trains of electrical stimulation. The frequency at which responding reached 50% of maximum (M50) and the maximum rate of responding (asymptote) were used to measure drug effects. Granisetron (0.01-0.1 mg/kg i.p ) and ondansetron (0.03-0.3 mg/kg i.p ) had no effect on either parameter. In contrast, cocaine (20 mg/kg i.p ) potentiated rewarded responding, reducing M50 values, but neither granisetron (0.01-3.0 mg/kg i.p ) nor ondansetron (0.03-0.3 mg/kg i.p ) blocked this effect. Neither did granisetron (0.1-10.0 mg/kg i.p ) alter the effect of lower doses of cocaine (10 mg/kg i.p.). These data suggest that 5 -HT( 3) receptors do not play a significant role in mediating responding maintained by ICSS in the rat through hypothalamic electrodes. Neither do they modulate cocaine-induced potentiation of the behaviour.     

5-HT3 receptor antagonists, a new approach in emesis: a review of ondansetron, granisetron and tropisetron.

In recent years a new class of agents, the serotonin type 3 receptor antagonists, has been identified. This article reviews the preclinical, pharmacological and clinical data of ondansetron, granisetron and tropisetron, the first representatives of this group. Preclinical work showed that the drugs interfere with a variety of physiological processes, and hold promise for clinical utility in a wide range of areas. To date, these agents have proven, both in early clinical and comparative studies, to be potent antiemetic agents in patients receiving cisplatin and non-cisplatin chemotherapy as well as radiotherapy. In comparative studies the antiemetic efficacy mostly has been superior to conventional antiemetic drugs with regard to the acute chemotherapy-related symptoms; whereas their role in delayed emesis needs further investigation. This also applies for their role as an antiemetic in other types of nausea and vomiting (post-operative). Toxic effects have been modest, no extrapyramidal reactions have been reported. Potential clinical use in psychiatric disorders has been suggested, and the results of clinical trials are awaited.     

5-HT3 receptor antagonists

The 5-HT₃ receptor is a ligand-gated ion channel widely distributed in the central and peripheral nervous systems. Many selective 5-HT₃ receptor antagonists have been developed; animal studies with such compounds suggested their potential therapeutic value in combating emesis and a wide range of CNS diseases including anxiety, schizophrenia, drug dependence and Alzheimer’s disease. Their successful introduction as anti-emetics, with irritable bowel syndrome emerging as a further indication have partially fulfilled this initial promise. However, the CNS area has been less productive and, to date, no selective 5-HT₃ receptor antagonist has been approved for use in a CNS disease.     

5-HT(3) receptor antagonists

The 5-HT(3) receptor is a ligand-gated ion channel widely distributed in the central and peripheral nervous systems. Many selective 5-HT(3) receptor antagonists have been developed; animal studies with such compounds suggested their potential therapeutic value in combating emesis and a wide range of CNS diseases including anxiety, schizophrenia, drug dependence and Alzheimer's disease. Their successful introduction as anti-emetics, with irritable bowel syndrome emerging as a further indication have partially fulfilled this initial promise. However, the CNS area has been less productive and, to date, no selective 5-HT(3) receptor antagonist has been approved for use in a CNS disease.     

5-HT3受体阻滞剂帕洛诺司琼

帕洛诺司琼（palonosetron）是新型5-HT3受体阻滞剂,适用于中～重度呕吐化疗所引起的恶心、呕吐,其与传统5-HT3受体阻滞剂相比,具有疗效高、作用时间长、用量小、不良反应少的优点.现对帕洛诺司琼的作用机制、药动学、安全性以及临床应用等做一简单综述.     

Block of the delayed rectifier current (IK) by the 5-HT3 antagonists ondansetron and granisetron in feline ventricular myocytes.

1. We investigated the effects of two 5-HT3 antagonists, ondansetron and granisetron, on the action potential duration (APD) and the delayed rectifier current (IK) of feline isolated ventricular myocytes. Whole-cell current and action potential recordings were performed at 37 degrees C with the patch clamp technique. 2. Ondansetron and granisetron blocked IK with a KD of 1.7 +/- 1.0 and 4.3 +/- 1.7 microM, respectively. At a higher concentration (30 microM), both drugs blocked the inward rectifier (IKl). 3. The block of IK was dependent on channel activation. Both drugs slowed the decay of IK tail currents and produced a crossover with the pre-drug current trace. These results are consistent with block and unblock from the open state of the channel. 4. Granisetron showed an intrinsic voltage-dependence as the block increased with depolarization. The equivalent voltage-dependency of block (delta) was 0.10 +/- 0.04, suggesting that granisetron blocks from the intracellular side at a binding site located 10% across the transmembrane electrical field. 5. Ondansetron (1 microM) and granisetron (3 microM) prolonged APD by about 30% at 0.5 Hz. The prolongation of APD by ondansetron was abolished at faster frequencies (3 Hz) showing reverse rate dependence. 6. In conclusion, the 5-HT3 antagonists, ondansetron and granisetron, are open state blockers of the ventricular delayed rectifier and show a clear class III action.     

The anxiolytic-like effects of 5-hydroxytryptamine3 (5-HT3) receptor antagonists.

The effect of six 5-HT3 receptor antagonists: ondansetron (0.01-3 mg/kg ip), granisetron (0.01-1 mg/kg ip), zacopride (0.01-3 mg/kg ip), tropisetron (0.001-0.1 mg/kg ip), MDL 72222 (0.01-3 mg/kg ip) and DAU 6215 (0.01-3 mg/kg sc) were examined in the conflict drinking test (Vogel test) and in the elevated plus-maze test in rats. Ondansetron (0.1-0.3 or 1 mg/kg), zacopride (0.1-1 mg/kg) and tropisetron (0.01 mg/kg) increased the punished responding in the Vogel test and showed anxiolytic effects in the elevated plus-maze test. Their effects were limited to a narrow dose range and were not dose-dependent. Granisetron (0.1 mg/kg) exhibited an anti-conflict activity, but was ineffective in the elevated plus-maze test. MDL 72222 and DAU 6215 were ineffective in both those tests. On the other hand, diazepam (2.5-10 mg/kg), used as a reference drug, was active in either procedure and its effects were dose-dependent. These results indicate that an anxiolytic-like activity is not a common characteristic of 5-HT3 receptor antagonists. Moreover, even the anxiolytic action of drugs which were active in the experimental models used should be accepted with caution.     

Anxiolytic potential of 5-HT3 receptor antagonists.

The 5-HT3 receptor antagonists such as ondansetron have been shown to have anxiolytic-like activity in a wide range of preclinical tests: in the mouse black: white test, the rat social interaction test, the rat elevated X-maze and the marmoset human threat test. Ondansetron, like other 5-HT3 receptor antagonists appears to have important advantages over existing anxiolytic therapies. Thus, the 5-HT3 receptor antagonists are not sedative, they do not have addictive liabilities, there are no problems of withdrawing from chronic treatment and they can be used following benzodiazepine withdrawal. Such compounds even inhibit the behavioural syndrome associated with withdrawal from drugs of abuse, nicotine, alcohol, cocaine, opiates. The preclinical data, therefore, indicates the 5-HT3 receptor antagonists as novel anxiolytics of the future, and there is new clinical work in support of this suggestion.     

The effects of ondansetron, a 5-HT3 receptor antagonist, on cognition in rodents and primates

The selective 5-HT3 receptor antagonist, onansetron, has been assessed in three tests of cognition in the mouse, rat and marmoset. In a habituation test in the mouse, ondansetron facilitated performance in young adult and aged animals, and inhibited an impairment in habituation induced by scopolamine, electrolesions or ibotenic acid lesions of the nucleus basalis magnocellularis. Arecoline failed to improve basal performance in young adult mice but inhibited the impairment caused by scopolamine and lesions of the nucleus basalis magnocellularis. In the T-maze reinforced alternation task in rats, ondansetron and arecoline antagonised a scopolamine-induced impairment. In an object discrimination and reversal learning task in the marmoset, assessed using a Wisconsin General Test Apparatus, ondansetron improved performance in a reversal learning task. We conclude that ondansetron potently improves basal performance in rodent and primate tests of cognition and inhibits the impairments in performance caused by cholinergic deficits.     

Temperature,food intake,and locomotor activity effects of a 5-HT3 receptor agonist and two 5-HT3 receptor antagonists in rats

This study investigated three physiologic functions known to be modulated by serotonin — temperature, food intake and locomotor activity — using the 5-HT₃ receptor agonist,m-chlorophenylbiguanide (m-CPBG), and two 5-HT₃ antagonists, MDL-72222 and ondansetron. m-CPBG produced dose-dependent elevations in rectal temperature. MDL-72222, which had no effects on temperature when given alone, significantly attenuated m-CPBG-induced hyperthermia. Food intake in food-deprived rats was reduced during the first hour by the highest dose of m-CPBG. Food intake was also dose-dependently reduced by MDL-72222; m-CPBG plus MDL-72222 led to greater reductions in food intake. Food intake in freely fed rats was unaffected by m-CPBG or MDL-72222. Locomotor activity was unaffected by m-CPBG, but was dose-dependently reduced by MDL-72222, an effect which may have contributed to its hypophagic effects. Ondansetron, used in ten-fold lower doses than MDL-72222, was inactive in all of these paradigms. These data: (1) provide some evidence for 5-HT₃ receptor-mediated changes in temperature; (2) are in agreement with two prior studies which reported locomotor activity reductions following 5-HT₃ antagonists; but (3) do not support an important role for 5-HT₃ receptors in the regulation of food intake in rats.     

5-HT_3受体拮抗剂抑制化疗致吐的研究进展

目的通过对5-HT3受体特点的研究和5-HT3受体参与的化疗致吐机制的剖析,阐明5-HT3受体拮抗剂对抗化疗致吐方面的作用机制和临床应用。方法综述国内外相关文献19篇,对相关研究的进展和成果进行总结。结果5-HT3受体拮抗剂通过在外周和中枢选择性拮抗5-HT3受体,有效控制化疗致吐的发生。因其效果显著、不良反应小而得到了较好的临床应用。结论5-HT3受体拮抗剂可选择性阻断5-HT3受体,从而有效控制化疗导致的呕吐。     

The effects of 5-HT3 receptor antagonists on cisplatin-induced emesis in the pigeon.

In the present study, the emetic effect of the anticancer drug cisplatin, and the protective effects of 5-HT3 receptor antagonists against cisplatin emesis were investigated in the pigeon. The experimental set-up involved the i.v. administration of drugs and subsequent observation of the percentage of vomiting animals and the number of emetic episodes per vomiting animal. It was observed that cisplatin induced dose-dependent emesis in the pigeon. 5-HT3 receptor antagonists afforded partial protection against cisplatin emesis, although some of them, i.e. indole, indole-like derivatives and zacopride, displayed intrinsic emetic activity. A serotonergic mechanism appears to be involved in both cisplatin- and 5-HT3 receptor antagonist-induced emesis, since pretreatment with an inhibitor of 5-HT synthesis, para-chlorophenylalanine (pCPA), prevented vomiting induced by either cisplatin or 5-HT3 receptor antagonists. It is concluded that the intrinsic emetic effects of 5-HT3 receptor antagonists provide pharmacological evidence of species differences in the properties of 5-HT3 receptors.     

Emerging differences between 5-HT3 receptor antagonists.

A brief review is presented of some recently described 5-HT3 receptor antagonists. These antagonists are primarily targeted for use as anti-emetics. However, evidence is emerging that there are differences in their basic pharmacology. This evidence is reviewed in terms of the selectivity of the antagonists in binding studies and also of their efficacy in emesis and gastric emptying. The possibility that these differences may translate into meaningful clinical differences between the available 5-HT3 receptor antagonists in their use as anti-emetics is also discussed.     

Electrocardiographic effects of zatosetron and ondansetron,two 5HT3 receptor antagonists,in anesthetized dogs

The pharmacology of 5-hydroxytryptamine₃ (5HT₃)-antagonists is an area under active investigation, and several agents of this class are currently under development for multiple therapeutic indications. Recently, two 5HT₃ receptor antagonists of a tropane derived series, ICS 205 930 and zatosetron, have been shown to alter electrocardiographic properties of heart muscle. A prototypical, but structurally distinct (imidazole) 5HT₃-antagonist, ondansetron, was examined for its comparative cardiovascular activity in anesthetized dogs at intravenous doses of 0.66–5.25 mg/kg. Similar to zatosetron, a significant, dose-dependent prolongation of the duration of the action potential of the electrocardiogram (Q-T_c interval) occurred following ondansetron exposure, with a maximum increase of 28%. Other cardiovascular parameters (heart rate, mean arterial pressure, pulmonary pressure, cardiac output, peripheral vascular resistance, stroke volume and work index) were essentially unchanged by ondansetron treatment. At equivalent 5HT₃ blocking doses, both ondansetron and zatosetron prolonged the Q-T_c interval in anesthetized dogs similarly. However, for both compounds, the doses required to increase Q-T_c interval were higher than the doses required to demonstrate 5HT₃ receptor blockade. The fact that ondansetron, an imidazole, exhibited electrophysiological effects on cardiac muscle like the 5HT₃ receptor antagonists derived from tropane suggests that the electrocardiographic effects are related to some property shared by 5HT₃ receptor antagonists rather than a property of the tropane structure.     

Restraint accentuates the effects of 5-HT2 receptor antagonists and a 5-HT1A receptor agonist on lordosis behavior

The effect of restraint on lordosis behavior was examined in proestrous and ovariectomized, hormone-primed rats. Restraint durations from 5 to 60 min had no effect on lordosis behavior of proestrous rats. There was also no effect of 5 min restraint on lordosis behavior of ovariectomized rats hormonally primed with 10 microg estradiol benzoate and 500 microg progesterone. However, after intraperitoneal treatment with 1.0 mg/kg ketanserin tartrate (ketanserin), 5 min of restraint significantly reduced lordosis behavior of both groups of rats. The 5-min restraint combined with 0.50 or 0.75 mg/kg ketanserin reduced lordosis to mount (L/M) ratios of ovariectomized rats, while L/M ratios of proestrous rats were inhibited only by the 1.0 mg/kg dose. Increasing the restraint duration (10 or 15 min) reduced the dose of ketanserin necessary to reduce the L/M ratios of proestrous rats. Treatment with the selective serotonin (5-HT)(2C) receptor antagonist, SB206553 (2.5 or 5.0 mg/kg), in combination with 5 min of restraint, also reduced L/M ratios of hormonally primed, ovariectomized rats. The neural sites responsible for ketanserin's additivity with restraint are unknown, but infusion of the drug into the ventromedial nucleus of the hypothalamus (VMN) did not mimic the systemic treatment. However, 5 min of restraint did enhance the effects of VMN infusion with the 5-HT(1A) receptor agonist, 8-OH-DPAT. In contrast, 8-OH-DPAT's systemic potency was not enhanced by restraint. These findings support the hypothesis that a mild stressor increases the lordosis-inhibiting effects of 5-HT(1A) receptor agonists and that 5-HT(2) receptors may protect against such disruption of lordosis behavior.     

Blockade of the discriminative stimulus effects of ethanol with 5-HT3 receptor antagonists

The ability of selective 5-HT₃ receptor antagonists to block the discriminative stimulus effects of ethanol was investigated in pigeons trained with food reinforcement to discriminate ethanol (1.5 g/kg; IG) from water. The 5-HT₃ receptor antagonists that are substituted tropines, ICS 205-930 (0.1–0.56 mg/kg) and MDL 72222 (3.0–17.0 mg/kg), blocked ethanol-appropriate responding, in a dose-dependent manner, suggesting that some of the discriminative stimulus effects of ethanol are mediated via the 5-HT₃ receptor. The blockade the discriminative stimulus effects of ethanol occurred in the presence of approximately 25–40 mM blood ethanol levels. Furthermore, the ethanol dose-effect function was shifted to the right by increasing doses of MDL 72222, suggesting a surmountable antagonism of the discriminative stimulus effects of ethanol. However, the benzamide zacopride (0.56–1.7 mg/kg), which is also a 5-HT₃ receptor antagonist, did not block the discriminative stimulus effects of ethanol. In addition, the dopaminergic antagonist haloperidol and the 5-HT₂ receptor antagonist ketanserin also failed to block the ethanol discrimination. The results suggest that 5-HT₃ mediated neurotransmission is an important component of ethanol's discriminative stimulus effects, but that the structural characteristics of the selective 5-HT₃ receptor antagonists influence their ability to block this action of ethanol. Furthermore, these findings implicate a significant role of 5-HT₃ activity in the behavioral effects of ethanol that may provide a pharmacological means for therapeutic intervention of alcohol abuse.     

The effect of 5-HT3 receptor antagonists on the discriminative stimulus effects of amphetamine.

The discriminative stimulus induced in rats by amphetamine has previously been shown to be due to raised mesolimbic dopamine levels. As 5-HT3 receptor antagonists have been shown to inhibit hyperactivity resulting from raised mesolimbic dopamine levels, the present study examined their effects against the amphetamine discriminative stimulus. None of the 5-HT3 receptor antagonists tested (MDL 72,222EF, 0.3-10 mg/kg s.c.; MDL 73,147EF, 0.3-10 mg/kg s.c.; ICS 205-930, 0.01-10.0 mg/kg s.c.; ondansetron, 0.1-1000 micrograms/kg s.c.) antagonised the effects of amphetamine in this test. This suggests that 5-HT3 receptors cannot modulate the effects of raised mesolimbic dopamine in pathways involved in the interoceptive effects of amphetamine.     

Advances in use of the 5-HT3 receptor antagonists

Nausea and vomiting continue to rank as important side effects for cancer patients receiving chemotherapy. The class of drugs known as the 5-HT3 receptor antagonists have become widely used for chemotherapy-induced nausea and vomiting, and are considered a standard part of care for moderately- and highly-emetogenic chemotherapy in combination with corticosteroids. Ondansetron (Zofran, Glaxo Wellcome), granisetron (Kytril, SmithKline Beecham) and dolasetron (Anzemet, Hoechst Marion Roussel) are commercially available in the US. Intravenous forms of all three drugs have demonstrated efficacy in preventing acute (< or = 24 h following chemotherapy) nausea and emesis due to moderately- and highly-emetogenic chemotherapy. Oral forms of the drugs have been shown to be effective in prevention of nausea and emesis due to moderately-emetogenic chemotherapy. More recently, oral 5-HT3 receptor antagonists have demonstrated efficacy in the prevention of nausea and vomiting due to highly-emetogenic chemotherapy as well. Comparative trials between the three agents have shown no clinically important differences in outcome and they should be considered clinically equivalent. Optimal oral anti-emetic regimens for high-dose chemotherapy with bone marrow or stem cell transplantation remain to be determined and future oral studies should target this population. In general, the decision of which 5-HT3 receptor antagonist to select for formulary inclusion should be based on the dose of anti-emetic used and the acquisition cost of the agents being compared. The oral route should be used whenever possible.     

Effects of 5-HT3 receptor antagonists on 5-HT and nicotinic depolarizations in guinea-pig submucosal neurones.

1. Intracellular recordings were made from neurones of the guinea-pig submucosal plexus. The effects of several 5-hydroxytryptamine3 (5-HT3) receptor antagonists on depolarizations produced by ionophoretic application of 5-HT and acetylcholine, as well as on fast excitatory postsynaptic potentials (fast e.p.s.ps) produced by nerve stimulation were examined. 2. ICS 205-930, GR 38032F, MDL 72222, cocaine and curare all inhibited the fast e.p.s.p. as well as the depolarizations in response to 5-HT and acetylcholine (ACh) ionophoresis in a dose-dependent fashion. 3. IC50 values for ICS 205-930, GR 38032F, MDL 72222, cocaine and curare in inhibiting the 5-HT mediated depolarizations were 12 nM, 100 nM, 3 microM, 3 microM and 20 microM, respectively. 4. IC50 values for ICS 205-930, GR 38032F, MDL 72222, cocaine and curare in inhibiting the nicotinic depolarizations were 4 microM, 12 microM, 11 microM, 6 microM and 17 microM, respectively. Similar IC50 values were obtained for inhibition of the fast e.p.s.ps by these antagonists. 5. The nicotinic receptor blocker, hexamethonium, inhibited the nicotinic depolarization and the fast e.p.s.p. with IC50 values of 10 microM. Hexamethonium (10 microM-5 mM) did not alter the depolarization induced by 5-HT. 6. These results demonstrate that the pharmacological profile of 5-HT3 receptors present on submucosal neurones is identical to that of 5-HT3 receptors on myenteric neurones and, thus, provide evidence that the enteric neuronal 5-HT3 receptor forms a receptor subtype distinct from that characterized in other parts of the autonomic nervous system.