The psychopharmacology of 5-HT3 receptors.

The review presents evidence that 5-HT3 receptors within the brain may contribute to the control of behavior. 5-HT3 receptor antagonists GR38032F, zacopride, ICS 205-930 and other agents are very potent in reducing mesolimbic dopamine hyperactivity caused by the injection of amphetamine or infusion of dopamine into the rat nucleus accumbens and amygdala, and the ventral striatum of the marmoset. Such actions are distinguished from those of neuroleptic agents by a failure to reduce normal levels of activity or to induce a rebound hyperactivity after discontinuation of treatment. Indeed, the 5-HT3 receptor antagonists can prevent the neuroleptic-induced rebound hyperactivity. Further evidence that 5-HT3 receptors moderate limbic dopamine function is shown by their ability to reduce both the behavioral hyperactivity and changes in limbic dopamine metabolism caused by DiMe-C7 injection into the ventral tegmental area. The 5-HT3 receptor antagonists also have an anxiolytic profile in the social interaction test in the rat, the light/dark exploration test in the mouse, the marmoset human threat test and behavioral observations in the cynomolgus monkey. They differ from the benzodiazepines by an absence of effect in the rat water lick conflict test and a withdrawal syndrome. Importantly, the 5-HT3 receptor antagonists are highly effective to prevent the behavioral syndrome following withdrawal from treatment with diazepam, nicotine, cocaine and alcohol. Intracerebral injection techniques in the mouse indicate that the dorsal raphe nucleus and amygdala may be important sites of 5-HT3 receptor antagonist action to inhibit aversive behavior. Studies with GR38032F indicate an additional effect in reducing alcohol consumption in the marmoset. The identification and distribution of 5-HT3 receptors in the brain using a number of 5-HT3 receptor ligands, [3H]65630, [3H]zacopride and [3H]ICS 205-930 correlates between studies, and the 5-HT3 recognition sites in cortical, limbic and other areas meet the criteria for 5-HT3 receptors to mediate the above behavioral effects. Thus the use of 5-HT3 receptor antagonists reveals an important role for 5-hydroxytryptamine in the control of disturbed behavior in the absence of effect on normal behavior. The profile of action of the 5-HT3 receptor antagonists has generated a major clinical interest in their potential use for schizophrenia, anxiety and in the control of drug abuse.

Antiemetic properties of the 5HT3-receptor antagonist, GR38032F.

GR38032F is a highly selective 5HT3-receptor antagonist which inhibits vomiting induced by cisplatin, cyclophosphamide or X-radiation in the ferret. Since cisplatin selectively increased the levels of 5HT and 5HIAA in the intestinal mucosa, a possible site of the antiemetic action of GR38032F may be on 5HT3-receptors on vagal afferents in the small intestine. The potent antiemetic action of GR38032F should be of clinical value in reducing the nausea and vomiting associated with radiotherapy or chemotherapy of cancer.

Pharmacology and preclinical antiemetic properties of ondansetron.

Ondansetron (GR 38032) has potent and highly selective antagonist properties at the 5-hydroxytryptamine (5-HT, serotonin) 5-HT3 receptor. The selectivity ratio for ondansetron on 5-HT3 receptors compared with actions on other neurotransmitter receptor types is greater than 1,000. The antiemetic properties of ondansetron have been determined in ferrets against the nausea and vomiting induced by cisplatin, cyclophosphamide, and whole-body radiation. Ondansetron (intravenous 0.01 to 0.1 mg/kg or subcutaneous 0.1 to 0.5 mg/kg) or metoclopramide (1.0 to 4.0 mg/kg) cause dose-dependent inhibitions of the vomiting induced by each of these procedures. Unlike ondansetron, the effects of metoclopramide are accompanied by moderate to marked behavioral depression. Since metoclopramide is 50 times more potent on dopamine D2 receptors than on 5-HT3 receptors, the behavioral depression is likely due to profound blockade of dopamine receptors. The 5-HT3 receptors have been shown to be present peripherally on vagal afferent fibers and are densely located in the vomiting center of the hindbrain. The current hypothesis is that there may be both a peripheral and a central site of action for ondansetron and other 5-HT3 antagonists. The lack of antagonist activity on dopamine and other non-5-HT3 receptors indicates that, unlike metoclopramide, ondansetron will not cause extrapyramidal or other dose-limiting side effects.

Alpha-adrenoceptor-mediated antinociception and sedation in the rat and dog.

The present study compared the potency of a range of alpha-adrenoceptor agonists in producing antinociception and sedation in the rat and dog. In the rat, the selective alpha 2-adrenoceptor agonists, guanabenz, UK 14304 and guanfacine, were more potent as sedative agents than as antinociceptive agents. For compounds which have similar activities at both alpha 1 and alpha 2-adrenoceptors, such as clonidine, alinidine, oxymetazoline and naphazoline, there was little separation between effective doses for antinociception and sedation. In marked contrast, the selective alpha 1-adrenoceptor agonists, ST 587 and methoxamine, were more potent as antinociceptive agents than as sedatives. Similarly, ICI 106,270 and CP 18,534, two agonists with a greater alpha 1 to alpha 2-adrenoceptor ratio than clonidine, were also more potent in antinociceptive tests than in sedative tests. In the conscious dog, clonidine was 8-10 times more potent than ICI 106,270 and CP 18,534 at increasing nociceptive thresholds to mild electrical stimulation of the toothpulp. At equi-antinociceptive doses, the ranked order of potency for inducing sedation was clonidine greater than or equal to ICI 106,270 greater than CP 18,534. Dose-related bradycardia was also induced by each of the three alpha-adrenoceptor agonists at antinociceptive doses. These data suggest that antinociceptive activity can probably be mediated by either alpha 1 or alpha 2-adrenoceptors, whereas sedation appears to be mediated solely by the alpha 2-subtype. Thus, it may be possible to separate the antinociceptive and sedative effects of sympathomimetic agents, but it is unlikely that these agents would be completely devoid of cardiovascular effects.

Antagonism of alpha-adrenoceptor agonist-induced antinociception in the rat.

The present study investigated the effects of WB4101, a selective alpha 1-adrenoceptor blocking agent, and idazoxan, a selective alpha 2-adrenoceptor blocking agent, on antinociception and sedation in the rat mediated by adrenoceptors. Selective alpha 1-adrenoceptor agonists, e.g. ST587 and methoxamine induced antinociception but only elicited slight sedation; their antinociceptive effects were antagonized by WB4101 but not by idazoxan. In contrast, the marked sedative and antinociceptive effects induced by the selective alpha 2-adrenoceptor agonist, UK 14,304, were attenuated by idazoxan, but were little affected by WB4101. The mixed alpha 1/alpha 2-adrenoceptor agonists, clonidine and ICI 106,270, had differing profiles with respect to their antagonist interactions; the antinociceptive and sedative effects induced by clonidine were antagonized by idazoxan, whereas the antinociceptive effects of ICI 106,270 were antagonized by WB4101. The slight sedative effects induced by ICI 106,270 were not attenuated by either WB4101 or idazoxan; therefore, these studies give no insight into the mechanism of action for sedation induced by ICI 106,270. These data suggest that antinociception may be mediated by either alpha 1 or alpha 2-adrenoceptors; whereas sedation is predominantly alpha 2-adrenoceptor mediated.

Synthesis of exo-3-phenylbicyclo[3.2.1]oct-3-en-2-amine and related compounds as potential analgesics.

Several analogues (21 and 29-50) of exo-3-phenylbicyclo[3.2.1]oct-3-en-2-amine (1) were prepared, a compound that had been found to have marked antinociceptive activity in the inflamed-paw pressure test in rats. Two synthetically versatile methods leading to these compounds are described. In this series, antinociceptive activity increases with increasing size of the amine substituent, reaching an optimum with N(Me)Et (32), but this is always associated with central nervous system (CNS) stimulant activity. The antinociceptive activity of these compounds is most likely due to an action that is similar to that of amphetamine rather than to an interaction with an opiate receptor. The endo diastereoisomer 22 and the benzo analogue 11 were both devoid of antinociceptive and CNS stimulant activity.

A classification of opiate receptors that mediate antinociception in animals.

1 To investigate the opiate receptors that mediate antinociception, the activity profiles of opioid analgesic drugs have been determined against different nociceptive stimuli in the mouse and rat. 2 In tests that employ heat as the nociceptive stimulus, mu-opiate receptor agonists, such as morphine, pethidine and dextropropoxyphene, had steep and parallel dose-response curves and were capable of achieving maximum effects. In addition, the antinociceptive potency ratios of these drugs in heat tests were similar to those for analgesia in man. 3 The kappa-agonists, such as ethylketazocine, nalorphine, Mr2034 and pentazocine, were essentially inactive against heat nociception except at doses that caused sedation and motor incapacitation. 4 In the writhing and paw pressure tests both mu- and kappa-agonists produced steep and parallel dose-response curves. 5 It is concluded that both mu- and kappa-opiate receptors mediate antinociception in animals and that the interactions of analgesic drugs with these receptors may be classified in terms of their antinociceptive activities against qualitatively different nociceptive stimuli.

Factors limiting the rate of termination of the neuromuscular blocking action of fazadinium dibromide.

1 Reasons for the termination of the neuromuscular blocking action of fazadinium dibromide have been investigated. 2 In the anaesthetized cat, maximum neuromuscular block of tibialis anterior muscle twitches following rapid intravenous injection of fazadinium was obtained as the injection bolus passed through the muscle, indicating the fazadinium very readily crosses capillary membranes. 3. The half-life of plasma clearance of fazadinium was about 1 min in both cat and man, despite a 10 fold difference in duration of action in these species. Plasma samples were bioassayed for neuromuscular blocking activity on an isolated, superfused phrenic nerve-diaphragm preparation of the rat. 4 In the anaesthetized cat, occlusion of the renal or hepatic circulations did not prolong the neuromuscular blocking action of single doses of fazadinium. Repeated doses accumulated slowly when the hepatic circulation was occluded but not when the renal circulation was occluded. 5 Fazadinium is eliminated from the body by both the liver and kidneys but the rates of these processes are insufficient to account for the initial rapid plasma clearance. 6 The rate-limiting step for the termination of the neuromuscular blocking action of fazadinium is most likely to be the rate of drug-receptor dissociation

Pharmacological characterization of 5-hydroxytryptamine-induced depolarization of the rat isolated vagus nerve.

A study has been made of the pharmacology of the 5-hydroxytryptamine (5-HT)-induced depolarization responses that can be recorded extracellularly from the rat isolated cervical vagus nerve. Phenylbiguanide (PBG) and 2-methyl-5-hydroxytryptamine (2-methyl-5-HT) were found to mimic the effects of 5-HT on the vagus nerve. Their EC50 values were respectively 2.0 fold and 3.9 fold greater than that of 5-HT. Metoclopramide behaved as a reversible competitive antagonist of depolarization induced by PBG and 2-methyl-5-HT, with pKB values of 6.48 +/- 0.04, respectively. These agreed well with the pKB value of 6.60 +/- 0.04 obtained previously for metoclopramide against 5-HT on the rat vagus nerve. 5-HT, PBG and 2-methyl-5-HT had no demonstrable agonist effects at non-5-HT receptors on the rat vagus nerve. Tropacaine and m-chlorophenylpiperazine were found to behave as reversible competitive antagonists of 5-HT-induced depolarization of the vagus nerve. The pKB values were 6.29 +/- 0.03 and 6.90 +/- 0.03, respectively. Quipazine, MDL 72222 and ICS 205-930 were also shown to be effective antagonists of 5-HT on the vagus nerve. However, although these compounds were highly potent, they all caused a marked concentration-dependent reduction in the amplitude of the maximum response to 5-HT. This behaviour was not consistent with a simple reversible competitive mechanism. The results are discussed with reference to the current classification of mammalian peripheral neuronal 5-HT receptors.

Determination of receptors that mediate opiate side effects in the mouse.

The effects of mu and kappa-opiate receptor agonists were studied in a variety of tests in the mouse designed to correspond to clinical side-effects in man. These included sedation, decrease in pupil diameter, Straub tail, decrease in body temperature, decrease in respiratory rate and inhibition of gut propulsion. The mu-receptor agonists tested produced opiate side-effects in the mouse at doses between 2.4 and 34 times higher than their antinociceptive doses in the abdominal constriction test. Their ranked orders of potency in producing these effects were very similar to their order of antinociceptive potency. In contrast, the kappa-receptor agonists only produced opiate side-effects at doses between 29 and greater than 2500 times higher than their antinociceptive doses. There was no correlation between the potency ratios in these tests and in the abdominal constriction test. It is concluded that mu-receptor agonists may produce both their antinociceptive effects and opiate side-effects by interacting with the mu-receptor. The kappa-receptor agonists have previously been shown to produce antinociception via the kappa-receptor, but the opiate-like side-effects which appear with some of the drugs at much higher doses are probably due either to interaction with the mu-receptor or to some other non-specific action.

Further studies on opiate receptors that mediate antinoception: tooth pulp stimulation in the dog.

1 The antinociceptive activities of morphine, codeine and dextropropoxyphene (micro-agonists), buprenorphine and Mr 2034 [(-)5,9-dimethyl-2-(tetrahydrofurfuryl)-2'-hydroxy-6,7-benzomorphan](k-agonists ) have been determined against nociceptive responses to electrical stimulation of the tooth pulp in the conscious dog. 2 Dose-dependent increases in nociceptive threshold were obtained for all of the analgesic drugs tested at doses within their antinociceptive range as determined in nociceptive pressure and chemical tests in rodents.

Reversal by beta-funaltrexamine of the antinociceptive effect of opioid agonists in the rat.

The effect of the irreversible opioid receptor antagonist, beta-funaltrexamine (beta-FNA), on antinociception produced by mu- and kappa-receptor agonists was studied in the rat. beta-FNA, 20 to 80 mg kg-1, s.c., given 24 h before testing, produced a dose-related antagonism of the effects of morphine in the paw pressure, hotplate and tail-flick tests. Following the 80 mg kg-1 dose, the degree of antagonism of morphine was stable for up to 48 h after dosing, but was reduced by 5 days and had disappeared by 8 days. In the paw pressure test, beta-FNA, 40 mg kg-1, s.c., antagonized the effects of fentanyl, buprenorphine, tifluadom, ethylketocyclazocine and proxorphan; it was without effect against the highly selective kappa-agonist, U-50,488. In light of these results, the possible opioid receptor selectivities of both the agonists and beta-FNA are reassessed.

Pharmacological and certain chemical properties of AH 10407, an unusually short-acting, competitive neuromuscular blocking drug, and some related compounds.

1,1-Azobis[3-methyl-2-phenylbenzimidazolinium]dimethanesulphonate (AH 10407) has an ultrashort, competitive neuromuscular blocking action in the mouse, cat, dog, Cynamolgus monkey and cotton-eared marmoset. 2 AH 10407 is chemically unstable in bicarbonate-containing solutions and is degraded to inactive products. The half-life of AH 10407 in vitro in dog and human whole blood and in Krebs physiological solution is about 1.0 minute. In distilled water and in HCO-3-deficient Krebs solution AH 10407 is much more stable. Base catalyzed degradation is shown to be the prime determinant of the duration of action of the drug. 3 Some pharmacological properties of AH 11244 and AH 11056, close analogues of AH 10407, are briefly described and the duration of their neuromuscular blocking actions rationalized by reference to their chemical stabilities.

Influence of 5-hydroxytryptamine uptake on the apparent 5-hydroxytryptamine antagonist potency of metoclopramide in the rat isolated superior cervical ganglion.

Metoclopramide, 1 X 10(-6) -1 X 10(-4) M, was found to behave as a reversible, competitive antagonist of 5-hydroxytryptamine (5-HT)-induced depolarization of the rat isolated vagus nerve (VN) and superior cervical ganglion (SCG). The pKB values were 6.60 (+/- 0.04) and 5.74 (+/- 0.07), respectively. The possibility that this apparent difference in potency was due to saturable 5-HT uptake was investigated. The SCG, but not the VN, accumulated tritium-labelled 5-HT via a saturable, sodium- and temperature-dependent mechanism. Ganglionic 5-HT uptake was blocked by desmethylimipramine (IC50 1.4 X 10(-6)M), chlorimipramine (8.7 X 10(-9) M), zimelidine (1.5 X 10(-7) M), paroxetine (4.3 X 10(-8) M) and citalopram (6.2 X 10(-8) M). The 5-HT uptake inhibitor paroxetine, 1 X 10(-6) M, did not modify the apparent 5-HT antagonist potency of metoclopramide on the VN, but raised the pKB obtained against 5-HT on the SCG from 5.74 (+/- 0.07) to 6.25 (+/- 0.03). It is suggested that the observed difference in the potency of metoclopramide as a 5-HT antagonist on the rat VN and SCG was due to saturable 5-HT uptake in the latter preparation. The results do not support a difference in the 5-HT receptors mediating depolarization on the VN and SCG.

Antinociceptive actions of morphine and buprenorphine given intrathecally in the conscious rat.

1 The antinociceptive effects of morphine and buprenorphine given intrathecally and subcutaneously have been compared in the conscious rat. 2 In the paw pressure test, when given subcutaneously buprenorphine 0.001-0.1 mg/kg s.c., was approximately 100 times more potent than morphine 0.1-3 mg/kg s.c., but in the hot plate test, buprenorphine 0.03-3.0 mg/kg s.c., produced a bell-shaped dose-response curve of low maximum effect and was about equipotent with morphine 0.03-3 mg/kg s.c. 3 When given intrathecally buprenorphine 10 micrograms and morphine, 10-60 micrograms, were approximately equipotent in both paw pressure and hot plate tests. Furthermore, morphine produced these effects at 1/25th of the minimum effective parenteral dose while the dose of buprenorphine exceeded the parenteral dose. 4 It is concluded that the predominant site of the analgesic action of buprenorphine is supraspinal. The significance of these findings in relation to the role of spinal opiate receptors is discussed.

Differential sensitivity of models of antinociception in the rat, mouse and guinea-pig to mu- and kappa-opioid receptor agonists.

1 A range of opioid receptor agonists were tested for activity in five antinociceptive models: the acetylcholine-induced abdominal constriction, tail-flick and hot plate tests in the mouse and the paw pressure test in the rat and guinea-pig. 2 Agonists acting preferentially at the kappa-opioid receptor were significantly more potent in the guinea-pig than in the rat paw pressure test, whereas mu-receptor preferring agonists were equipotent in the two tests. The mouse abdominal constriction test was of equal sensitivity to the guinea-pig pressure test for both types of agonist. 3 The mouse tail-flick and hot plate tests were progressively less sensitive than the other three tests, particularly to kappa-receptor preferring agonists. 4 The efficacy of an agonist can also markedly affect its activity in antinociceptive tests. Thus, partial kappa-agonists were weak or inactive in the rat paw pressure test, and partial agonists at both mu- and kappa-opioid receptors were relatively weak in the tests in which heat was the noxious stimulus, particularly the mouse hot plate test. 5 The mouse abdominal constriction test is suggested as the most appropriate antinociceptive model for testing a broad range of opioid agonists, whilst the relative potency of a drug in the rat and guinea-pig paw pressure tests may indicate the degree to which it is selective for kappa-opioid receptors in vivo.

Involvement of the median raphe nucleus in antinociception induced by morphine, buprenorphine and tilidine in the rat.

1 Antinociception induced by three analgesics with differing profiles of activity, morphine, buprenorphine and tilidine, have been evaluated in the hot plate and paw pressure tests after administration by the subcutaneous route and directly into the median raphe nucleus in the conscious rat. 2 Behavioural and neurological effects of the three analgesics were also assessed. 3 The typical profiles of antinociceptive activity induced by the three analgesics were qualitatively similar after either route of administration. Morphine induced naloxone-sensitive dose-dependent effects in both tests. Buprenorphine showed naloxone-sensitive effects with a bell-shaped dose-response curve in the thermal test but dose-dependent activity in the pressure test. Tilidine induced naloxone-sensitive dose-dependent effects in the thermal test but demonstrated naloxone-insensitive activity in the paw pressure test. 4 The behavioural and neurological effects of the analgesics in the dose range used would not have affected the animals' ability to respond to the nociceptive stimuli. 5 The results suggest that the median raphe could participate in drug-induced antinociception. The mechanisms by which this might occur are discussed.

Determination of the receptor selectivity of opioid agonists in the guinea-pig ileum and mouse vas deferens by use of beta-funaltrexamine.

The irreversible inhibitor of mu-opioid receptor-mediated effects, beta-funaltrexamine (beta-FNA), was used to investigate the selectivity of various opioid agonists at mu-opioid receptors in the electrically stimulated guinea-pig ileum and mouse vas deferens preparations in vitro. In the guinea-pig ileum, pretreatment with beta-FNA (3 X 10(-8) - 3 X 10(-6)M) produced a concentration-dependent antagonism of the inhibitory effect produced by the mu-opioid receptor agonist [D-Ala2, MePhe4, Gly(ol)5]enkephalin (DAGO). High concentrations of beta-FNA (3 X 10(-6) - 1 X 10(-5)M) also antagonized the inhibitory effects of the kappa-opioid agonist U50488. Pretreatment of guinea-pig ileum with beta-FNA at 1 X 10(-6)M resulted in blockade of the effect of some opioid agonists. The compounds which showed the largest rightward shifts in their concentration-response curves, and hence the greatest mu/kappa opioid receptor selectivity, were nalbuphine, [D-Ser2, Leu5]enkephalinyl-Thr6(DSLET), morphine, DAGO and normorphine. Responses to tifluadom, Mr 2034, ethylketocyclazocine, butorphanol, nalorphine, proxorphan and U50488 were not inhibited by beta-FNA. In the mouse vas deferens, pre-treatment with beta-FNA (1 X 10(-6)M) produced a similar shift in the dose-response curves for normorphine as in the guinea-pig ileum. The concentration-response curves for the delta-receptor agonists [D-Ala2, D-Leu5] enkephalin (DADLE) and DSLET were, however, also shifted, indicating that beta-FNA will also block delta-opioid receptors. Since beta-FNA does not block kappa-opioid receptor-mediated effects, it can be used in the guinea-pig ileum preparation as a selective mu-receptor inhibitor. However, its lack of selectivity between mu- and delta-opioid receptors should be taken into account in many other isolated tissues and experiments in vivo.

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. 8. It is concluded that the 5-HT3 receptor antagonist GR38032F, and the neuroleptic agents fluphenazine, sulpiride and haloperidol, can reduce raised mesolimbic dopaminergic activity in the rat and marmoset. GR38032F is distinguished from the dopamine receptor antagonists by, firstly, its ability to return the hyperactivity response to control values, without excessive suppression of locomotion even on enhanced dosage regimes and, secondly, by the lack of rebound hyperactivity following abrupt discontinuation of its treatment.

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.