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To study the functional contributions of the 5-HT4 receptor subtype of serotonin (5-HT), we have generated knockout mice lacking the 5-HT4 receptor gene. The male mutant mice exhibit a hyposensitivity to anorexic stress. Our recent data indicate that the pharmacological inactivation, using a systemic injection of the 5-HT4 receptor antagonist RS39604 (0.5 mg/kg), suppressed restraint stress-induced anorexia in wild-type female mice. In parallel, the same treatment reduced the 3,4-N-methylenedioxymethamphetamine (" ecstasy", 10 mg/kg)-induced anorexia in male wild-type mice. Our neurochemical analyses suggest that the mechanisms underlying feeding disorders in 5-HT4 receptor knockout mice are related to a lesser efficacy of 5-HT (hypothalamus, nucleus accumbens), leptin and the cocaine-amphetamine related transcript to reduce food intake following stress.

The principal stakes of depression treatment are to accelerate and enhance the clinical effects of antidepressant drug. The onset of antidepressant action of Serotonin (5HT) selective reuptake inhibitors (SSRIs) was attributed in part to the decrease in firing activity of serotonin neurons produced by the activation of raphe 5HT1A autoreceptors at the time of treatment initiation. Pindolol, an antagonist at somatodendritic pre-synaptic 5HT1A receptors has been investigated as a potential accelerator or potentialisator of antidepressant response. Six open label studies and 12 controlled studies were identified for revue. The first open-label pilot study was conducted by Artigas et al. They showed promising results with pindolol, both in the acceleration of antidepressant response and in improving the efficacy of antidepressant. On the basis of these results five open-label studies were conducted. The open label studies suggest that pindolol accelerate the antidepressant response of serotoninergics therapeutics. The augmentation of antidepressant response was not clearly demonstrated by these studies particularly in the treatment of refractory depression. For example, Dinan et Scott that found the addition of pindolol in association with SSRI therapy had a poor efficacy. In the twelve controlled studies, 4 tried to underscore the shortening of the onset and the augmentation of efficacy of SSRI by pindolol [Berman et al., Maes et al., Perez et al., Tome et al. ], 3 tried to underscore shortening of the onset [Bordet, Zanardi ] and 3 tried to underscore the augmentation of efficacy [Maes et al., Moreno et al., Perez et al. ]. One study tried to underscore the augmentation of efficacy of sleep deprivation by pindolol and another one the shortening of the onset of ECT. Six studies included depressive resistant patients. Three studies were carried out with fluoxetine, 1 with fluvoxamine, 3 with paroxetine, 1 with trazodone. Two -studies were investigated with several antidepressant treatments. The results of the studies indicate one acceleration of antidepressant response in 6 studies, one augmentation of efficacy in 5 studies. Two studies clearly demonstrate that pindolol may -augment and accelerate antidepressant response. Three studies did not confirm these observations. Several points can be examined. For pindolol: 3 authors have demonstrated that the effect of pindolol did not rely upon small antidepressant effect mediated by b-blockers properties, because anxiety was not predominantly improved by pindolol plus SSRI while depressive symptoms were clearly improved. On the basis of data issues from recent positron emission tomography (PET) studies, several authors suggested that the dose of pindolol used in most clinical trials (3 yen 2,5 mg day-1) might be insufficient to induce a substantial occupancy of 5-HTA receptors (Rabiner et al. It is possible that higher doses will show a more evident benefit. On the whole, pindolol seemed to be well tolerated. Adverse effects most commonly reported were increased irritability, insomnia and nausea. Pindolol had poor adverse effects in cardiovascular functions. The variation of the results of the controlled studies can be explained by different points: Firstly by difficulty to determine good criterion of resistance. The most simplistic definition of treatment resistance is the failure to achieve and sustain euthymia with adequate antidepressant treatment. Secondly by the fact that depressive patients who present antecedents of depressive illness seem to be worst responders to the association pindolol/serotoninergic antidepressant than patients suffering of first episode of depression. We observed one antecedent of depression in the group of resistant patients who were good responders to the association pindolol/antidepressant therapy. We observed three anterior episodes of depression in negatives studies of the association pindolol/antidepressant therapy. Thirdly by the fact that the failure of the antidepressant treatment at the time of earlier (or actual) episode seems to be a criterion for less responsiveness to the association of this antidepressant treatment with pindolol. In fact, the open label studies who demonstrated efficacy of the association between pindolol and serotoninergic therapy in major resistant depression were realized with new antidepressant molecule for the episode. Other controlled trials could confirm these facts. Most of the studies failed to retrace clearly the historicity of depression, and it may be interesting in future investigations to analyze the response of the association -compared to the status of the patient with the antidepressant therapy. Further perspective could be envisaged especially in the utilization of pindolol for the treatment of pathologies which are usually treated with a serotoninergic antidepressant -therapy. For example, the antagonist 5HT(1A) Way 100635 was experimented with success in animals in order to augment the efficacy of clomipramine in the treatment of chronic pain. In other respects several psychopharmacogenetics studies could be investigated to examine, for instance, the role of the 5-HT transporter and its implication in the response to pindolol and antidepressant association. In summary, pindolol accele-rates, and in some cases enhances the clinical action of antidepressant drugs. It appears that this augmentation strategy has more limited effect on treatment resistant patient but there is experimental evidence for using higher doses in future augmentation trial.

It is now accepted that serotonin can either initiate or aggravate myocardial ischaemia through a vasoconstrictor action and platelet activation. It is therefore possible that substances likely to neutralize the effects of serotonin could be used, without any danger, in humans with ischaemic heart disease. This type of action may therefore be exerted by 5-HT2 antagonists, such as naftidrofuryl. A recent double-blind clinical study has in fact shown that administration of naftidrofuryl versus placebo leads to better exercise tolerance, with an increase in the maximum level and delay in ST segment shift (increase in the threshold of onset of ischaemia). The purpose of this study was therefore to evaluate, in an animal model (pig) of acute myocardial ischaemia (occlusion of the proximal section of the left anterior descending coronary artery), the action of serotonin, naftidrofuryl and a combination of both substances on the following parameters: 1) electrophysiological (sinus heart rate, ST segment shift, T-wave amplitude, duration of monophasic action potentials, intraventricular conduction time); 2) haemodynamic (systolic, diastolic and mean blood pressure, first derivative of rate of increase of left ventricular pressure with time: LV dP/dt max); and 3) biochemical (malonedialdehyde concentration as an index, cell peroxidation index, creatine phosphate and adenosine triphosphate). It was found that co-infusion of serotonin aggravated the myocardial ischemia and that naftidrofuryl exerted beneficial effects on the serotonin-mediated aggravation of myocardial ischaemia.

We used knockout mice and receptor antagonist strategies to investigate the contribution of the serotonin (5-hydroxytryptamine, 5-HT) 5-HT1B receptor subtype in mediating the effects of selective serotonin reuptake inhibitors (SSRIs). Using in vivo intracerebral microdialysis in awake mice, we show that a single systemic administration of paroxetine (1 or 5 mg/kg, i.p.) increased extracellular serotonin levels [5-HT]ext in the ventral hippocampus and frontal cortex of wild-type and mutant mice. However, in the ventral hippocampus, paroxetine at the two doses studied induced a larger increase in [5-HT]ext in knockout than in wild-type mice. In the frontal cortex, the effect of paroxetine was larger in mutants than in wild-type mice at the 1 mg/kg dose but not at 5 mg/kg. In addition, either the absence of the 5-HT1B receptor or its blockade with the mixed 5-HT1B/1D receptor antagonist, GR 127935, potentiates the effect of a single administration of paroxetine on [5-HT]ext more in the ventral hippocampus than in the frontal cortex. Furthermore, we demonstrate that SSRIs decrease immobility in the forced swimming test; this effect is absent in 5-HT1B knockout mice and blocked by GR 127935 in wild-type suggesting therefore that activation of 5-HT1B receptors mediate the antidepressant-like effects of SSRIs. Taken together these data demonstrate that 5-HT1B autoreceptors appear to limit the effects of SSRI on dialysate 5-HT levels particularly in the hippocampus while presynaptic 5-HT1B heteroreceptors are likely to be required for the antidepressant activity of SSRIs.

Migraine is one of the few pathologies which gave rise to a tremendous number of physiopathological hypotheses. The variability of its clinical features and of the crisis initiating triggers, together with the numerous functional and/or biological abnormalities reported in migrainous patients, led to multiple 'theories' about migraine. For instance, migraine attacks may be associated with modifications of cerebral blood flow, and/or alterations at the cellular (neuronal and peripheral: platelets, mast cells, etc.) and subcellular (mainly mitochondrial) levels leading to variations of parameters such as serotonin, vasoactive neuropeptides, histamine, nitric oxide, neuroactive amino acids, etc. However, these modifications are mainly related to migraine attacks but not to migrainous patients. These emphasize how important is the distinction between the crisis mechanism(s) and the determinism of migraine illness. Despite the absence of any true animal model of migraine attack, the obtention, through the activation of the trigemino-vascular complex, of an experimental meningeal neurogenic inflammation was a clear breakthrough for the understanding of the migraine attack. Concerning the determinism of migraine, its familial characteristic has been known for a long time, but genetic studies started only recently. Despite some important contributions, the respective roles of genetic and environmental factors, as well as the transmission mode of migraine, remain largely to be determined. Practically, these genetic data, which really concern only a very peculiar form of migraine--the familial hemiplegic one--do not have presently any diagnostic or therapeutic application.

Due to its vascular and platelet 5-HT2 receptor antagonist properties and its metabolic properties, naftidrofuryl specifically counteracts local ischaemic phenomena. One of its major indications is the treatment of intermittent claudication, but it is well known that peripheral arterial disease is the sign of diffuse arterial disease, associated with particularly lethal coronary disease. Recent studies increasingly implicate serotonin (5-HT) in coronary ischaemic processes. In view of the similarities between these pathophysiological data and the characteristics of this molecule, we decide to evaluate the coronary protection afforded by naftidrofuryl and its safety. This multicentre double-blind placebo-controlled study was conducted in 51 patients over a period of one month. Inclusion criteria were stable angina with an electrically positive stress test, despite antianginal treatment either by beta-blocker or by calcium channel blocker. Follow-up comprised clinical assessment and a stress test on inclusion and at 1 month. The groups were comparable on inclusion. Overall, the results showed a greater improvement with naftidrofuryl than with reference treatment for all parameters studied. Significant differences were observed in favour of the verum group for time to onset of ST depression, the maximum level reached, the number of stress tests which became negative and the patient's global assessment. No problems of interaction with concomitant treatments, particularly beta-blockers, calcium channel blockers or antiarrhythmics was observed. This study shows that naftidrofuryl allows improvement of ergometric parameters and especially elevation of the ischaemic threshold on exertion.

Objective: To evaluate the clinical and electromyographic (EMG) effects of ketanserin (K), a serotoninergic receptor antagonist (5-HT2), on postoperative shivering (POS)., Study Design: Prospective, randomised, double-blind study., Patients: Fifty ASA class 1 and 2 patients with major clinical postoperative tremor were studied., Methods: POS was assessed clinically (0 = nil, 1 = moderate, 2 = severe). Inclusion criterion was a POS of 2 at admission in the recovery room. The mean arterial blood pressure, rectal temperature, SpO2 were recorded at admission (T0) and subsequently at T5, T10, T15, T30 and T60 minutes. Either 10 mg of K (n = 25) or a corresponding volume of a placebo (P) (n = 25) were intravenously injected. The EMG activity of the deltoid and quadriceps muscles was recorded continuously. Blood lactic acid concentration was measured at the end of POS. Results are expressed as mean +/- SEM. Parametric values were analysed with unpaired Student's t-test, and nonparametric values with chi 2 analysis. P < 0.05 was accepted., Results: Demographic data, duration of anaesthesia, postoperative temperature, oxygen saturation, blood pressure and blood lactate concentration were similar between groups. The POS duration in the K group was significantly shorter than in the P group: 8.8 +/- 1.5 min and 15.5 +/- 1.5 min respectively (P < 0.01). The number of patients in the K group experiencing POS at T5 and T10 was significantly lower, when compared with those who had received the P (P < 0.05)., Conclusion: At a dose of 10 mg, K administered in patients with POS during recovery, reduced significantly the duration and intensity of the shivering without noticeable side effects. This study suggests that this 5-HT2 antagonist is an efficient therapeutic tool for POS in adults.

Aims: The aim of this study was to determine, using specific antagonists, whether 5-HT3 receptors participate in triggering transient lower esophageal sphincter relaxations, independently or in relation with their CCKergic control., Methods: Esophageal, lower esophageal sphincter and fundus pressure were manometrically monitored in 5 conscious dogs. Gastric distensions with air at constant pressure (1.0 and 1.7 kPa) were performed during 30 min under IV infusion of CCK8S (0.5 microgram/kg/h) or NaCl 9/1000 and were preceded (10 min) by IV administration of 5-HT3 receptors antagonists (ondansetron 0.2-500 micrograms/kg and granisetron 100 micrograms/kg) or NaCl 9/1000., Results: The number of transient relaxations induced by a 1.7 kPa gastric distension (7.9 +/- 0.4/30 min) was dose-dependently reduced by ondansetron (1-100 micrograms/kg) and by granisetron (100 micrograms/kg). Ondansetron (100 micrograms/kg) did not modify the number of relaxations under a 1.0 kPa gastric pressure (2.7 +/- 0.4 vs 2.6 +/- 0.4/30 min) but reduced the increase of the occurrence of relaxations induced by CCK8S under a gastric pressure of 1.0 and 1.7 kPa., Conclusion: These results suggest that the CCK control in triggering transient lower esophageal sphincter relaxations is modulated by serotonin via 5-HT3 receptors subtypes.

Most tests used for the screening of 5-HT3 receptor antagonists are not completely specific but they give satisfactory results when they are used in battery. In cancer chemotherapy and radiotherapy, 5-HT3 receptor antagonists are very active against acute emesis but delayed and anticipatory vomiting remains difficult to cure. Potential activities of 5-HT3 receptor antagonists as neuroleptics, anxiolytics and agents useful against dependence and cognitive disorders pose some problems in animal psychopharmacology and remain to be clinically validated.

The aim of this work was to describe the alterations of colonic motility and transit induced by an experimental, histologically verified, degranulation of mast cells, provoked by the compound BrX-537A, and to determine the role of serotonin and histamine by specific antagonists, in the rat. Colonic myoelectrical activity was inhibited by BrX-537A (2 mg/kg IP) in a biphasic manner. The initial profound inhibition, lasting 30 min, during which the frequency of spike bursts decreased from 9.2 +/- 1.1 to 1.4 +/- 0.5/10 min, was followed by a sustained (5 h) period of moderate inhibition (5.2 +/- 0.5 spike bursts/10 min). In the same way, BrX-537A increased the mean retention time of a marker injected in the proximal colon (10.8 +/- 1.4 h vs 7.4 +/- 0.4 h). Neither serotoninergic nor histaminergic antagonists, at a dose of 1 mg/kg IP, modified the primary drastic inhibition of colonic motility during the first 20 minutes. After, a selective time-related blockade of this inhibition was observed. Granisetron blocked the inhibition from the 30th minute on, methysergide from the 120th minute on, and chlorpheniramine, between the 20th and 60th minutes. In conclusion, the inhibitory effect of mast cell degranulation depends on serotonin and histamine release, in a time-related manner, and implicates the H1, 5-HT3 and 5-HT1 or 2 receptors.

Crystallographic results coupled with theoretical calculations, NMR analyses, and molecular graphic design have been used to investigate the three-dimensional structures of different Na(+)-dependent D-2 antagonists. Three putative pharmacophoric elements, a nitrogen lone pair, a phenyl ring, and a carbonyl moiety, are similarly oriented in all these compounds. Moreover, a stereoelectronic model can be deducted from the molecular electrostatic potential maps. Conversely, for Na(+)-independent analogs, the two latter pharmacophoric elements play a subordinate role, but two electron regions are systematically localized on the other side of the molecule. The three pharmacophoric elements of the Na(+)-dependent D-2 antagonists have been identified in the 5HT-3 antiserotoninergic drugs, but only in terms of chemical functions.

Several binding sites for serotonin or 5-hydroxytryptamine (5-HT) were identified by using selective agonists and antagonists. Today, 5-HT3 receptor types are considered to occupy a critical position in the emetic pathway. The discovery of 5-HT3 receptor antagonists originated from metoclopramide, an antidopaminergic drug introduced in France 25 years before as a modifier of digestive motricity; it represents a therapeutic advance, since it led to the first class of antiemetic drugs specifically designed to prevent severe cytotoxic drugs-evoked emesis and devoid of noticeable side-effects. It must be emphasized upon the necessity of developing new experimental tests in living animals and performing controlled trials on patients under chemotherapy to achieve this progress.

The synthesis of benzamides derived from 1-substituted-3-methoxy or 3-hydroxy-4-piperidinamine resulted in the selection of a substituted benzamide, cisapride, which displays potent gastrokinetic properties. Pharmacological studies showed that cisapride improves both motility and transit of the oesophagus, the stomach, the small and large intestines. Moreover it markedly improves gastropyloroduodenal coordination. The gastrokinetic effects of cisapride are largely due to an enhanced release of acetylcholine from cholinergic nerves in the myenteric plexus (plexus of Auerbach) along the digestive tract. This explains why the therapeutic efficacy of cisapride reaches from the oesophagus into the large intestine.

Shortly after the introduction of the first neuroleptics a serotonin hypothesis of schizophrenia has been proposed. But neuroleptics in animals and in man were found to produce effects more consistently related to inhibition of the dopaminergic than of any other type of neurotransmission. However, two early neuroleptics, pipamperone and clozapine, act pharmacologically more on 5-HT2 than on D2 receptors. Both have a distinct clinical profile and low EPS liability. The development of selective 5-HT2-antagonists, devoid of LSD-like properties, resulted in a first compound, ritanserin. Clinically, the highly specific 5-HT2-antagonism of ritanserin improves dysthymia, increases slow wave sleep and supports classical neuroleptic treatment by decreasing negative symptoms and EPS. These properties, being valuable by themselves, have been associated to dopamine D2-antagonism in the new antipsychotic risperidone, which is an extremely potent 5-HT2-antagonist. At doses of 5 mg daily risperidone acts on both negative and positive symptoms of schizophrenia in the virtual absence of EPS.

As well as being present in all mammals, yawning occurs, at least in its mandibular component, in all vertebrates. The existence of pathological and pharmacologically induced yawning justifies study of this everyday ENT reflex. Its mechanism remains uncertain. The most likely hypothesis would seem to be stimulation of the reticular system of the brain-stem by signals originating in masseteric neuromuscular spindles sensitive to stretching. Serotoninergic inhibition from the dorsal raphe, a fall in hypothalamic dopaminergic inhibitory tone, followed by ocytocinergic hippocampal activation and then more diffuse cholinergic activation of cranial nerve motor nuclei seems likely. Various hormonal or socio-environmental influences can modify the activity of these different systems. The physiological consequences and the communicative value of yawning become more diversified with the phylogenetic evolution of the subject. Yawning appears to correspond to an alertness reflex which has acquired a paralinguistic value with evolution and may have a role in protection or social cohesion.

This paper describes the synthesis and the pharmacological characteristics of the first radioiodinated ligand of central 5-HT3 receptors: [125I]iodo-zacopride. Specific sites having a high affinity (Kd = 4.3 nM) for [125I]iodo-zacopride have been found in membranes from the rat entorhinal cortex. In addition, a highly significant correlation (r = 0.995) existed between the Ki of several 5-HT-related drugs for displacing both [125I]iodo-zacopride from its specific binding sites, and [3H]zacopride from 5-HT3 receptors. Finally, [125I]iodo-zacopride was successfully used for the autoradiographic mapping of 5-HT3 receptors in the rat central nervous system.

During traumatic regeneration of Planaria Polycelis tenuis, determination of serotonin, noradrenaline and dopamine levels revealed important variations of serotonin and catecholamines from the time of excision. The use of specific inhibitors of these hormones delayed regeneration whereas simultaneous addition of an hormone and its antagonist restores a standard time of regeneration. Serotonin acts through adenylate cyclase system. Results allow us to assume that dopamine acts through the same mechanism. The action of noradrenaline is so far not elucidated although propranolol (beta antagonist) delays or inhibits completely regeneration.

Bronchoconstriction due to aerosolized histamine (H), 5-hydroxytryptamine (5-HT) and combined administration of both substances has been studied on 53 guinea-pigs. The results are consistant with: a major bronchoconstrictor effect obtained with H than with 5-HT; a potentiation of the individual effects of H and 5-HT in two thirds of the guinea-pigs, by the combined administration of the two drugs simultaneously; a more potent antagonistic effect of Ketanserin against 5-HT than against H; potentiation due to the combined administration of 5-HT and H is suppressed by Ketanserin; neither vagal reflexes nor cholinergic receptors seem to interfere with the bronchospastic response of the guinea-pig to H and 5-HT.

Clonidine displays immobility-reducing effects in the mouse swimming model at doses (0.06-16 mg/kg IP) which decrease spontaneous motility. Tricyclic antidepressants evoke a similar dissociation in motor activity. The immobility-reducing effect of clonidine (1 mg/kg at 30 min pretesting) was reversed by yohimbine (4 mg/kg) but was unaffected by prazosin (2 mg/kg) or alpha-methyl-paratyrosine (100 mg/kg), and was enhanced by reserpine (2.5 mg/kg). Mediation by alpha-2 postjunctional receptors was thus suggested. However, two 5-HT receptor blockers--methysergide (2 mg/kg) and ketanserin (8 mg/kg)--increased this effect of clonidine whereas the non selective agonist 5-MeODMT (1 mg/kg) reduced clonidine action. Conversely, pretreatment with a subthreshold dose of clonidine (0.06 mg/kg at 45 min pretesting) made effective subthreshold doses of three 5-HT uptake inhibitors (citalopram 2 mg/kg, indalpine and fluvoxamine 4 mg/kg) and of the 5-HT1 receptor agonist 8-OH-DPAT (0.5 mg/kg). According to these data, the mouse swimming model would trigger functional relationships between central alpha-noradrenergic and serotonergic mechanisms.