piperidines and 4-chlorophenylalanine-methyl-ester

The influence of two selective serotonin reuptake inhibitors (SSRIs), litoxetine and fluoxetine, has been studied on 5-HT4 receptor-mediated relaxation in the rat isolated oesophageal muscularis mucosae. In carbachol-precontracted oesophageal tissues, 5-hydroxytryptamine (5-HT) (0.1 nM-1 microM) induced concentration-dependent relaxations. Concentration-response curves were monophasic and reproducible. Litoxetine at concentrations without antimuscarinic properties (10 nM-1 microM) caused concentration-dependent relaxations, which reduced carbachol tone up to 37%. Higher litoxetine concentrations (3 microM-300 microM) were associated with marked relaxation up to the abolition of carbachol tone. The overall curve profile of litoxetine was biphasic in nature with a high (10 nM-1 microM) and a low (3 microM-300 microM) potency phase. Unlike 5-HT, the second curve of litoxetine was not reproducible, with a reduction involving mainly the low potency phase. Compared to litoxetine, fluoxetine caused minimal relaxation (less than 10% at 1 microM). Treatment of rats with parachlorophenylalanine (pCPA: 375 mg kg-1 per day, for two days), to deplete endogenous 5-HT stores, did not modify the relaxant effect of 5-HT, while it significantly reduced the high potency phase of litoxetine. In tissues from untreated rats, this phase was reduced by the 5-HT4 receptor antagonist GR 125487 (10 nM) to an extent similar (P = 0.20: ANOVA for continuous-by-class effects) to that induced by pCPA treatment. However, in tissues from pCPA treated animals GR 125487 (10 nM) exerted a slight but significant antagonism of litoxetine response (P = 0.037: ANOVA for continuous-by-class effects) mainly involving the high potency phase. In tissues from untreated rats, litoxetine (1 microM) increased the relaxant effects of 5-HT, while in tissues from pCPA treated animals it exerted a small but significant depression of the maximal response to 5-HT, without changing its potency value. Fluoxetine (1 microM) slightly, but significantly, antagonized the relaxant effect of 5-HT in an unsurmountable manner. In conclusion, litoxetine up to 1 microM relaxed the rat isolated oesophageal muscularis mucosae through a mechanism involving release of endogenous 5-HT, which in turn activates 5-HT4 receptors. However, based on results with GR 125487 in tissues from pCPA treated rats, a small component of litoxetine-induced relaxation may involve a direct activation of 5-HT4 receptors. It is unlikely that bloc

Topics: Animals; Carbachol; Dose-Response Relationship, Drug; Drug Interactions; Esophagus; Fenclonine; Fluoxetine; In Vitro Techniques; Indoles; Male; Muscle Relaxation; Muscle, Smooth; Piperidines; Rats; Rats, Wistar; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Sulfonamides

The inhibitory potencies of selective serotonin (5-hydroxytryptamine, 5-HT) uptake inhibitors on isolation-induced aggressive behaviour in male mice were studied. Furthermore, the role of postsynaptic 5-HT1A receptors in the mediation of aggressive behaviour was studied. The selective 5-HT uptake inhibitors, sertraline, floxetine, femoxetine and fluvoxamine, showed weak antiaggressive effects, and citalopram and paroxetine were ineffective. This rank of potencies corresponded with neither uptake inhibitory potencies in vitro nor potentiation of 1-5-hydroxytryptophan (1,5-HTP)-induced motor effects in vivo, as citalopram and paroxetine were among the most potent compounds in these tests. A subeffective dose of 1,5-HTP (110 mumol/kg = 25 mg/kg, s.c.) potentiated the antiaggressive effect of citalopram and paroxetine more than 110 and 1600 times, respectively. The effects of sertraline, fluvoxamine, fluoxetine and femoxetine were only potentiated 3, 36, 4 and 16 times, respectively. The 5-HT releasing compound fenfluramine inhibited the aggressive behaviour dose dependently, and depletion of 5-HT by treatment with p-chloro-phenylalanine methyl ester attenuated this effect significantly. p-Chloro-phenylalanine methyl ester was ineffective itself, but potentiated the antiaggressive effect of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamin)tetralin (8-OH-DPAT). The beta-adrenoceptor/5-HT1A receptor antagonist, (-)-penbutolol, reversed the antiaggressive effects of 8-OHDPAT. In conclusion, selective 5-HT uptake inhibitors act in different ways on isolation-induced aggressive behaviour, and postsynaptic 5-HT1A receptors are involved in mediating the aggressive behaviour.

Topics: 1-Naphthylamine; 5-Hydroxytryptophan; 8-Hydroxy-2-(di-n-propylamino)tetralin; Aggression; Analysis of Variance; Animals; Behavior, Animal; Brain; Citalopram; Dose-Response Relationship, Drug; Fenclonine; Fluoxetine; Fluvoxamine; Male; Mice; Paroxetine; Penbutolol; Piperidines; Rats; Rats, Wistar; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Selective Serotonin Reuptake Inhibitors; Sertraline; Synaptosomes

Topics: Amino Acid Sequence; Animals; Benzamides; Biphenyl Compounds; Blood Pressure; Cerebral Ventricles; Fenclonine; Heart Rate; Injections, Intraventricular; Male; Molecular Sequence Data; Motor Activity; Neurokinin A; Neuropeptides; Oligopeptides; Piperidines; Rats; Rats, Wistar; Stereotyped Behavior; Tachykinins