Antidepressant properties of the 5-HT4 Receptor partial agonist, SL65.0155: Behavioral and neurochemical studies in rats

This study was undertaken to investigate the potential antidepressant-like properties of SL65.0155, a serotonin 5-HT4 Receptor partial agonist, in male rats of the Wistar strain tested in the forced swim test (FST), an experimental model widely used to assess antidepressant-like activity. The expression of hippocampal neurotrophic factors, such as the brain-derived neurotrophic factor (BDNF), the phosphorilated cAMP response element-binding protein (p-CREB), the B cell lymphoma-2 (Bcl-2), the Bax and the vascular endothelium growth factor (VEGF) were also evaluated by Western Blot analysis. Different groups of rats received intraperitoneally (i.p.) injections of SL65.0155 (0.1, 0.5 and 1??mg/kg), clomipramine (50??mg/kg), citalopram (15??mg/kg) or vehicle, respectively, 24, 5 and 1??h prior to the FST. Compared to the control group, SL65.0155 (0.5 and 1??mg/kg), clomipramine or citalopram injected animals showed an increased swimming and climbing behavior and reduced immobility time in the FST. Interestingly, this effect was not due to changes in the locomotor activity since all treated groups failed to show any change in motor ability as assessed in the open field test. Western blot analysis of hippocampal homogenates showed an enhancement of p-CREB, BDNF Bcl-2 and VEGF protein levels in SL65.0155 treated groups, but not in citalopram or clomipramine treated groups, used here as positive control. No change was found in Bax expression in any treated group. These findings give further support to the hypothesis that the stimulation of serotonin 5-HT4 Receptors may be a therapeutic target for depression. ?? 2009 Elsevier Inc. All rights reserved.

Cognitive effects of SL65.0155, a serotonin 5-HT4 Receptor partial agonist, in animal models of amnesia

Given that several data suggest the involvement of serotonergic (5-HT) system, particularly the serotonin 5-HT4 Receptors, in memory processes; this study was undertaken to investigate the role of serotonin 5-HT4 Receptors in different experimental models of amnesia in male Swiss mice or in male Sprague-Dawley rats, tested in learning and memory tasks. Amnesia was induced in mice by intracerebroventricular (i.c.v.) injection of ??-amyloid 1-42 fragment (BAP 1-42; 400 pmol/mouse) or of galanin (GAL) 1-29 (3????g/mouse). Another group of animals was exposed to carbon monoxide (CO). Treatments were made 14??days, 15??min or 8??days prior to the learning trial of a step-through passive avoidance paradigm, respectively. Latency to re-enter the dark box appeared to be reduced in all treatment groups. Intraperitoneal (i.p.) administration of SL65.0155 (5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-(2-phenylethyl)-4-piperidinyl]-1,3,4-oxadiazol-2(3H)-one-monohydrochloride), a serotonin 5-HT4 Receptor partial agonist (1??mg/kg/day), for 7??days prior to the learning trial, inhibited the amnesic effect of both peptides increasing the latency to re-enter the dark box also in mice exposed to CO. In rats with ibotenate-induced lesions of the nucleus basalis magnocellularis (NBM) or prenatally exposed to methylazoxymethanol (MAM), SL65.0155 (1??mg/kg/day, i.p.) administered for 7??days, improved the learning and memory capacity in animals tested in shuttle-box active avoidance and radial maze tests. These findings give further support to the hypothesis of SL65.0155 cognition-enhancing activity across a range of tasks. ?? 2006 Elsevier B.V. All rights reserved.

Appearance of a ventricular 5-HT4 Receptor-mediated inotropic response to serotonin in heart failure

Background : Current pharmacological treatment of congestive heart failure (CHF) addresses changes in neurohumoral stimulation or cardiac responsiveness to such stimulation. Yet, undiscovered neurohumoral changes, adaptive or maladaptive, may occur in CHF and suggest novel pharmacological treatment. Serotonin [5-hydroxytryptamine (5-HT)] enhances contractility and causes arrhythmias through 5-HT4 Receptors in human atrium and ventricle but not through rat ventricular 5-HT4 Receptors.

Objective : We investigated whether CHF could induce ventricular responsiveness to serotonin.

Methods : Postinfarction CHF was induced in male Wistar rats by coronary artery ligation. Contractility was measured in left ventricular papillary muscles 6 weeks after infarction. Messenger RNA was quantified by RT-PCR and cAMP by RIA.

Results : Serotonin caused positive inotropic (−logEC50=7.5) and lusitropic effects in CHF but not Sham papillary muscles. The inotropic effect of 10 μM serotonin in CHF (31.3 ± 2.2%) was of similar size as the effect of 10 μM isoproterenol (34.0 ± 1.7%). The effects of serotonin were antagonised by GR113808 (0.5–5 nM), consistent with mediation through 5-HT4 Receptors. This was further supported by positive inotropic effects of the 5-HT4-selective partial agonist RS67506. Carbachol blunted the serotonin responses and serotonin increased ventricular and cardiomyocyte cAMP, consistent with coupling to Gs and adenylyl cyclase. Quantitative RT-PCR revealed fourfold increased 5-HT4(b) mRNA expression in CHF vs. Sham ventricles.

Conclusion : Functional ventricular 5-HT4 Receptors are induced by myocardial infarction and CHF of the rat heart. We propose that they are a model for ventricular 5-HT4 Receptors of human failing heart and may play a pathophysiological role in heart failure.

Comparison of the densities of 5-HT4 Receptors, beta 1- and beta 2-adrenoceptors in human atrium: functional implications.

We measured in human atrium the density of 5-HT4 Receptors, labelled with [125I]-SB 207710 (1-butyl-4-piperidinyl) methyl 8-amino-7-iodo-1, (4-benzodioxan-5-carboxylate), and compared it with the density of β1- and β2-adrenoceptors, labelled with (−)-[125I]-cyanopindolol. [125I]-SB 207710 (5–1200 pmol/l) labelled a small population of saturable binding sites (Bmax ≈ 4 fmol/mg protein) with a pKD of 9.7 and with 5-HT4 Receptor characteristics, as assessed with competing ligands. The density of atrial binding sites with 5-HT4 Receptor characteristics was 10 and 5 times lower, respectively, than the density of β1- and β2-adrenoceptors. We suggest that the small 5-HT4 Receptor population may in part explain why the positive inotropic effects of 5-HT are smaller than those of catecholamines mediated through β1- and β2-adrenoceptors.

Labelling with [125I]‐SB 207710 of a small 5‐HT4 Receptor population in piglet right atrium: functional relevance

Abstract
1. We investigated the affinity of SB 207710 for sinoatrial 5-HT4 Receptors and the density of right atrial 5-HT4 Receptors with [125I]-SB 207710 in right atria of new-born piglets. 2. SB 207710 (1-100 nM) antagonized the 5-HT-evoked tachycardia surmountably with a pKB of 9.8. 3. [125I]-SB 207710 (5-1500 pM) labelled a small population of saturable binding sites with a pKD of 10.1 and with 5-HT4 Receptor characteristics. The density of atrial binding sites with 5-HT4 Receptor characteristics was 174 and 22 times lower respectively than those of atrial beta 1- and beta 2-adrenoceptors, labelled with (-)-[125I]-cyanopindolol. 4. We suggest that the small 5-HT4 Receptor population may in part explain why the maximal tachycardia caused by 5-HT is smaller than that caused by catecholamines.

Antidepressant properties of the 5-HT4 Receptor partial agonist, SL65.0155: Behavioral and neurochemical studies in rats

This study was undertaken to investigate the potential antidepressant-like properties of SL65.0155, a serotonin 5-HT4 Receptor partial agonist, in male rats of the Wistar strain tested in the forced swim test (FST), an experimental model widely used to assess antidepressant-like activity. The expression of hippocampal neurotrophic factors, such as the brain-derived neurotrophic factor (BDNF), the phosphorilated cAMP response element-binding protein (p-CREB), the B cell lymphoma-2 (Bcl-2), the Bax and the vascular endothelium growth factor (VEGF) were also evaluated by Western Blot analysis. Different groups of rats received intraperitoneally (i.p.) injections of SL65.0155 (0.1, 0.5 and 1??mg/kg), clomipramine (50??mg/kg), citalopram (15??mg/kg) or vehicle, respectively, 24, 5 and 1??h prior to the FST. Compared to the control group, SL65.0155 (0.5 and 1??mg/kg), clomipramine or citalopram injected animals showed an increased swimming and climbing behavior and reduced immobility time in the FST. Interestingly, this effect was not due to changes in the locomotor activity since all treated groups failed to show any change in motor ability as assessed in the open field test. Western blot analysis of hippocampal homogenates showed an enhancement of p-CREB, BDNF Bcl-2 and VEGF protein levels in SL65.0155 treated groups, but not in citalopram or clomipramine treated groups, used here as positive control. No change was found in Bax expression in any treated group. These findings give further support to the hypothesis that the stimulation of serotonin 5-HT4 Receptors may be a therapeutic target for depression. ?? 2009 Elsevier Inc. All rights reserved.

Cognitive effects of SL65.0155, a serotonin 5-HT4 Receptor partial agonist, in animal models of amnesia

Given that several data suggest the involvement of serotonergic (5-HT) system, particularly the serotonin 5-HT4 Receptors, in memory processes; this study was undertaken to investigate the role of serotonin 5-HT4 Receptors in different experimental models of amnesia in male Swiss mice or in male Sprague-Dawley rats, tested in learning and memory tasks. Amnesia was induced in mice by intracerebroventricular (i.c.v.) injection of ??-amyloid 1-42 fragment (BAP 1-42; 400 pmol/mouse) or of galanin (GAL) 1-29 (3????g/mouse). Another group of animals was exposed to carbon monoxide (CO). Treatments were made 14??days, 15??min or 8??days prior to the learning trial of a step-through passive avoidance paradigm, respectively. Latency to re-enter the dark box appeared to be reduced in all treatment groups. Intraperitoneal (i.p.) administration of SL65.0155 (5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-(2-phenylethyl)-4-piperidinyl]-1,3,4-oxadiazol-2(3H)-one-monohydrochloride), a serotonin 5-HT4 Receptor partial agonist (1??mg/kg/day), for 7??days prior to the learning trial, inhibited the amnesic effect of both peptides increasing the latency to re-enter the dark box also in mice exposed to CO. In rats with ibotenate-induced lesions of the nucleus basalis magnocellularis (NBM) or prenatally exposed to methylazoxymethanol (MAM), SL65.0155 (1??mg/kg/day, i.p.) administered for 7??days, improved the learning and memory capacity in animals tested in shuttle-box active avoidance and radial maze tests. These findings give further support to the hypothesis of SL65.0155 cognition-enhancing activity across a range of tasks. ?? 2006 Elsevier B.V. All rights reserved.