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Connie Sanchez - One of the best experts on this subject based on the ideXlab platform.
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vortioxetine a novel antidepressant with multimodal activity review of preclinical and clinical data
Pharmacology & Therapeutics, 2015Co-Authors: Connie Sanchez, Karen Asin, Francesc ArtigasAbstract:Vortioxetine, a novel antidepressant for the treatment of major depressive disorder (MDD), is a 5-HT3, 5-HT7 and 5-HT1D Receptor antagonist, 5-HT1B Receptor partial agonist, 5-HT1A Receptor agonist and serotonin (5-HT) transporter (SERT) inhibitor. Here we review its preclinical and clinical properties and discuss translational aspects. Vortioxetine increases serotonergic, noradrenergic, dopaminergic, cholinergic, histaminergic and glutamatergic neurotransmission in brain structures associated with MDD. These multiple effects likely derive from its interaction with 5-HT-Receptor-mediated negative feedback mechanisms controlling neuronal activity. In particular, 5-HT3 Receptors may play a prominent role, since their blockade i) increases pyramidal neuron activity by removing 5-HT3 Receptor-mediated excitation of GABA interneurons, and ii) augments SSRI effects on extracellular 5-HT. However, modulation of the other 5-HT Receptor subtypes also likely contributes to vortioxetine's pharmacological effects. Preclinical animal models reveal differences from SSRIs and SNRIs, including antidepressant-like activity, increased synaptic plasticity and improved cognitive function. Vortioxetine had clinical efficacy in patients with MDD: 11 placebo-controlled studies (including one in elderly) with efficacy in 8 (7 positive, 1 supportive), 1 positive active comparator study plus a positive relapse prevention study. In two positive studies, vortioxetine was superior to placebo in pre-defined cognitive outcome measures. The clinically effective dose range (5-20mg/day) spans ~50 to >80% SERT occupancy. SERT and 5-HT3 Receptors are primarily occupied at 5mg, while at 20mg, all targets are likely occupied at functionally relevant levels. The side-effect profile is similar to that of SSRIs, with gastrointestinal symptoms being most common, and a low incidence of sexual dysfunction and sleep disruption possibly ascribed to vortioxetine's Receptor modulation.
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Effect of the multimodal acting antidepressant vortioxetine on rat hippocampal plasticity and recognition memory.
Progress in neuro-psychopharmacology & biological psychiatry, 2014Co-Authors: Cécile Bétry, Alan L. Pehrson, Connie Sanchez, Adeline Etievant, Nasser HaddjeriAbstract:Depression is frequently associated with cognitive disturbances. Vortioxetine is a multimodal acting antidepressant that functions as a 5-HT3 and 5-HT7 and 5-HT1D Receptor antagonist, 5-HT1B Receptor partial agonist, 5-HT1A Receptor agonist and inhibitor of the 5-HT transporter. Given its pharmacological profile, the present study was undertaken to determine whether vortioxetine could modulate several preclinical parameters known to be involved in cognitive processing. In the dorsal hippocampus of anaesthetized rats, the high-frequency stimulation of the Schaffer collaterals provoked a stable long-term potentiation (LTP) of ~25%. Interestingly, vortioxetine (10mg/kg, i.p.) counteracted the suppressant effect of elevated platform stress on hippocampal LTP induction. In the novel object recognition test, vortioxetine (10mg/kg, i.p.) increased the time spent exploring the novel object during the retention test and this pro-cognitive effect was prevented by the partial 5-HT3 Receptor agonist SR57227 (1mg/kg, i.p.). Finally, compared to fluoxetine, sustained administration of vortioxetine (5mg/kg/day, s.c.) induced a rapid increase of cell proliferation in the hippocampal dentate gyrus. In summary, vortioxetine prevented the effect of stress on hippocampal LTP, increased rapidly hippocampal cell proliferation and enhanced short-term episodic memory, via, at least in part, its 5-HT3 Receptor antagonism. Taken together, these preclinical data suggest that the antidepressant vortioxetine may have a beneficial effect on human cognitive processes.
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vortioxetine restores reversal learning impaired by 5 ht depletion or chronic intermittent cold stress in rats
The International Journal of Neuropsychopharmacology, 2014Co-Authors: Ashley Wallace, Alan L. Pehrson, David A. Morilak, Connie SanchezAbstract:Current treatments for depression, including serotonin-specific reuptake inhibitors (SSRIs), are only partially effective, with a high incidence of residual symptoms, relapse, and treatment resistance. Loss of cognitive flexibility, a component of depression, is associated with dysregulation of the prefrontal cortex. Reversal learning, a form of cognitive flexibility, is impaired by chronic stress, a risk factor for depression, and the stress-induced impairment in reversal learning is sensitive to chronic SSRI treatment, and is mimicked by serotonin (5-HT) depletion. Vortioxetine, a novel, multimodal-acting antidepressant, is a 5-HT3, 5-HT7 and 5-HT1D Receptor antagonist, a 5-HT1B Receptor partial agonist, a 5-HT1A Receptor agonist, and inhibits the 5-HT transporter. Using adult male rats, we first investigated the direct effects of vortioxetine, acting at post-synaptic 5-HT Receptors, on reversal learning that was compromised by 5-HT depletion using 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), effectively eliminating any contribution of 5-HT reuptake blockade. PCPA induced a reversal learning impairment that was alleviated by acute or sub-chronic vortioxetine administration, suggesting that post-synaptic 5-HT Receptor activation contributes to the effects of vortioxetine. We then investigated the effects of chronic dietary administration of vortioxetine on reversal learning that had been compromised in intact animals exposed to chronic intermittent cold (CIC) stress, to assess vortioxetine's total pharmacological effect. CIC stress impaired reversal learning, and chronic vortioxetine administration prevented the reversal-learning deficit. Together, these results suggest that the direct effect of vortioxetine at 5-HT Receptors may contribute to positive effects on cognitive flexibility deficits, and may enhance the effect of 5-HT reuptake blockade.
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vortioxetine disinhibits pyramidal cell function and enhances synaptic plasticity in the rat hippocampus
Journal of Psychopharmacology, 2014Co-Authors: Elena Dale, Hong Zhang, Steven C Leiser, Yixin Xiao, Charles R Yang, Niels Plath, Connie SanchezAbstract:Vortioxetine, a novel antidepressant with multimodal action, is a serotonin (5-HT)3, 5-HT7 and 5-HT1D Receptor antagonist, a 5-HT1B Receptor partial agonist, a 5-HT1A Receptor agonist and a 5-HT transporter (SERT) inhibitor. Vortioxetine has been shown to improve cognitive performance in several preclinical rat models and in patients with major depressive disorder. Here we investigated the mechanistic basis for these effects by studying the effect of vortioxetine on synaptic transmission, long-term potentiation (LTP), a cellular correlate of learning and memory, and theta oscillations in the rat hippocampus and frontal cortex. Vortioxetine was found to prevent the 5-HT-induced increase in inhibitory post-synaptic potentials recorded from CA1 pyramidal cells, most likely by 5-HT3 Receptor antagonism. Vortioxetine also enhanced LTP in the CA1 region of the hippocampus. Finally, vortioxetine increased fronto-cortical theta power during active wake in whole animal electroencephalographic recordings. In comparison, the selective SERT inhibitor escitalopram showed no effect on any of these measures. Taken together, our results indicate that vortioxetine can increase pyramidal cell output, which leads to enhanced synaptic plasticity in the hippocampus. Given the central role of the hippocampus in cognition, these findings may provide a cellular correlate to the observed preclinical and clinical cognition-enhancing effects of vortioxetine.
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vortioxetine but not escitalopram or duloxetine reverses memory impairment induced by central 5 ht depletion in rats evidence for direct 5 ht Receptor modulation
European Neuropsychopharmacology, 2014Co-Authors: Jesper Borno Jensen, Connie Sanchez, Gennady N Smagin, Kristian Gaarn Du Jardin, Dekun Song, David P Budac, Alan L. PehrsonAbstract:Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3 ,5 -HT 7 and 5-HT1D Receptor antagonist, 5-HT1B Receptor partial agonist, 5-HT1A Receptor agonist and 5-HT transporter (SERT) inhibitor that enhances memory in normal rats in novel object recognition (NOR) and conditioned fear (Mork et al., 2013). We hypothesized that vortioxetine's 5-HT Receptor mechanisms are involved in its memory effects, and therefore investigated these effects in 5-HT depleted rats. Four injections of the irreversible tryptophan hydroxylase inhibitor 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA, 86 mg/kg, s.c.) induced 5-HT depletion, as measured in hippocampal homogenate and microdialysate. The effects of acute challenge with vortioxetine or the 5-HT releaser fenfluramine on extracellular 5-HT were measured in PCPA-treated and control rats. PCPA's effects on NOR and spontaneous alternation (SA) performance were assessed along with the effects of acute treatment with 5-hydroxy-L-tryptophan (5-HTP), vortioxetine, the selective 5-HT reuptake inhibitor escitalopram, or the 5-HT norepinephrine reuptake inhibitor duloxetine. SERT occupancies were estimated by ex vivo autoradiography. PCPA depleted central 5-HT by 490% in tissue and microdialysate, and impaired NOR and SA performance. Restoring central 5-HT with 5-HTP reversed these deficits. At similar SERT occupancies (490%) vortioxetine, but not escitalopram or duloxetine, restored memory performance. Acute fenfluramine significantly
Michael A. Moskowitz - One of the best experts on this subject based on the ideXlab platform.
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effects of pnu 109 291 a selective 5 ht1d Receptor agonist on electrically induced dural plasma extravasation and capsaicin evoked c fos immunoreactivity within trigeminal nucleus caudalis
Neuropharmacology, 1999Co-Authors: Michael F Cutrer, Michael A. Moskowitz, Gamze Ayata, Christian WaeberAbstract:Abstract We studied the effects of PNU-109 291 [(S)-(−)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-methyl-isochroman-6-carboxamide], a Receptor agonist showing 5000-fold selectivity for primate 5-HT1D versus 5-HT1B Receptors (Ennis et al., J. Med. Chem. 41, 2180–2183), on dural neurogenic inflammation and on c-fos like immunoreactivity within trigeminal nucleus caudalis evoked by electrical and chemical activation of trigeminal afferents, respectively. Subcutaneous injection of PNU-109 291 in male guinea pigs dose-dependently reduced dural extravasation of [125I]-labeled bovine serum albumin evoked by trigeminal ganglion stimulation with an IC50 of 4.2 nmol kg−1. A dose of 73.3 nmol kg−1 blocked the response completely. The selective 5-HT1B/1D Receptor antagonist GR-127 935 (≥2 μmol kg−1 i.v.) prevented this effect. In addition, the number of c-fos immunoreactive cells within guinea pig trigeminal nucleus caudalis induced by chemical meningeal stimulation (intracisternally administered capsaicin) was reduced by more than 50% with PNU-109 291 (≥122.2 nmol kg−1 administered s.c. 45 min before and 15 min after capsaicin). These data indicate that the 5-HT1D Receptor subtype plays a significant role in suppressing meningeal neurogenic inflammation and attenuating trigeminal nociception in these guinea pig models. Since 5-HT1D Receptor mRNA and protein are expressed in trigeminal ganglia but not vascular smooth muscle, the 5-HT1D Receptor subtype may become a useful therapeutic target for migraine and related headaches.
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The 5-HT1D Receptor antagonist GR-127,935 prevents inhibitory effects of sumatriptan but not CP-122,288 and 5-CT on neurogenic plasma extravasation within guinea pig dura mater.
Neuropharmacology, 1997Co-Authors: F. M. Cutrer, Michael A. Moskowitz, Christian WaeberAbstract:Abstract The aim of this study was to examine whether GR-127,935, a 5-HT1B/1D Receptor antagonist, blocks the inhibitory effects of sumatriptan, CP-122,288 and 5-carboxamidotryptamine (5-CT) on plasma protein extravasation, within guinea pig and rat dura mater, following electric stimulation of the trigeminal ganglion. Binding studies first established that GR-127,935 shows a 500-fold selectivity for 5-HT1D binding sites (labeled by [3H]L-694,247) versus 5-HT1F binding sites (labeled by 3H]sumatriptan in the presence of 50 nM 5-carboxamidotryptamine) in guinea pig forebrain homogenates (pKD ± SD = 7.0 ± 0.2 at 5-HT1F sites and 9.7 ± 0.1 at 5-HT1D sites). In guinea pigs, GR-127,935 showed partial agonist activity and inhibited dural plasma protein extravasation. Increasing doses of GR-127,935 reversed the effect of sumatriptan, but did not affect the action of 5-CT and CP-122,288 (at a dose as high as 2 μmol/kg). Sumatriptan, CP 122,288 and 5-CT dose-responsively inhibited plasma protein extravasation. At a dose of 2 μmol/kg (but not at 0.2 μmol/kg), GR-127,935 right-shifted the dose-response curve of sumatriptan. No significant rightward shift was observed in the dose-response of CP-122,288 and 5-CT. In rats, GR-127,935 did not show any significant partial agonist activity. A dose of 0.2 μmol/kg was sufficient to right-shift the dose-response curve of sumatriptan. These data suggest that sumatriptan inhibits neurogenic inflammation via 5-HT1Dα Receptors in guinea pigs and 5-HT1Dβ (5-HT1B) Receptors in rats. Additional Receptor subtypes are likely to be involved in the inhibition of plasma extravasation by CP-122,288 and 5-CT. Pertussis toxin reduced the inhibitory effects of both sumatriptan and 5-CT, but not of muscimol, known to act at GABAA Receptors. These results suggest that 5-CT, as well as sumatriptan, act at a Receptor linked to an inhibitory G-protein. © 1997 Elsevier Science Ltd. All rights reserved.
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selective 5 ht1d alpha serotonin Receptor gene expression in trigeminal ganglia implications for antimigraine drug development
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: G W Rebeck, Kenneth I Maynard, Bradley T Hyman, Michael A. MoskowitzAbstract:Abstract Pharmacological data suggest that the actions of antimigraine drugs such as sumatriptan may be mediated by 5-HT1D-like serotonin Receptors on trigeminovascular nerve endings. We sought molecular evidence for the expression of an mRNA species encoding the 5-HT1D Receptor subtype in guinea pig and human trigeminal ganglia, using the polymerase chain reaction with oligonucleotides uniquely homologous to the coding sequences of the 5-HT1B/D family (human 5-HT1D alpha and 5-HT1D beta; rat 5-HT1B). A single band of predicted size was observed in samples from guinea pig trigeminal ganglia; sequence analysis revealed the presence of a single message, which was 85% and 71% identical to the human 5-HT1D alpha and 5-HT1D beta Receptor DNA sequences, respectively. Similar analyses of postmortem human trigeminal ganglia revealed the presence of 5-HT1D alpha, but not 5-HT1D beta, Receptor message. Inasmuch as one recent report found that mRNA encoding only the 5-HT1D beta Receptor subtype was expressed by vascular smooth muscle of the central nervous system, the present findings suggest the importance of developing selective 5-HT1D alpha Receptor agonists as a strategy to reduce the risk of myocardial infarction and possibly stroke that complicates the acute treatment of migraine headache.
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cp 93 129 a potent and selective 5 ht1b Receptor agonist blocks neurogenic plasma extravasation within rat but not guinea pig dura mater
British Journal of Pharmacology, 1991Co-Authors: Toshio Matsubara, Michael A. Moskowitz, Barkjang ByunAbstract:Pretreatment with CP-93,129 blocked plasma extravasation in rat dura mater induced by electrical trigeminal ganglion stimulation when administered at greater than or equal to 140 nmol kg-1, i.v. but did not affect plasma leakage in guinea-pig at 460 or 1400 nmol kg-1. Sumatriptan, a 5-HT1D-like Receptor agonist, blocked plasma extravasation in the guinea-pig model when administered at 7 nmol kg-1. In as much as CP-93,129 binds with micromolar affinities to 5-HT1A, 5-HT1C, 5-HT1D, and 5-HT2 recognition sites, and with nanomolar affinity to the 5-HT1B Receptor subtype, blockade of plasma extravasation in the rat dura mater may be mediated by 5-HT1B Receptors whereas the 5-HT1D Receptor may be more relevant to the guinea-pig.
Alan L. Pehrson - One of the best experts on this subject based on the ideXlab platform.
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Effect of the multimodal acting antidepressant vortioxetine on rat hippocampal plasticity and recognition memory.
Progress in neuro-psychopharmacology & biological psychiatry, 2014Co-Authors: Cécile Bétry, Alan L. Pehrson, Connie Sanchez, Adeline Etievant, Nasser HaddjeriAbstract:Depression is frequently associated with cognitive disturbances. Vortioxetine is a multimodal acting antidepressant that functions as a 5-HT3 and 5-HT7 and 5-HT1D Receptor antagonist, 5-HT1B Receptor partial agonist, 5-HT1A Receptor agonist and inhibitor of the 5-HT transporter. Given its pharmacological profile, the present study was undertaken to determine whether vortioxetine could modulate several preclinical parameters known to be involved in cognitive processing. In the dorsal hippocampus of anaesthetized rats, the high-frequency stimulation of the Schaffer collaterals provoked a stable long-term potentiation (LTP) of ~25%. Interestingly, vortioxetine (10mg/kg, i.p.) counteracted the suppressant effect of elevated platform stress on hippocampal LTP induction. In the novel object recognition test, vortioxetine (10mg/kg, i.p.) increased the time spent exploring the novel object during the retention test and this pro-cognitive effect was prevented by the partial 5-HT3 Receptor agonist SR57227 (1mg/kg, i.p.). Finally, compared to fluoxetine, sustained administration of vortioxetine (5mg/kg/day, s.c.) induced a rapid increase of cell proliferation in the hippocampal dentate gyrus. In summary, vortioxetine prevented the effect of stress on hippocampal LTP, increased rapidly hippocampal cell proliferation and enhanced short-term episodic memory, via, at least in part, its 5-HT3 Receptor antagonism. Taken together, these preclinical data suggest that the antidepressant vortioxetine may have a beneficial effect on human cognitive processes.
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vortioxetine restores reversal learning impaired by 5 ht depletion or chronic intermittent cold stress in rats
The International Journal of Neuropsychopharmacology, 2014Co-Authors: Ashley Wallace, Alan L. Pehrson, David A. Morilak, Connie SanchezAbstract:Current treatments for depression, including serotonin-specific reuptake inhibitors (SSRIs), are only partially effective, with a high incidence of residual symptoms, relapse, and treatment resistance. Loss of cognitive flexibility, a component of depression, is associated with dysregulation of the prefrontal cortex. Reversal learning, a form of cognitive flexibility, is impaired by chronic stress, a risk factor for depression, and the stress-induced impairment in reversal learning is sensitive to chronic SSRI treatment, and is mimicked by serotonin (5-HT) depletion. Vortioxetine, a novel, multimodal-acting antidepressant, is a 5-HT3, 5-HT7 and 5-HT1D Receptor antagonist, a 5-HT1B Receptor partial agonist, a 5-HT1A Receptor agonist, and inhibits the 5-HT transporter. Using adult male rats, we first investigated the direct effects of vortioxetine, acting at post-synaptic 5-HT Receptors, on reversal learning that was compromised by 5-HT depletion using 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), effectively eliminating any contribution of 5-HT reuptake blockade. PCPA induced a reversal learning impairment that was alleviated by acute or sub-chronic vortioxetine administration, suggesting that post-synaptic 5-HT Receptor activation contributes to the effects of vortioxetine. We then investigated the effects of chronic dietary administration of vortioxetine on reversal learning that had been compromised in intact animals exposed to chronic intermittent cold (CIC) stress, to assess vortioxetine's total pharmacological effect. CIC stress impaired reversal learning, and chronic vortioxetine administration prevented the reversal-learning deficit. Together, these results suggest that the direct effect of vortioxetine at 5-HT Receptors may contribute to positive effects on cognitive flexibility deficits, and may enhance the effect of 5-HT reuptake blockade.
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vortioxetine but not escitalopram or duloxetine reverses memory impairment induced by central 5 ht depletion in rats evidence for direct 5 ht Receptor modulation
European Neuropsychopharmacology, 2014Co-Authors: Jesper Borno Jensen, Connie Sanchez, Gennady N Smagin, Kristian Gaarn Du Jardin, Dekun Song, David P Budac, Alan L. PehrsonAbstract:Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3 ,5 -HT 7 and 5-HT1D Receptor antagonist, 5-HT1B Receptor partial agonist, 5-HT1A Receptor agonist and 5-HT transporter (SERT) inhibitor that enhances memory in normal rats in novel object recognition (NOR) and conditioned fear (Mork et al., 2013). We hypothesized that vortioxetine's 5-HT Receptor mechanisms are involved in its memory effects, and therefore investigated these effects in 5-HT depleted rats. Four injections of the irreversible tryptophan hydroxylase inhibitor 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA, 86 mg/kg, s.c.) induced 5-HT depletion, as measured in hippocampal homogenate and microdialysate. The effects of acute challenge with vortioxetine or the 5-HT releaser fenfluramine on extracellular 5-HT were measured in PCPA-treated and control rats. PCPA's effects on NOR and spontaneous alternation (SA) performance were assessed along with the effects of acute treatment with 5-hydroxy-L-tryptophan (5-HTP), vortioxetine, the selective 5-HT reuptake inhibitor escitalopram, or the 5-HT norepinephrine reuptake inhibitor duloxetine. SERT occupancies were estimated by ex vivo autoradiography. PCPA depleted central 5-HT by 490% in tissue and microdialysate, and impaired NOR and SA performance. Restoring central 5-HT with 5-HTP reversed these deficits. At similar SERT occupancies (490%) vortioxetine, but not escitalopram or duloxetine, restored memory performance. Acute fenfluramine significantly
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vortioxetine but not escitalopram or duloxetine reverses memory impairment induced by central 5 ht depletion in rats evidence for direct 5 ht Receptor modulation
European Neuropsychopharmacology, 2014Co-Authors: Jesper Borno Jensen, Connie Sanchez, Gennady N Smagin, Kristian Gaarn Du Jardin, Dekun Song, David P Budac, Alan L. PehrsonAbstract:Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3, 5-HT7 and 5-HT1D Receptor antagonist, 5-HT1B Receptor partial agonist, 5-HT1A Receptor agonist and 5-HT transporter (SERT) inhibitor that enhances memory in normal rats in novel object recognition (NOR) and conditioned fear (Mork et al., 2013). We hypothesized that vortioxetine's 5-HT Receptor mechanisms are involved in its memory effects, and therefore investigated these effects in 5-HT depleted rats. Four injections of the irreversible tryptophan hydroxylase inhibitor 4-chloro-dl-phenylalanine methyl ester hydrochloride (PCPA, 86mg/kg, s.c.) induced 5-HT depletion, as measured in hippocampal homogenate and microdialysate. The effects of acute challenge with vortioxetine or the 5-HT releaser fenfluramine on extracellular 5-HT were measured in PCPA-treated and control rats. PCPA's effects on NOR and spontaneous alternation (SA) performance were assessed along with the effects of acute treatment with 5-hydroxy-l-tryptophan (5-HTP), vortioxetine, the selective 5-HT reuptake inhibitor escitalopram, or the 5-HT norepinephrine reuptake inhibitor duloxetine. SERT occupancies were estimated by ex vivo autoradiography. PCPA depleted central 5-HT by >90% in tissue and microdialysate, and impaired NOR and SA performance. Restoring central 5-HT with 5-HTP reversed these deficits. At similar SERT occupancies (>90%) vortioxetine, but not escitalopram or duloxetine, restored memory performance. Acute fenfluramine significantly increased extracellular 5-HT in control and PCPA-treated rats, while vortioxetine did so only in control rats. Thus, vortioxetine restores 5-HT depletion impaired memory performance in rats through one or more of its Receptor activities.
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antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine lu aa21004 assessed by behavioural and neurogenesis outcomes in mice
Neuropharmacology, 2013Co-Authors: Jean-philippe Guilloux, Alan L. Pehrson, Bjarke Ebert, Alain M. Gardier, Indira Mendezdavid, Bruno P Guiard, Christelle Reperant, Sophie Orvoen, Silke Miller, Connie SanchezAbstract:Vortioxetine (Lu AA21004) is an investigational novel antidepressant with multimodal activity that functions as a 5-HT3, 5-HT7 and 5-HT1D Receptor antagonist, 5-HT1B Receptor partial agonist, 5-HT1A Receptor agonist and inhibitor of the 5-HT transporter in vitro. Here we explore its anxiolytic and antidepressant potential in adult mice. Vortioxetine was assessed in BalB/cJ@RJ mice using the open-field and forced-swim tests (acute: p.o. 1 h, repeated: daily p.o. 21 days), and in 129S6/SvEvTac mice using the novelty suppressed feeding paradigm (acute: p.o. 1 h, sustained: daily p.o. 14 or 21 days). Fluoxetine and diazepam were controls. Acute and repeated dosing of vortioxetine produced more pronounced anxiolytic- and antidepressant-like activities than fluoxetine. Vortioxetine significantly increased cell proliferation and cell survival and stimulated maturation of immature granule cells in the subgranular zone of the dentate gyrus of the hippocampus after 21 days of treatment. After 14 days, a high dose of vortioxetine increased dendritic length and the number of dendrite intersections, suggesting that vortioxetine accelerates the maturation of immature neurons. Vortioxetine displays an antidepressant and anxiolytic profile following repeated administration associated with increased neurogenesis at several stages. Vortioxetine effects were observed at low levels of 5-HT transporter occupancy, suggesting an alternative mechanism of action to 5-HT reuptake inhibition.
R G Hill - One of the best experts on this subject based on the ideXlab platform.
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an immunocytochemical investigation of human trigeminal nucleus caudalis cgrp substance p and 5 ht1d Receptor immunoreactivities are expressed by trigeminal sensory fibres
Cephalalgia, 2002Co-Authors: David W Smith, Lars Edvinsson, R G Hill, Jenny LongmoreAbstract:5-HT1D (but not 5-HT1B )-Receptor immunoreactivity (i.r.) can be detected on trigeminal fibres within the spinal trigeminal tract of the human brainstem. The present study used immunohistochemical and morphometric techniques to determine the proportions of trigeminal fibres expressing substance P, CGRP or 5-HT1D -Receptor immunoreactivities. Co-localization studies between 5-HT1D -Receptor and substance P- or CGRP-i.r. were also performed. Brainstem material was obtained with consent (four donors) and the total number of immunoreactive fibres within the trigeminal tract was estimated using random field sampling. A greater proportion of fibres (>1 mum diameter) expressed CGRP-i.r. (80 +/- 6%) compared with substance P-i.r. (46 +/- 7%) or 5-HT1D -Receptor-i.r. (25 +/- 1%). 5-HT1D -Receptor-i.r. was co-localized on some CGRP- or substance P-i.r. fibres. This suggests that 5-HT1D -Receptors can regulate the release of CGRP and substance P and may be relevant to the clinical effectiveness of 5-HT1B/1D -Receptor agonists in the treatment of migraine and other cranial pain syndromes. (Less)
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comparison of the vasoconstrictor properties of the 5 ht1d Receptor agonists rizatriptan mk 462 and sumatriptan in human isolated coronary artery outcome of two independent studies using different experimental protocols
Functional Neurology, 1997Co-Authors: J Longmore, C M Boulanger, B Desta, W N Schofield, Alaric Taylor, R J Hargreaves, Morris J Brown, A Ferro, R G HillAbstract:Rizatriptan (MK-462) is a novel 5-HT1D-Receptor agonist and is effective in the treatment of migraine headache. As angiographic studies have shown that the prototypic 5-HT1D/1B-Receptor agonist sumatriptan can cause coronary artery constriction in patients with mild coronary artery disease, we have compared the contractile effects of rizatriptan on human isolated coronary artery with those of sumatriptan and 5-HT. Two different experimental protocols were used. In Study 1 (to avoid agonist desensitisation and interaction effects), arterial segments were exposed to a single agonist (either 5-HT, sumatriptan or rizatriptan) and in Study 2 each arterial segment was exposed to all three agonists with randomised first exposure to sumatriptan or rizatriptan. In both these studies the maximum contractions evoked by sumatriptan and rizatriptan were found to be smaller than those evoked by 5-HT, and the maximum contraction evoked by rizatriptan was significantly smaller than that for sumatriptan.
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5 ht1d Receptor agonists and human coronary artery reactivity in vitro crossover comparisons of 5 ht and sumatriptan with rizatriptan and l 741 519
British Journal of Clinical Pharmacology, 1996Co-Authors: J Longmore, C M Boulanger, B Desta, R G Hill, W N Schofield, Alaric TaylorAbstract:1Rizatriptan (MK-462, (N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine)) and its structurally related analogue L-741,519 (N-methyl-4-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]piperidine) are novel 5-HT1D-Receptor agonists. Rizatriptan has shown efficacy as an anti-migraine agent in clinical trials. Since angiographic studies in patients have shown that sumatriptan (an established 5-HT1D-Receptor agonist) can cause coronary artery vasoconstriction, we compared the effects of rizatriptan and L-741,519 with those of 5-HT and sumatriptan on endothelium-denuded segments of human coronary artery in vitro. 2Coronary arteries were obtained from explanted hearts from patients undergoing cardiac transplantation (n=16 viable arteries from 13 males, 3 females, aged 38–68 years) and arterial segments (5–6 mm in length) were mounted in organ baths for isometric tension recording. Each segment was first exposed to 45mm KCl and then to 5-HT (1 nm–100 μm). Concentration–effect curves to rizatriptan and sumatriptan (Study 1, n=6 or 7 arteries) or sumatriptan and L-741,519 (Study 2, n=8 arteries) were then performed in a consecutive and random manner. The response to repeated application of 5-HT was obtained in separate segments. 3One artery showed severe atheroma and was not included in the analysis. ANOVA showed that 5-HT responsiveness varied significantly between arteries from different patients, but not between arterial segments from the same patient. Desensitization was seen consistently across all agonists but did not significantly affect inter-agonist comparisons. 4There was graded effectiveness in the ability of the agonists to cause contraction with the rank order of Emax values being 5-HTsumatriptan>L-741,519>rizatriptan. In terms of EC50 values, L-741,519 was significantly more potent than sumatriptan. 5The present study (using a ‘cross-over’ experimental protocol) confirms our previous observation that rizatriptan is less effective than sumatriptan in causing contraction of human isolated coronary artery. Furthermore, it shows that the lower maximum contractile response to rizatriptan, compared with that of sumatriptan, is not merely the consequence of variability in response to 5-HT1D- Receptor agonists between patients or between segments from the same artery.
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differences in the effects of ketanserin and gr127935 on 5 ht Receptor mediated responses in rabbit saphenous vein and guinea pig jugular vein
European Journal of Pharmacology, 1995Co-Authors: Z Razzaque, Jeanette Longmore, R G HillAbstract:Abstract Ketanserin has higher affinity for 5-HT1Dα Receptors compared to 5-HT1Dβ Receptors, whereas, GR127935 (N-[4-methoxy-3-(4-methyl-1-mpiperazinyl)phenyl]-2(methyl-4(-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1-biphenyl]-4-carboxamide), a novel and selective 5-HT1D Receptor antagonist, has higher affinity for 5-HT1Dβ Receptors compared to 5-HT1Dα Receptors. In the present study, we compared the effects of ketanserin and GR127935 on sumatriptan-induced responses of rabbit saphenous vein and guinea-pig jugular vein. In rabbit saphenous vein, contractile responses elicited by sumatriptan were antagonised by ketanserin (pA2 = 6.76) and GR127935 (apparent pA2 = 9.4). In guinea-pig jugular vein, concentration-dependent relaxations evoked by sumatriptan were antagonised by ketanserin and GR127935 (apparent pA2 = 5.9 and 10, respectively). Ketanserin but not GR127935, inhibited Ca2+-induced contraction of depolarised strips of guinea-pig ileum longitudinal muscle/myenteric plexus, however, in rabbit saphenous vein and guinea-pig jugular vein, 5-HT Receptor mediated responses were insensitive to nifedipine (Ca2+ channel blocker), eliminating the possibility that the inhibitory effects of ketanserin and GR127935 were due to the blockade of voltage-operated Ca2+ channels. Thus, antagonism by ketanserin and GR127935 confirms the presence of 5-HT1D Receptors in rabbit saphenous vein and guinea-pig jugular vein. The differential effects of ketanserin and GR127935 on responses elicited by sumatriptan in rabbit saphenous vein and guinea-pig jugular vein may reflect either species differences in 5-HT1D Receptors or the involvement of 5-HT1Dα and 5-HT1Dβ Receptor subtypes.
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the chemical evolution of n n dimethyl 2 5 1 2 4 triazol 4 yl 1h indol 3 yl ethylamine l 741 604 and analogues potent and selective agonists for 5 ht1d Receptors
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Francine Sternfeld, Margaret S. Beer, R Baker, Alec Guiblin, Richard Alexander Jelley, Austin John Reeve, Howard B Broughton, Victor G Matassa, Josephine A Stanton, Richard HargreavesAbstract:Optimisation of a series of 5-(heterocyclyl)tryptamines led to the identification of the symmetrically substituted, N-4 linked 1,2,4-triazole as the best indole C-5 substituent for 5-HT1D Receptor affinity and selectivity. The triazole (8) is the most potent and selective, orally bioavailable, 5-HT1D Receptor agonist identified to date, showing an order of magnitude greater potency than the clinical compound sumatriptan with improved subtype selectivity.
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synthesis and serotonergic activity of n n dimethyl 2 5 1 2 4 triazol 1 ylmethyl 1h indol 3 yl ethylamine and analogues potent agonists for 5 ht1d Receptors
Journal of Medicinal Chemistry, 1995Co-Authors: Leslie J Street, R Baker, W B Davey, Alec Guiblin, Richard Alexander Jelley, Austin John Reeve, H Routledge, Francine Sternfeld, A P Watt, Margaret S. BeerAbstract:The synthesis and the 5-HT Receptor activity of a novel series of N,N-dimethyltryptamines substituted in the 5-position with an imidazole, triazole, or tetrazole ring are described. The objective of this work was to identify potent and selective 5-HT1D Receptor agonists with high oral bioavailability and low central nervous system penetration. Compounds have been prepared in which the azole ring is attached through either nitrogen or carbon to the indole. Conjugated and methylene-bridged derivatives have been studied (n = 0 or 1). Substitution of the azole ring has been explored either alpha or beta to the point of attachment to indole. In a series of N-linked azoles (X = N), simple unsubstituted compounds have high affinity and selectivity for 5-HT1D Receptors. It is proposed that for good affinity and selectivity a hydrogen bond acceptor interaction with the 5-HT1D Receptor, through a beta-nitrogen in the azole ring, is required. In a series of C-linked triazoles and tetrazoles (X = C), optimal affinity and selectivity for the 5-HT1D Receptor was observed when the azole ring is substituted at the 1-position with a methyl or ethyl group. This study has led to the discovery of the 1,2,4-triazole 10a (MK-462) as a potent and selective 5-HT1D Receptor agonist which has high oral bioavailability and rapid oral absorption. The in vitro activity and the preliminary pharmacokinetics of compounds in this series are presented.
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Stereoselective actions of the isomers of metitepine at 5-HT1D Receptors in the guinea pig brain.
Neuropharmacology, 1993Co-Authors: Lynn O. Wilkinson, Lynda M. Hawkins, Margaret S. Beer, Marcel Hibert, Derek N. MiddlemissAbstract:Abstract The present studies examined the relative antagonist potencies of the optical isomers of the 5-HT Receptor antagonist metitepine at the 5-HT1D binding site labelled by the novel radioligand serotonin-O-carboxymethylglycyl [125]iodotyrosinamide ([125I]GTI), and at the terminal 5-HT autoReceptor in guinea pig frontal cortex, a proposed model of 5-HT1D Receptor activation. The pharmacological specificity of the [125I]GTI binding site in guinea pig frontal cortex was similar to previously published studies in the bovine cortical 5-HT1D recognition site labelled with [3H]5-HT. The (+) isomer of metitepine displaced [125I]GTI binding with a lower affinity (64 nM) than did the (−) isomer (18 nM), which was equiactive with the racemic mixture. The (−) isomer of metitepine was more effective than the (+) isomer at attenuating the inhibitory effects of 5-HT and sumatriptan at the guinea pig terminal 5-HT autoReceptor; the apparent pA2 of the (−) isomer was 8.0 (sumatriptan) and 7.7 (5-HT) while the apparent pA2 of the (+) isomer was 7.1 (sumatriptan) and 6.8 (5-HT). The (−) isomer was more effective than the (+) isomer at enhancing stimulated [3H]5-HT release. These findings support the identification of the guinea pig 5-HT terminal autoReceptor as a 5-HT1D Receptor and reinforce the species homology between the 5-HT1B and 5-HT1D Receptors.