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Berend Olivier - One of the best experts on this subject based on the ideXlab platform.
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a study of time and sex dependent effects of vortioxetine on rat sexual behavior possible roles of direct receptor modulation
Neuropharmacology, 2017Co-Authors: Alan L. Pehrson, Berend Olivier, Ronald S Oosting, Maria Gulinello, Connie SanchezAbstract:Treatment-related sexual dysfunction is a common side effect of antidepressants and contributes to patient non-compliance or treatment cessation. However, the multimodal antidepressant, vortioxetine, demonstrates low sexual side effects in depressed patients. To investigate the mechanisms involved, sexual behavior was assessed in male and female rats after acute, and repeated (7 and 14 days) treatment with vortioxetine, Flesinoxan (a 5-HT1A receptor agonist), CP-94253 (a 5-HT1B receptor agonist), or ondansetron (a 5-HT3 receptor antagonist). These selective ligands were chosen to simulate vortioxetine's direct modulation of these receptors. Paroxetine was also included in the male study. Acute and repeated treatment with vortioxetine at doses corresponding to clinical levels (based on serotonin transporter occupancy) had minimal effects on sexual behavior in male and female rats. High dose vortioxetine plus Flesinoxan (to mimic predicted clinical levels of 5-HT1A receptor occupancy by vortioxetine) facilitated male rat sexual behavior (acutely) while inhibiting female rat proceptive behavior (both acutely and after 14 days treatment). The selective serotonin reuptake inhibitor, paroxetine, inhibited male sexual behavior after repeated administration (7 and 14 days). Flesinoxan alone facilitated male sexual behavior acutely while inhibiting female rat proceptive behavior after repeated administration (7 and 14 days). CP-94253 inhibited sexual behavior in both male and female rats after repeated administration. Ondansetron had no effect on sexual behavior. These findings underline the complex serotonergic regulation of sexual behavior and indicate that the low sexual side effects of vortioxetine found in clinical studies are likely associated with its direct modulation of serotonin receptors.
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stress induced hyperthermia and basal body temperature are mediated by different 5 ht 1a receptor populations a study in sert knockout rats
European Journal of Pharmacology, 2008Co-Authors: Jocelien D A Olivier, Edwin Cuppen, Berend Olivier, Judith R Homberg, A R Cools, Bart A EllenbroekAbstract:Disturbances in the serotonergic system are implicated in many central nervous system disorders. The serotonin transporter (SERT) regulates the serotonin homeostasis in the synapse. We recently developed a rat which lacks the serotonin transporter (SERT(-/-)). It is likely that adaptive changes take place at the level of pre- and postsynaptic 5-HT receptors. Because autonomic responses are often used to measure 5-HT(1A) receptor function, we analysed these responses by examining the effects of a 5-HT(1A) receptor agonist and antagonist under in vivo conditions in the SERT(-/-) rat. Moreover, we studied the effect of a mild stressor on the body temperature (stress-induced hyperthermia) because of the known involvement of 5-HT(1A) receptors in this phenomenon. Results show that core body temperature did not differ between genotypes under basal, non-stressed conditions. Compared to SERT(+/+) rats, stress-induced hyperthermia was reduced in SERT(-/-) rats. The 5-HT(1A) receptor agonist [R(+)-N-(2[4-(2,3-dihydro-2-2-hydroxy-methyl-1,4-benzodioxin-5-yl)-1-piperazininyl]ethyl)-4-fluorobenzoamide HCl (Flesinoxan) reduced stress-induced hyperthermia in both genotypes. The Flesinoxan-induced hypothermia in SERT(+/+) rats was blocked by the 5-HT(1A) receptor antagonist [N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl) cyclohexane carboxamide 3HCl (WAY100635). Moreover, WAY100635-induced hyperthermia in SERT(-/-), but not in SERT(+/+) rats. In SERT(-/-) rats, WAY100635 completely blocked the Flesinoxan-induced reduction of stress-induced hyperthermia. Interestingly, Flesinoxan-induced hypothermia was absent in SERT(-/-) rats. It is concluded that the SERT knockout rat reveals that 5-HT(1A) receptors modulating stress-induced hyperthermia belong to a population of receptors that differs from that involved in hypothermia.
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effects of repeated testing in two inbred strains on Flesinoxan dose response curves in three mouse models for anxiety
European Journal of Pharmacology, 2004Co-Authors: Adriaan J Bouwknecht, Berend Olivier, Jan Van Der Gugten, Lucianne Groenink, Richard PaylorAbstract:Abstract Over the last decade, many genetically modified mice have been developed as models for psychiatric diseases such as anxiety. Limited availability of such mutant mice highlights the importance of studying the possibility of repeatedly testing the same individuals. We tested mice four times with 1-week intervals with the same dose of the 5-HT1A receptor agonist Flesinoxan (0–0.3–1.0–3.0 mg/kg s.c.) in three anxiety-related paradigms: light–dark exploration, open-field activity and stress-induced hyperthermia. The two inbred strains studied were the highly anxious 129S6/SvEvTac (S6) and low-anxiety C57BL/6J (B6) mice. The results indicate that the effects of repeated testing were relatively mild. B6 mice showed some mild habituation in the open-field test when treated with vehicle, whereas S6 mice developed reduced initial activity in the light–dark box after drug treatment. In contrast, responses to Flesinoxan treatment were strong and highly consistent for most parameters. In the open-field and light–dark tests, B6 mice showed reduced activity and anxiogenic-like behavioral responses, whereas S6 mice were minimally affected. Anxiolytic-like responses were found in both strains in the stress-induced hyperthermia paradigm. We conclude that B6 and S6 mice can be tested repeatedly with agents such as 5-HT1A receptor agonists with 1-week intervals in the three paradigms tested.
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behavioral and physiological mouse models for anxiety effects of Flesinoxan in 129s6 svevtac and c57bl 6j mice
European Journal of Pharmacology, 2004Co-Authors: Adriaan J Bouwknecht, Berend Olivier, Jan Van Der Gugten, Lucianne Groenink, Richard PaylorAbstract:Abstract Serotonin 1A (5-HT 1A ) receptors are involved in anxiety. This study focuses on the role of genetic factors on the anxiety-related effects of 5-HT 1A receptor stimulation using both a within subject design. The effects of 5-HT 1A receptor activation were studied in high- and low-anxiety mice (129S6/SvEvTac (S6) and C57BL/6J (B6), respectively) in behavioral and physiological anxiety-related assays. These two strains were also selected because they are frequently used in gene-targeting studies. Mice were treated with the selective 5-HT 1A receptor agonist Flesinoxan (0–0.3–1.0–3.0 mg/kg s.c.) and tested in either the open-field activity test, the light–dark exploration test, or the stress-induced hyperthermia paradigm. Flesinoxan unexpectedly increased anxiety, but also decreased activity on several behavioral measures in B6 mice. Flesinoxan produced only minimal effects in the behavioral tests in the high-anxiety S6 strain. In contrast, the physiological hyperthermia response showed anxiolytic-like effects of Flesinoxan in both strains. Our data indicate that the role of 5-HT 1A receptor activation on anxiety-related responses is dependent on genetic background and selected paradigm used to assess anxiety. These findings indicate that it is critical to use a multi-level approach to develop mouse models for human diseases. In addition, the implication of such findings for studies on genetically modified mice is discussed.
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5 ht1b receptor knockout mice show no adaptive changes in 5 ht1a receptor function as measured telemetrically on body temperature and heart rate responses
Brain Research Bulletin, 2002Co-Authors: Adriaan J Bouwknecht, Berend Olivier, Theo H. Hijzen, Jan Van Der Gugten, R A A Maes, Rene HenAbstract:Abstract Two presynaptic receptors play an important role in the regulation of serotonergic neurotransmission, i.e., the 5-HT1A and 5-HT1B receptor. The present study focuses on putative adaptive changes in the 5-HT1A receptor system in mice that lack 5-HT1B receptors (5-HT1B KO). 5-HT1A receptor sensitivity was assessed in vivo in two models of presynaptic 5-HT1A receptor activity: agonist-induced hypothermia and prevention of stress-induced hyperthermia. The effects of 5-HT1A receptor activation by Flesinoxan (0.1–3.0 mg/kg s.c.) were determined telemetrically on body temperature and heart rate in 5-HT1B KO and wild-type (WT) mice. Flesinoxan induced hypothermia dose-dependently without affecting heart rate and prevented stress-induced hyperthermia and tachycardia equipotently in both genotypes. Specificity of these responses was confirmed by blockade with the selective 5-HT1A receptor antagonist WAY100635 (1.0 mg/kg s.c.). The importance of continuous sampling in freely moving subjects to improve appropriate characterization of mutants is discussed. 5-HT1B KO mice showed no shift in 5-HT1A receptor sensitivity compared to WT mice. This study found no indications for adaptive changes in presynaptic 5-HT1A receptor function in 5-HT1B KO mice as measured telemetrically on body temperature and heart rate responses.
Jan Van Der Gugten - One of the best experts on this subject based on the ideXlab platform.
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effects of repeated testing in two inbred strains on Flesinoxan dose response curves in three mouse models for anxiety
European Journal of Pharmacology, 2004Co-Authors: Adriaan J Bouwknecht, Berend Olivier, Jan Van Der Gugten, Lucianne Groenink, Richard PaylorAbstract:Abstract Over the last decade, many genetically modified mice have been developed as models for psychiatric diseases such as anxiety. Limited availability of such mutant mice highlights the importance of studying the possibility of repeatedly testing the same individuals. We tested mice four times with 1-week intervals with the same dose of the 5-HT1A receptor agonist Flesinoxan (0–0.3–1.0–3.0 mg/kg s.c.) in three anxiety-related paradigms: light–dark exploration, open-field activity and stress-induced hyperthermia. The two inbred strains studied were the highly anxious 129S6/SvEvTac (S6) and low-anxiety C57BL/6J (B6) mice. The results indicate that the effects of repeated testing were relatively mild. B6 mice showed some mild habituation in the open-field test when treated with vehicle, whereas S6 mice developed reduced initial activity in the light–dark box after drug treatment. In contrast, responses to Flesinoxan treatment were strong and highly consistent for most parameters. In the open-field and light–dark tests, B6 mice showed reduced activity and anxiogenic-like behavioral responses, whereas S6 mice were minimally affected. Anxiolytic-like responses were found in both strains in the stress-induced hyperthermia paradigm. We conclude that B6 and S6 mice can be tested repeatedly with agents such as 5-HT1A receptor agonists with 1-week intervals in the three paradigms tested.
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behavioral and physiological mouse models for anxiety effects of Flesinoxan in 129s6 svevtac and c57bl 6j mice
European Journal of Pharmacology, 2004Co-Authors: Adriaan J Bouwknecht, Berend Olivier, Jan Van Der Gugten, Lucianne Groenink, Richard PaylorAbstract:Abstract Serotonin 1A (5-HT 1A ) receptors are involved in anxiety. This study focuses on the role of genetic factors on the anxiety-related effects of 5-HT 1A receptor stimulation using both a within subject design. The effects of 5-HT 1A receptor activation were studied in high- and low-anxiety mice (129S6/SvEvTac (S6) and C57BL/6J (B6), respectively) in behavioral and physiological anxiety-related assays. These two strains were also selected because they are frequently used in gene-targeting studies. Mice were treated with the selective 5-HT 1A receptor agonist Flesinoxan (0–0.3–1.0–3.0 mg/kg s.c.) and tested in either the open-field activity test, the light–dark exploration test, or the stress-induced hyperthermia paradigm. Flesinoxan unexpectedly increased anxiety, but also decreased activity on several behavioral measures in B6 mice. Flesinoxan produced only minimal effects in the behavioral tests in the high-anxiety S6 strain. In contrast, the physiological hyperthermia response showed anxiolytic-like effects of Flesinoxan in both strains. Our data indicate that the role of 5-HT 1A receptor activation on anxiety-related responses is dependent on genetic background and selected paradigm used to assess anxiety. These findings indicate that it is critical to use a multi-level approach to develop mouse models for human diseases. In addition, the implication of such findings for studies on genetically modified mice is discussed.
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5 ht1b receptor knockout mice show no adaptive changes in 5 ht1a receptor function as measured telemetrically on body temperature and heart rate responses
Brain Research Bulletin, 2002Co-Authors: Adriaan J Bouwknecht, Berend Olivier, Theo H. Hijzen, Jan Van Der Gugten, R A A Maes, Rene HenAbstract:Abstract Two presynaptic receptors play an important role in the regulation of serotonergic neurotransmission, i.e., the 5-HT1A and 5-HT1B receptor. The present study focuses on putative adaptive changes in the 5-HT1A receptor system in mice that lack 5-HT1B receptors (5-HT1B KO). 5-HT1A receptor sensitivity was assessed in vivo in two models of presynaptic 5-HT1A receptor activity: agonist-induced hypothermia and prevention of stress-induced hyperthermia. The effects of 5-HT1A receptor activation by Flesinoxan (0.1–3.0 mg/kg s.c.) were determined telemetrically on body temperature and heart rate in 5-HT1B KO and wild-type (WT) mice. Flesinoxan induced hypothermia dose-dependently without affecting heart rate and prevented stress-induced hyperthermia and tachycardia equipotently in both genotypes. Specificity of these responses was confirmed by blockade with the selective 5-HT1A receptor antagonist WAY100635 (1.0 mg/kg s.c.). The importance of continuous sampling in freely moving subjects to improve appropriate characterization of mutants is discussed. 5-HT1B KO mice showed no shift in 5-HT1A receptor sensitivity compared to WT mice. This study found no indications for adaptive changes in presynaptic 5-HT1A receptor function in 5-HT1B KO mice as measured telemetrically on body temperature and heart rate responses.
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effects of Flesinoxan on corticosteroid receptor expression in the rat hippocampus
European Journal of Pharmacology, 2000Co-Authors: Rosana M Sibug, Berend Olivier, Jan Van Der Gugten, Josje C Compaan, Onno C Meijer, Ron E De KloetAbstract:Many agents that influence serotonergic neurotransmission modulate expression of hippocampal corticosteroid receptors. We have studied the effect of the specific 5-hydroxytryptamine, 5-HT1A, receptor agonist Flesinoxan on mRNA for glucocorticoid and mineralocorticoid receptors in the hippocampus and dorsal raphe nucleus. Since some responses to 5-HT1A receptor stimulation show a strong desensitization, we studied the effect of a single and repeated injections of Flesinoxan. Because of the close interrelationship between the serotonergic system and the hypothalamo-pituitary–adrenal axis, we also studied the possible involvement of corticosterone as a mediator of the effects of Flesinoxan. We found that a single injection of Flesinoxan (3 and 10 mg/kg subcutaneously, s.c.) after 3 h leads to a downregulation of glucocorticoid receptor mRNA in the hippocampus (dentate gyrus and CA1 areas) and dorsal raphe nucleus. This effect does not desensitize after a second treatment over 2 days. Mineralocorticoid receptor mRNA expression remained unaltered. The decrease in hippocampal glucocorticoid receptor mRNA expression occurs independently of circulating corticosterone since Flesinoxan reduced glucocorticoid receptor mRNA in the hippocampus of adrenalectomized rats with or without corticosterone replacement. These data indicate that the 5-HT1A receptor agonist Flesinoxan alters glucocorticoid receptor expression via a direct pathway independently of corticosterone and argues for an intrinsic effect selective for hippocampal glucocorticoid receptor mRNA.
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stress induced hyperthermia in mice effects of Flesinoxan on heart rate and body temperature
European Journal of Pharmacology, 2000Co-Authors: Adriaan J Bouwknecht, Berend Olivier, Theo H. Hijzen, Jan Van Der Gugten, R A A MaesAbstract:Stress-induced hyperthermia in mice has predictive validity for anxiolytic properties of drugs. In this paradigm, 60 min after drug administration rectal temperature is measured, which causes hyperthermia of 1–1.5°C (ΔT) in about 10 min. Flesinoxan, a selective 5-HT1A receptor agonist with anxiolytic-like properties, causes hypothermia, which complicates interpretation of stress-induced hyperthermia. Therefore, we combined Flesinoxan treatment and the stress paradigm with radiotelemetric measurement of body temperature and heart rate, which is also related to anxiety. Subjects were either undisturbed or injected with Flesinoxan (0–0.1–0.3–1.0 and 3.0 mg/kg), with or without the stress paradigm. Flesinoxan (1.0 and 3.0 mg/kg) caused a relatively long-lasting hypothermia, but did not lower heart rate. The rectal temperature procedure caused hyperthermia and tachycardia. Flesinoxan reduced the stress-induced hyperthermia and the tachycardia evoked by the stress procedure. Continuous radiotelemetric measurement of heart rate, apart from body temperature, revealed that Flesinoxan has anxiolytic-like properties in mice.
R A A Maes - One of the best experts on this subject based on the ideXlab platform.
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5 ht1b receptor knockout mice show no adaptive changes in 5 ht1a receptor function as measured telemetrically on body temperature and heart rate responses
Brain Research Bulletin, 2002Co-Authors: Adriaan J Bouwknecht, Berend Olivier, Theo H. Hijzen, Jan Van Der Gugten, R A A Maes, Rene HenAbstract:Abstract Two presynaptic receptors play an important role in the regulation of serotonergic neurotransmission, i.e., the 5-HT1A and 5-HT1B receptor. The present study focuses on putative adaptive changes in the 5-HT1A receptor system in mice that lack 5-HT1B receptors (5-HT1B KO). 5-HT1A receptor sensitivity was assessed in vivo in two models of presynaptic 5-HT1A receptor activity: agonist-induced hypothermia and prevention of stress-induced hyperthermia. The effects of 5-HT1A receptor activation by Flesinoxan (0.1–3.0 mg/kg s.c.) were determined telemetrically on body temperature and heart rate in 5-HT1B KO and wild-type (WT) mice. Flesinoxan induced hypothermia dose-dependently without affecting heart rate and prevented stress-induced hyperthermia and tachycardia equipotently in both genotypes. Specificity of these responses was confirmed by blockade with the selective 5-HT1A receptor antagonist WAY100635 (1.0 mg/kg s.c.). The importance of continuous sampling in freely moving subjects to improve appropriate characterization of mutants is discussed. 5-HT1B KO mice showed no shift in 5-HT1A receptor sensitivity compared to WT mice. This study found no indications for adaptive changes in presynaptic 5-HT1A receptor function in 5-HT1B KO mice as measured telemetrically on body temperature and heart rate responses.
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stress induced hyperthermia in mice effects of Flesinoxan on heart rate and body temperature
European Journal of Pharmacology, 2000Co-Authors: Adriaan J Bouwknecht, Berend Olivier, Theo H. Hijzen, Jan Van Der Gugten, R A A MaesAbstract:Stress-induced hyperthermia in mice has predictive validity for anxiolytic properties of drugs. In this paradigm, 60 min after drug administration rectal temperature is measured, which causes hyperthermia of 1–1.5°C (ΔT) in about 10 min. Flesinoxan, a selective 5-HT1A receptor agonist with anxiolytic-like properties, causes hypothermia, which complicates interpretation of stress-induced hyperthermia. Therefore, we combined Flesinoxan treatment and the stress paradigm with radiotelemetric measurement of body temperature and heart rate, which is also related to anxiety. Subjects were either undisturbed or injected with Flesinoxan (0–0.1–0.3–1.0 and 3.0 mg/kg), with or without the stress paradigm. Flesinoxan (1.0 and 3.0 mg/kg) caused a relatively long-lasting hypothermia, but did not lower heart rate. The rectal temperature procedure caused hyperthermia and tachycardia. Flesinoxan reduced the stress-induced hyperthermia and the tachycardia evoked by the stress procedure. Continuous radiotelemetric measurement of heart rate, apart from body temperature, revealed that Flesinoxan has anxiolytic-like properties in mice.
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Flesinoxan pretreatment differentially affects corticosterone prolactin and behavioural responses to a Flesinoxan challenge
Psychopharmacology, 1997Co-Authors: Lucianne Groenink, R A A Maes, Jan Van Der Gugten, Josje C Compaan, Berend OlivierAbstract:To determine whether alterations in 5-HT1A receptor mediated responses induced by a single injection with a selective 5-HT1A receptor agonist is a transient effect, or whether the (de)sensitisation is more persistent, rats were pretreated with the selective and full 5-HT1A receptor agonist, Flesinoxan (3 mg/kg SC once daily) for either 1 day or 1 week. Twenty-four hour after the last pretreatment injection, rats were challenged with Flesinoxan (3 mg/kg SC), and the effects on plasma corticosterone and prolactin levels, lower lip retraction and behaviour in the shock-probe burying test were determined. Several 5-HT1A receptor mediated responses were modified differentially following the Flesinoxan pretreatment. However, all changes induced by a single Flesinoxan injection remained present upon repeated Flesinoxan administration. The differential changes in the responses to Flesinoxan cannot easily be explained by differences in pre-or postsynaptically 5-HT1A mediated responses. The prolactin response to Flesinoxan, which is thought to be mediated postsynaptically, was enhanced, whereas the corticosterone response to Flesinoxan, which is also mediated postsynaptically, was attenuated. The presynaptically mediated lower lip retraction response was attenuated as well, whereas the behavioural effects of Flesinoxan remained relatively unaffected following repeated Flesinoxan administration. Upon prolonged Flesinoxan pretreatment, the changes induced by a single Flesinoxan injection remained present or increased further. Although repeated Flesinoxan administration (1 day and 1 week) resulted in 20% lower plasma Flesinoxan concentrations, this effect could not explain the neuroendocrine and behavioural findings.
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pretreatment with 5 ht1a receptor agonist Flesinoxan attenuates fos protein in rat hypothalamus
European Journal of Pharmacology, 1997Co-Authors: Josje C Compaan, R A A Maes, Jan Van Der Gugten, Lucianne Groenink, Berend OlivierAbstract:Abstract The 5-HT 1A receptor agonist Flesinoxan has anxiolytic activity and concurrently enhances plasma corticosterone levels in rats. After a second injection of Flesinoxan 24 h later, the corticosterone response disappears, but not the anxiolytic effects. Male rats received two injections with either Flesinoxan or vehicle within 24 h. Flesinoxan challenge enhanced Fos immunoreactivity in the paraventricular nucleus of the hypothalamus, the central amygdala, and the dorsolateral part of the bed nucleus of the stria terminalis and plasma corticosterone levels in the vehicle-pretreated rats. Flesinoxan pretreatment resulted in an attenuated response of plasma corticosterone levels and Fos-positive neurons in the paraventricular nucleus of the hypothalamus, but not in the central amygdala and the bed nucleus after a Flesinoxan challenge. The differential desensitization levels for both behaviour and neuroendocrine responses after Flesinoxan treatment seem to correspond to different organization levels in the brain, like limbic system and hypothalamus. © 1997 Elsevier Science B.V. All rights reserved.
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5 ht1a receptor agonist Flesinoxan enhances fos immunoreactivity in rat central amygdala bed nucleus of the stria terminalis and hypothalamus
European Journal of Neuroscience, 1996Co-Authors: Josje C Compaan, Lucianne Groenink, R A A Maes, J Van Der Gugten, Berend OlivierAbstract:5-Hydroxytryptamine-1A (5-HT1A) receptor agonists, including Flesinoxan, reduce anxiety and activate the hypothalamus-pituitary-adrenal (HPA) axis under basal conditions. In order to investigate the underlying neural mechanisms we investigated immunoreactivity for the immediate early gene protein product Fos (Fos-ir) in rat brains 1 h after Flesinoxan treatment (0.0, 0.3 or 3.0 mg/kg p.o.). Typically, 5-HT1A receptor-containing brain areas, such as the dorsal raphe nuclei, hippocampus, septum, diagonal band and the cortical and basomedial amygdala, do not show Fos-ir. Apparently, binding of Flesinoxan at the 5-HT1A receptor does not directly lead to activation of c-fos in the cell, probably due to its negative coupling to adenylate cyclase. However, in typically non-5HT1A receptor-containing brain areas Fos-ir is increased due to Flesinoxan treatment, as in the paraventricular nucleus of the hypothalamus (PVN), the dorsolateral part of the bed nucleus of the stria terminalis (BNSTdl) and the central amygdala (CeA). Flesinoxan-treated rats also exhibited higher plasma corticosterone levels than vehicle-treated animals, which suggests the involvement of corticotropin-releasing hormone (CRH) or vasopressin in the hypothalamus. After double immunolabelling (Fos/CRH or Fos/vasopressin), every CRH neuron detected in the PVN also contained Fos. Moreover, a significant correlation existed between the number of Fos-ir neurons in the PVN and the plasma corticosterone level. Hardly any Fos/vasopressin double labelling was visible in the PVN. Accordingly, Flesinoxan exerts its activating effects on the HPA axis via CRH neurons in the PVN. These effects are trans-synaptically mediated by other brain areas, such as the CeA and BNSTdl, which also show increased Fos-ir.
Lucianne Groenink - One of the best experts on this subject based on the ideXlab platform.
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effects of repeated testing in two inbred strains on Flesinoxan dose response curves in three mouse models for anxiety
European Journal of Pharmacology, 2004Co-Authors: Adriaan J Bouwknecht, Berend Olivier, Jan Van Der Gugten, Lucianne Groenink, Richard PaylorAbstract:Abstract Over the last decade, many genetically modified mice have been developed as models for psychiatric diseases such as anxiety. Limited availability of such mutant mice highlights the importance of studying the possibility of repeatedly testing the same individuals. We tested mice four times with 1-week intervals with the same dose of the 5-HT1A receptor agonist Flesinoxan (0–0.3–1.0–3.0 mg/kg s.c.) in three anxiety-related paradigms: light–dark exploration, open-field activity and stress-induced hyperthermia. The two inbred strains studied were the highly anxious 129S6/SvEvTac (S6) and low-anxiety C57BL/6J (B6) mice. The results indicate that the effects of repeated testing were relatively mild. B6 mice showed some mild habituation in the open-field test when treated with vehicle, whereas S6 mice developed reduced initial activity in the light–dark box after drug treatment. In contrast, responses to Flesinoxan treatment were strong and highly consistent for most parameters. In the open-field and light–dark tests, B6 mice showed reduced activity and anxiogenic-like behavioral responses, whereas S6 mice were minimally affected. Anxiolytic-like responses were found in both strains in the stress-induced hyperthermia paradigm. We conclude that B6 and S6 mice can be tested repeatedly with agents such as 5-HT1A receptor agonists with 1-week intervals in the three paradigms tested.
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behavioral and physiological mouse models for anxiety effects of Flesinoxan in 129s6 svevtac and c57bl 6j mice
European Journal of Pharmacology, 2004Co-Authors: Adriaan J Bouwknecht, Berend Olivier, Jan Van Der Gugten, Lucianne Groenink, Richard PaylorAbstract:Abstract Serotonin 1A (5-HT 1A ) receptors are involved in anxiety. This study focuses on the role of genetic factors on the anxiety-related effects of 5-HT 1A receptor stimulation using both a within subject design. The effects of 5-HT 1A receptor activation were studied in high- and low-anxiety mice (129S6/SvEvTac (S6) and C57BL/6J (B6), respectively) in behavioral and physiological anxiety-related assays. These two strains were also selected because they are frequently used in gene-targeting studies. Mice were treated with the selective 5-HT 1A receptor agonist Flesinoxan (0–0.3–1.0–3.0 mg/kg s.c.) and tested in either the open-field activity test, the light–dark exploration test, or the stress-induced hyperthermia paradigm. Flesinoxan unexpectedly increased anxiety, but also decreased activity on several behavioral measures in B6 mice. Flesinoxan produced only minimal effects in the behavioral tests in the high-anxiety S6 strain. In contrast, the physiological hyperthermia response showed anxiolytic-like effects of Flesinoxan in both strains. Our data indicate that the role of 5-HT 1A receptor activation on anxiety-related responses is dependent on genetic background and selected paradigm used to assess anxiety. These findings indicate that it is critical to use a multi-level approach to develop mouse models for human diseases. In addition, the implication of such findings for studies on genetically modified mice is discussed.
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The light-enhanced startle paradigm as a putative animal model for anxiety: effects of chlordiazepoxide, Flesinoxan and fluvoxamine
Psychopharmacology, 2001Co-Authors: Reinoud De Jongh, Lucianne Groenink, Jan Van Der Gugten, Berend OlivierAbstract:Rationale: Recently, a new putative animal model of anxiety, "light-enhanced startle" was introduced. By placing a rat in a brightly lit environment, which is a naturally aversive stimulus to rats, the amplitude of the startle response to a startle-eliciting noise burst is increased. Objectives: The present study aimed to determine the predictive validity of the light-enhanced startle as a putative model for anxiety. Methods: The effects of the GABAA-benzodiazepine receptor agonist chlordiazepoxide (CDP), the 5-HT1A receptor agonist Flesinoxan and the specific 5-HT reuptake inhibitor fluvoxamine on light-enhanced startle were studied. Results: Both CDP and Flesinoxan decreased startle potentiation, whereas fluvoxamine was devoid of any effects on potentiation. Effects on baseline startle amplitude were only seen after CDP administration. Conclusions: The present experiment provides evidence for the predictive validity of the light-enhanced startle as an animal model for anxiety. Due to the use of an unconditioned anxiogenic stimulus, the light-enhanced startle offers several benefits over animal models that depend on conditioning. Drug effects can be ascribed more directly to effects on anxiety, as opposed to memory retrieval and, as shown in this study, non-specific drug effects can easily be detected without the interference of contextual fear.
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infusion of Flesinoxan into the amygdala blocks the fear potentiated startle
Neuroreport, 2000Co-Authors: Lucianne Groenink, Theo H. Hijzen, Rosemarie J E Joordens, Anneloes Dirks, Berend OlivierAbstract:In a previous study it was demonstrated that Flesinoxan, a selective serotonin (5-HT)1A receptor agonist, had anxiolytic properties in the fear-potentiated startle paradigm. The present study investigated the putative site of action of Flesinoxan in this paradigm. Flesinoxan infused either into the dorsal raphe nucleus or the median raphe nucleus did not affect startle potentiation. Bilateral infusion of Flesinoxan into the central nucleus of the amygdala on the other hand, dose-dependently blocked the fear-potentiated startle response. These data indicate that Flesinoxan exerts it anxiolytic effects in the fear-potentiated startle paradigm via the central nucleus of the amygdala, whereas the dorsal and median raphe nuclei are not directly involved in this process.
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Flesinoxan pretreatment differentially affects corticosterone prolactin and behavioural responses to a Flesinoxan challenge
Psychopharmacology, 1997Co-Authors: Lucianne Groenink, R A A Maes, Jan Van Der Gugten, Josje C Compaan, Berend OlivierAbstract:To determine whether alterations in 5-HT1A receptor mediated responses induced by a single injection with a selective 5-HT1A receptor agonist is a transient effect, or whether the (de)sensitisation is more persistent, rats were pretreated with the selective and full 5-HT1A receptor agonist, Flesinoxan (3 mg/kg SC once daily) for either 1 day or 1 week. Twenty-four hour after the last pretreatment injection, rats were challenged with Flesinoxan (3 mg/kg SC), and the effects on plasma corticosterone and prolactin levels, lower lip retraction and behaviour in the shock-probe burying test were determined. Several 5-HT1A receptor mediated responses were modified differentially following the Flesinoxan pretreatment. However, all changes induced by a single Flesinoxan injection remained present upon repeated Flesinoxan administration. The differential changes in the responses to Flesinoxan cannot easily be explained by differences in pre-or postsynaptically 5-HT1A mediated responses. The prolactin response to Flesinoxan, which is thought to be mediated postsynaptically, was enhanced, whereas the corticosterone response to Flesinoxan, which is also mediated postsynaptically, was attenuated. The presynaptically mediated lower lip retraction response was attenuated as well, whereas the behavioural effects of Flesinoxan remained relatively unaffected following repeated Flesinoxan administration. Upon prolonged Flesinoxan pretreatment, the changes induced by a single Flesinoxan injection remained present or increased further. Although repeated Flesinoxan administration (1 day and 1 week) resulted in 20% lower plasma Flesinoxan concentrations, this effect could not explain the neuroendocrine and behavioural findings.
Ansseau Marc - One of the best experts on this subject based on the ideXlab platform.
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5-Hydroxytryptamine 1A receptors, major depression, and suicidal behavior.
2005Co-Authors: Pitchot William, Hansenne Michel, Pinto Emmanuel, Fuchs Sonia, Reggers Jean, Ansseau MarcAbstract:BACKGROUND: Several lines of evidence suggest a clear relationship between serotonin (5-hydroxytryptamine, 5-HT) hypoactivity and suicidal behavior across several psychiatric diagnoses. Few data are available, however, regarding the possible specific role of 5-HT1A receptors in the biology of suicidality. Therefore, the aim of our study was to use a neuroendocrine strategy to test the hypothesis of a role for 5-HT1A receptors in the biology of suicidal behavior. METHODS: Hormonal (adrenocorticotropic hormone [ACTH], cortisol, prolactin [PRL]) and temperature responses after administration of Flesinoxan, a highly potent and selective 5-HT1A receptor full agonist, were assessed in 40 inpatients with major depression, divided into two subgroups (20 suicide attempters and 20 nonattempters), compared with 20 normal control subjects matched for gender and age. RESULTS: Compared with nonattempters, suicide attempters exhibited significantly lower PRL (p = .01), cortisol (p = .014), and temperature (p = .0002) responses. Prolactin (p = .007), cortisol (p = .04), and temperature (p = .00003) responses were also decreased in suicide attempters compared with normal control subjects. In contrast, we did not observe any significant differences in hormonal or temperature responses to Flesinoxan between depressed patients without a history of suicide attempt and normal control subjects. CONCLUSIONS: The present study tends to confirm the role of 5-HT and more specifically 5-HT1A receptors in the biology of suicidal behavior in major depression.Peer reviewe
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Hormonal and temperature responses to Flesinoxan in normal volunteers: an antagonist study
'Elsevier BV', 2004Co-Authors: Pitchot William, Wauthy Jacques, Legros Jean-jacques, Ansseau MarcAbstract:peer reviewedRATIONALE: Flesinoxan is a highly potent and selective 5-HT1A agonist. In a recent study, in normal volunteers, Flesinoxan induced a significant and dose-dependent increase in adrenocorticotropic hormone (ACTH), cortisol, prolactin (PRL), growth hormone (GH) and a decrease in body temperature. OBJECTIVES: In order to better define the role of 5-HT receptor subtypes in response to Flesinoxan, we assessed the influence of 5-HT1A and 5-HT2 antagonists on hormonal and temperature responses to Flesinoxan. METHODS: Hormonal and temperature responses were studied in 6 volunteers with or without pretreatment with pindolol (30 mg p.o.), a 5-HT1A antagonist, or ritanserin (10 mg p.o.), a selective 5-HT2 antagonist, using a double-blind crossover design. RESULTS: Pindolol significantly antagonized ACTH, PRL, GH and temperature responses to Flesinoxan and ritanserin exhibited similar activity on PRL and ACTH responses. CONCLUSIONS: These results show the role of 5-HT1A mechanisms in the PRL, ACTH, GH, and temperature responses to Flesinoxan, and the role of 5-HT2 mechanisms in PRL and ACTH responses. Therefore, they confirm the interest of Flesinoxan as a 5-HT neuroendocrine probe
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Hormonal and temperature responses to the 5-HT1a receptor agonist Flesinoxan in normal volunteers
2002Co-Authors: Pitchot William, Wauthy Jacques, Legros Jean-jacques, Hansenne Michel, Pinto Emmanuel, Fuchs Sonia, Reggers Jean, Ansseau MarcAbstract:RATIONALE: Flesinoxan is a highly potent and selective 5-HT(1A) agonist and appears to be a potentially interesting neuroendocrine serotonergic probe. OBJECTIVES: We assessed hormonal (ACTH, cortisol, prolactin and growth hormone) and temperature responses to Flesinoxan in normal volunteers. METHODS: In a double-blind placebo-controlled study, single doses of 0.5 mg and 1 mg were injected over 10 min into 12 healthy male volunteers at 1-week intervals. Temperature and hormonal responses were measured at times -30, 0, 15, 30, 60, 90, and 120 min. RESULTS: Flesinoxan induced a significant and dose-dependent increase in adrenocorticotropic hormone (ACTH), cortisol, prolactin (PRL), growth hormone (GH) and a decrease in body temperature. Tolerance to Flesinoxan was excellent. CONCLUSIONS: These results showed the role of 5-HT(1A) mechanisms in the PRL, ACTH, cortisol, GH, and temperature responses to Flesinoxan. In the present study, Flesinoxan appears a very promising serotonergic neuroendocrine probe.Peer reviewe
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Neuroendocrine evaluation of 5-HT1A function in male alcoholic patients
2002Co-Authors: Pinto Emmanuel, Pitchot William, Hansenne Michel, Fuchs Sonia, Reggers Jean, Ansseau MarcAbstract:Background: Preclinical evidences support the hypothesis of a serotonergic dysfunction in alcohol preference. In human, studies have demonstrated a serotonergic hypoactivity in alcoholism. However, little is known about the role of 5-HT1A receptors. Methods: We assessed the hormonal (prolactin and cortisol) responses to Flesinoxan (a highly potent and selective 5-HT1A agonist) in 12 male inpatients meeting DSM-IV criteria for alcohol dependence, 3 weeks after the last reported use of alcohol and antidepressants. These patients were compared to 10 male controls. Results: There was a highly significant difference between alcoholic patients and controls for the area under the curve relative (AUCr) values of prolactin responses. AUCr values of cortisol responses to Flesinoxan showed a trend towards lower values in alcoholics compared to controls. Conclusion: These results support the implication of the serotonergic system, and particularly a decreased sensitivity of post-synaptic 5-HT1A receptors, in alcoholism.Peer reviewe
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5-HT1A dysfunction in borderline personality disorder.
2002Co-Authors: Hansenne Michel, Pitchot William, Pinto Emmanuel, Reggers Jean, Scantamburlo Gabrielle, Fuchs S., Pirard S., Ansseau MarcAbstract:BACKGROUND: A number of challenge studies have reported abnormalities of serotonergic function in borderline personality disorder (BPD). There are, however, problems with the pharmacological probes used in these studies since fenfluramine and m-CPP are not only serotonergic agents but also induce release of catecholamines, particularly dopamine. Therefore, we tested whether subjects with BPD showed a blunted prolactin (PRL) response to Flesinoxan, a highly potent and selective 5-HT1A agonist. METHODS: Flesinoxan challenge test was carried out in 20 BPD in-patients and 20 healthy controls matched for gender but not for age. Since 16 BPD in-patients exhibited major depressive co-morbidity, a group of 20 depressed in-patients matched for gender but not for age was also included. RESULTS: BPD in-patients exhibited blunted PRL responses as compared to controls, whereas depressed in-patients did not differ from controls. Moreover, PRL responses were lower among BPD in-patients than among depressed in-patients. Among the BPD in-patients, PRL responses to Flesinoxan were lower in patients with past history of suicide attempts (N = 8) than in those with a negative history. CONCLUSIONS: The results show major involvement of serotonergic function in BPD and are consistent with previous studies linking lower serotonergic activity with impulsivity. More particularly, our data suggest that BPD is characterized by lower 5-HT1A receptor sensitivity. Moreover, the data support the involvement of 5-HT1A activity in suicidal behaviour. However, this conclusion is limited because other hormonal responses such as ACTH and cortisol were not assessed, and because BPD was assessed by a self-report questionnaire and not a structured clinical interview.Peer reviewe