Implication of 5-HT2 receptor subtypes in the mechanism of action of the GABAergic compound etifoxine in the four-plate test in Swiss mice

Bourin, Michel; Hascoët, Martine

doi:10.1016/j.bbr.2009.11.046

Cited by 11 publications

(9 citation statements)

References 38 publications

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“…In addition co-administration of the 5-HT 2A receptor agonist DOI together with a subthreshold dose of etifoxine induced an anti-punishment effect as well. Together these data indicate that the effect of etifoxine was modulated by 5-HT 2A ligands and that GABA and 5-HT can be co-released and act as co-transmitters in some regions of the central nervous system (CNS; Bourin and Hascoet, 2010). Several studies have suggested that 5-HT 2A receptors modulate learning and memory (Meneses, 2007a, b).…”

Section: Preclinical Genetic Approaches To Anxietymentioning

confidence: 84%

“…Furthermore, etifoxine, a GABA A receptor potentiator, dose-dependently increased the number of punished crossing in a four-plate test in mice (decreased anxiety). Interestingly this anti-punishment effect was blocked when a 5-HT 2A antagonist was administered (Bourin and Hascoet, 2010). In addition co-administration of the 5-HT 2A receptor agonist DOI together with a subthreshold dose of etifoxine induced an anti-punishment effect as well.…”

Section: Preclinical Genetic Approaches To Anxietymentioning

confidence: 99%

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The role of the serotonergic and GABA system in translational approaches in drug discovery for anxiety disorders

2013

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There is ample evidence that genetic factors play an important role in anxiety disorders. In support, human genome-wide association studies have implicated several novel candidate genes. However, illumination of such genetic factors involved in anxiety disorders has not resulted in novel drugs over the past decades. A complicating factor is the heterogeneous classification of anxiety disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) and diverging operationalization of anxiety used in preclinical and clinical studies. Currently, there is an increasing focus on the gene × environment (G × E) interaction in anxiety as genes do not operate in isolation and environmental factors have been found to significantly contribute to the development of anxiety disorders in at-risk individuals. Nevertheless, extensive research on G × E mechanisms in anxiety has not resulted in major breakthroughs in drug discovery. Modification of individual genes in rodent models has enabled the specific study of anxiety in preclinical studies. In this context, two extensively studied neurotransmitters involved in anxiety are the gamma-aminobutyric acid (GABA) and 5-HT (5-hydroxytryptamine) system. In this review, we illustrate the complex interplay between genes and environment in anxiety processes by reviewing preclinical and clinical studies on the serotonin transporter (5-HTT), 5-HT1A receptor, 5-HT2 receptor, and GABAA receptor. Even though targets from the serotonin and GABA system have yielded drugs with known anxiolytic efficacy, the relation between the genetic background of these targets and anxiety symptoms and development of anxiety disorders is largely unknown. The aim of this review is to show the vast complexity of genetic and environmental factors in anxiety disorders. In light of the difficulty with which common genetic variants are identified in anxiety disorders, animal models with translational validity may aid in elucidating the neurobiological background of these genes and their possible role in anxiety. We argue that, in addition to human genetic studies, translational models are essential to map anxiety-related genes and to enhance our understanding of anxiety disorders in order to develop potentially novel treatment strategies.

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Section: Preclinical Genetic Approaches To Anxietymentioning

confidence: 84%

Section: Preclinical Genetic Approaches To Anxietymentioning

confidence: 99%

The role of the serotonergic and GABA system in translational approaches in drug discovery for anxiety disorders

2013

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“…Despite the results of clinical studies, there is controversial evidence in the literature about the impact of etifoxine on spontaneous locomotor activity in animals (Schlichter et al 2000;Girard еt al. 2009;Verleye et al 2009;Bourin and Hascoët 2010). In our previous experiments (Zagorchev et al 2018) we reported a decrease of the direct single twitch response in isolated rat nerve-skeletal muscle preparations induced by etifoxine.…”

Section: Introductionmentioning

confidence: 93%

Etifoxine does not impair muscle tone and motor function in rats as assessed by in vivo and in vitro methods

Kokova¹,

Zagorchev²,

Apostolova³

et al. 2020

gpb

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The purpose of our study is to evaluate the effects of the translocator protein (TSPO) ligand etifoxine on muscle tone and locomotor activity. In addition, the mechanism of action of etifoxine on the presynaptic membrane and neuromuscular junction is investigated. These effects of etifoxine were examined employing the following methods: 1) in vivo experiments using bar holding test and activity cage test, and 2) comparative in vitro studies with nifedipine on indirectly-elicited twitches of striated abdominal muscle preparations. Etifoxine in doses 50 mg/kg and 100 mg/kg i.p. does not produce any significant changes in locomotor activity and muscle tone of intact rats. Nifedipine (10-5 М) induces a significant decrease in the muscle force of striated muscle preparations. Etifoxine (10-8-10-4 М) has no significant effect on indirectly-elicited twitch tension. Results show that the TSPO ligand etifoxine has no myorelaxant effect. The activation of TSPO is not associated with a reduction in muscle tone and motor impairment. Etifoxine does not affect the presynaptic membrane and its influence on L-type Ca 2+-channels is insignificant. Etifoxine does not act as a competitive antagonist of acetylcholine and does not impair the impulse transmission in the neuromuscular junction.

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“…Given the numerous interactions between these two neurotransmission systems, it is relevant to investigate possible interactions between etifoxine and serotonergic receptor ligands. Bourin et al, demonstrated in a mouse model of anxiety that the anxiolytic effect of etifoxine is modulated by the co-administration of 5-HT 2A ligands 46. A serotonergic mechanism is thus involved in the anxiolytic effect of etifoxine.…”

Section: Interactions Of Etifoxine With the Gabaa Receptormentioning

confidence: 99%

<p>An update on the anxiolytic and neuroprotective properties of etifoxine: from brain GABA modulation to a whole-body mode of action</p>

Nuss¹,

Ferreri²,

Bourin³

2019

NDT

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Treating the signs and symptoms of anxiety is an everyday challenge in clinical practice. When choosing between treatment options, anxiety needs to be understood in the situational, psychiatric, and biological context in which it arises. Etifoxine, a non-benzodiazepine anxiolytic drug belonging to the benzoxazine class, is an effective treatment for anxiety in response to a stressful situation. In the present review, we focused on several aspects of the cerebral and somatic biological mechanisms involved in anxiety and investigated the extent to which etifoxine’s mode of action can explain its anxiolytic activity. Its two mechanisms of action are the modulation of GABAergic neurotransmission and neurosteroid synthesis. Recent data suggest that the molecule possesses neuroprotective, neuroplastic, and anti-inflammatory properties. Etifoxine was first shown to be an effective anxiolytic in patients in clinical studies comparing it with clobazam, sulpiride, and placebo. Randomized controlled studies have demonstrated its anxiolytic efficacy in patients with adjustment disorders (ADs) with anxiety, showing it to be superior to buspirone and comparable to lorazepam and phenazepam, with a greater number of markedly improved responders and a better therapeutic index. Etifoxine’s noninferiority to alprazolam has also been demonstrated in a comparative trial. Significantly less rebound anxiety was observed after abrupt cessation of etifoxine compared with lorazepam or alprazolam. Consistent with this finding, etifoxine appears to have a very low dependence potential. Unlike lorazepam, it has no effect on psychomotor performance, vigilance, or free recall. Severe adverse events are in general rare. Skin and subcutaneous disorders are the most frequently reported, but these generally resolve after drug cessation. Taken together, its dual mechanisms of action in anxiety and the positive data yielded by clinical trials support the use of etifoxine for treating the anxiety signs and symptoms of individuals with ADs.

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Implication of 5-HT2 receptor subtypes in the mechanism of action of the GABAergic compound etifoxine in the four-plate test in Swiss mice

Cited by 11 publications

References 38 publications

The role of the serotonergic and GABA system in translational approaches in drug discovery for anxiety disorders

The role of the serotonergic and GABA system in translational approaches in drug discovery for anxiety disorders

Etifoxine does not impair muscle tone and motor function in rats as assessed by in vivo and in vitro methods

<p>An update on the anxiolytic and neuroprotective properties of etifoxine: from brain GABA modulation to a whole-body mode of action</p>

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