Anxiolytique | EPFL Graph Search

Les anxiolytiques () sont des médicaments utilisés contre l'anxiété. Différentes molécules et différentes substances naturelles ou artificielles ont des effets anxiolytiques. Plusieurs catégories de médicaments, comme les benzodiazépines, ou de substances psychotropes, comme le GHB et ses précurseurs, sont utilisées pour leurs effets anxiolytiques. Il existe différentes classes de molécules anxiolytiques (voir classement ATC des anxiolytiques) : Agonistes GABA Les agonistes GABA sont les anxiolytiques les plus utilisés. Ils présentent un risque d'accoutumance et de mésusage à des fins de toxicomanie. Ils font l'objet d'un contrôle strict et sont délivrés uniquement sur ordonnance. Du fait de ces inconvénients, d'autres types de médication (antihistaminiques, antidépresseurs, neuroleptiques) sont souvent prescrits par les psychiatres pour le traitement sur le long terme des troubles anxieux. Les benzodiazépines sont la classe d'anxiolytiques agoniste GABA apparus sur le

The impact of anxiety and reward-seeking traits on social competition and the role of the mesolimbic dopaminergic system

Laura Lozano Montes

Social hierarchies are established across a range of different taxa in the animal kingdom. Given that hierarchy inequalities are highly present in nowadays society and the health problems that low rank individuals suffer from this, it is surprising that not much is known about the underlying neurobiological mechanisms that predispose an individual to become dominant or submissive. We aimed to have a better understanding of personality-related factors (such as anxiety and reward-seeking behaviors) and underlying brain mechanisms that predispose rats to become dominant. We aimed to study the neurobiological mechanisms involved in the modulation of dominance by anxiety. Peripheral injection of anxiolytic drugs has been shown to modulate the dopaminergic mesolimbic system by acting in the GABAergic neurons on the ventral tegmental area (VTA). Our studies specifically targeted GABAergic receptors within the VTA modulating both anxiety and dominance. However, the activation of GABAergic receptors in the nucleus accumbens (NAc) affected dominance but had no effect on anxiety. Furthermore, we found that the NAc is required for the effects of the anxiolytic diazepam on the establishment of social dominance. We assessed potential differences on the accumbal dopaminergic system in relation to anxiety. To this end, we assessed catecholamines levels by high performance liquid chromatography (HPLC) and confirmed the existence of differences in accumbal dopamine content between high and low anxious rats. Subsequently, we showed that pharmacological activation of D1 receptors within the NAc enhanced social dominance. In addition, activation of GABAergic receptors in the VTA, in addition to enhancing social dominance, enhanced the accumbal dopaminergic system. These findings lead us to hypothesize a critical role on the observed behavioral effects for the firing of the VTA dopaminergic neurons that project to the NAc. Subsequently, we investigated the consequences of phasically activating VTA dopaminergic neurons projecting to the NAc in a social competition test. To specifically modulate firing properties of dopaminergic neurons within the VTA of behaving animals, we performed optogenetic activation in TH::Cre rats infused with Cre-dependent virus expressing channelrhodopsin-2 (ChR2). Our results showed that phasic activation of the VTA dopaminergic neurons during the social competition test for palatable rewards was not sufficient to modify the output of the encounters. Winners of the social competition tests were found to have a trend for higher reward-seeking phenotype (lower latencies to get rewards on their last day of individual training) which leads us to subsequently study the role of reward-seeking trait on the rank attained in a social hierarchy. Our data indicates a role for reward-seeking behaviors during last day of individual training (on social competition for palatable rewards test) on the output of several social competition tests. Interestingly, the combination of phasic optical activation of VTA dopaminergic neurons during the last two days of training and during social competition increased dominance. Altogether, our studies have elucidated the effects of anxiety and reward-seeking traits on rat's hierarchy establishment. Furthermore, we were able to modulate the output of a social competition test by optical activations of the mesolimbic dopaminergic system.

EPFL2015

Image-Based Marker-Free Screening of GABA(A) Agonists, Antagonists, and Modulators

Damiano Banfi, Pascal Jourdain, Fabien Kuttler, Pierre Marquet, Benjamin Rappaz, Gerardo Turcatti

The ionotropic GABA(A) receptors represent the main target for different groups of widely used drugs having hypnotic and anxiolytic effects. So far, most approaches used to assess GABA activity involve invasive low -throughput electrophysiological techniques or rely on fluorescent dyes, preventing the ability to conduct noninvasive and thus nonperturbing screens. To address this limitation, we have developed an automated marker-free cell imaging method, based on digital holographic microscopy (DHM). This technology allows the automatically screening of compounds in multiple plates without having to label the cells or use special plates. This methodological approach was first validated by screening the GABA(A) receptor expressed in HEK cells using a selection of active compounds in agonist, antagonist, and modulator modes. Then, in a second blind screen of a library of 3041 compounds (mostly composed of natural products), 5 compounds having a specific agonist action on the GABA(A) receptor were identified. The hits validated from this unbiased screen were the natural products muscimol, neurosteroid alphaxalone, and three compounds belonging to the avermectin family, all known for having an agonistic effect on the GABA(A) receptor. The results obtained were exempt from false negatives (structurally similar unassigned hits), and false-positive hits were detected and discarded without the need for performing electrophysiological measurements. The outcome of the screen demonstrates the applicability of our screening by imaging method for the discovery of new chemical structures, particularly regarding chemicals interacting with the ionotropic GABA(A) receptor and more generally with any ligand-gated ion channels and transporters.

2019

Medium chain triglyceride diet reduces anxiety-like behaviors and enhances social competitiveness in rats

Carlos Canto Alvarez, Fiona Hollis, Maria del Carmen Sandi Perez

Medium-chain triglycerides (MCT) are emerging as unique dietary supplements that are potentially relevant for the amelioration of brain dysfunctions. MCT are converted into ketones and free medium chain fatty acids that, in the brain, are highly effective energy sources to mitochondria and potentially less harmful than glucose metabolism to neurons. Given the recently established link between mitochondrial dysfunction and high anxiety and depression, we performed this study to investigate the effectiveness of an MCT-enriched diet to ameliorate anxiety- and depression-related behaviors in rats. Male rats were distributed into groups, according to their anxiety-like behaviors in the elevated plus maze. Each group was given either MCT-supplemented diet or an isocaloric control diet for fifteen days. Starting from the eighth day of diet, rats were exposed to different behavioral tests. MCT-fed rats exhibited reduced anxiety-like behaviors and enhanced social competitiveness, while their coping responses in the forced swim test were not affected by the treatment. When evaluated at the end of the two-week MCT diet, mitochondrial respiration was reduced in the medial prefrontal cortex (mPFC) while unchanged in the nucleus accumbens. In the mPFC, enzymes related to glycolysis and oxidative phosphorylation were also decreased by MCT diet, while proteins controlling glucose and glutamate transport were increased. Altogether, our findings strongly suggest the effectiveness of MCT diet to exert anxiolytic effects. In the brain, our results point to the mPFC as a brain region in which MCT supplementation improves transport and control of energy substrates.

2018

The impact of anxiety and reward-seeking traits on social competition and the role of the mesolimbic dopaminergic system

Laura Lozano Montes

EPFL2015