An alpha 5-GABA receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in rats exposed to valproic acid in utero / Ícaro Silva FREITAS ; Dishary SHARMIN ; James M. COOK ; Francisco S. GUIMARÃES ; Felipe V. GOMES in Autism Research, 17-8 (August 2024)  

Public ISBD [article]  inAutism Research > 17-8 (August 2024) . - p.1534-1544 Titre : An alpha 5-GABA receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in rats exposed to valproic acid in utero Type de document : texte imprimé Auteurs : Ícaro Silva FREITAS, Auteur ; Dishary SHARMIN, Auteur ; James M. COOK, Auteur ; Francisco S. GUIMARÃES, Auteur ; Felipe V. GOMES, Auteur Article en page(s) : p.1534-1544 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Abstract Autism spectrum disorders (ASDs) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of 5-containing GABAA receptors ( 5-GABAARs) SH-053-2 F-R-CH3 (10 mg/kg) attenuates behavioral abnormalities in rats exposed to valproic acid (VPA) in utero, an established risk factor for autism. We also evaluated if animals exposed to VPA in utero present changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH-053-2 F-R-CH3 could attenuate these changes. SH-053-2 F-R-CH3 was administered intraperitoneally 30 min before each behavioral test and electrophysiology. In utero VPA exposure caused male and female rats to present increased repetitive behavior (self-grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH-053-2 F-R-CH3 attenuated the impairments in sociability and cognitive function in male VPA-exposed rats without attenuating the decreased social interaction in females. Adult male and female VPA-exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH-053-2 F-R-CH3. Despite sex differences, our findings indicate that 5-GABAARs positive allosteric modulators may effectively attenuate some core ASD symptoms. En ligne : https://doi.org/10.1002/aur.3178 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=533 [article] An alpha 5-GABA receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in rats exposed to valproic acid in utero [texte imprimé] / Ícaro Silva FREITAS, Auteur ; Dishary SHARMIN, Auteur ; James M. COOK, Auteur ; Francisco S. GUIMARÃES, Auteur ; Felipe V. GOMES, Auteur . - p.1534-1544. Langues : Anglais (eng) in Autism Research > 17-8 (August 2024) . - p.1534-1544 Index. décimale : PER Périodiques Résumé : Abstract Autism spectrum disorders (ASDs) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of 5-containing GABAA receptors ( 5-GABAARs) SH-053-2 F-R-CH3 (10 mg/kg) attenuates behavioral abnormalities in rats exposed to valproic acid (VPA) in utero, an established risk factor for autism. We also evaluated if animals exposed to VPA in utero present changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH-053-2 F-R-CH3 could attenuate these changes. SH-053-2 F-R-CH3 was administered intraperitoneally 30 min before each behavioral test and electrophysiology. In utero VPA exposure caused male and female rats to present increased repetitive behavior (self-grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH-053-2 F-R-CH3 attenuated the impairments in sociability and cognitive function in male VPA-exposed rats without attenuating the decreased social interaction in females. Adult male and female VPA-exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH-053-2 F-R-CH3. Despite sex differences, our findings indicate that 5-GABAARs positive allosteric modulators may effectively attenuate some core ASD symptoms. En ligne : https://doi.org/10.1002/aur.3178 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=533

Comparative Analysis of Cannabidiol and Risperidone on Behavioral and Neurochemical Outcomes, and Neurodevelopment Markers in a Zebrafish Model of Embryonic Exposure to Sodium Valproate / Karla C.M. COSTA in Autism Research, 18-12 (December 2025)  

Public ISBD [article]  inAutism Research > 18-12 (December 2025) . - p.2368-2381 Titre : Comparative Analysis of Cannabidiol and Risperidone on Behavioral and Neurochemical Outcomes, and Neurodevelopment Markers in a Zebrafish Model of Embryonic Exposure to Sodium Valproate Type de document : texte imprimé Auteurs : Karla C.M. COSTA, Auteur ; Tamires A.V. BRIGANTE, Auteur ; Pedro H. C. LIRIO, Auteur ; Gabriel G. FERNANDES, Auteur ; Franciele F. SCARANTE, Auteur ; Davi S. SCOMPARIN, Auteur ; Rafael R. FERREIRA, Auteur ; Maria A. VICENTE, Auteur ; Flavia R. ABE, Auteur ; Francisco S. GUIMARÃES, Auteur ; Jaime E. C. HALLAK, Auteur ; Jose A. CRIPPA, Auteur ; Danielle P. DE OLIVEIRA, Auteur ; Alline C. CAMPOS, Auteur Article en page(s) : p.2368-2381 Langues : Anglais (eng) Mots-clés : autism spectrum disorder  cannabidiol  endocannabinoids  lipid peroxidation  risperidone  zebrafish Index. décimale : PER Périodiques Résumé : ABSTRACT Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication deficits, repetitive behaviors, and sensory abnormalities. Sodium valproate (VPA) exposure during embryonic development is a well-established preclinical model for ASD, leading to increased oxidative stress in the developing brain, including lipid peroxidation, which affects cell proliferation and organization. This study aimed to investigate the potential therapeutic effects of cannabidiol (CBD) and risperidone (RISP) in reversing ASD-like behaviors and associated neurobiological alterations induced by embryonic VPA exposure in a zebrafish model. Zebrafish embryos were exposed to 125??M VPA for 2?days post-fertilization (dpf). At 3?4?dpf, embryos were treated with 0.06??M CBD or 1??M RISP. Behavioral assays were conducted to assess hyperlocomotion and aggressive behavior. At 7?dpf, lipid peroxidation levels were measured, and expression of glial fibrillary acidic protein (GFAP) and calcium/calmodulin (CaM) were analyzed to evaluate neurobiological changes. VPA exposure resulted in increased hyperlocomotion and aggression. CBD treatment effectively reversed these behaviors, while RISP showed limited efficacy. Additionally, CBD reduced lipid peroxidation and restored anandamide levels, whereas RISP did not exhibit these effects. CBD also normalized GFAP and CaM expression, indicating restoration of glial function and excitatory/inhibitory balance. CBD demonstrated a better efficacy and safety profile compared to RISP in reversing ASD-like behaviors and associated neurobiological alterations in the zebrafish model. These findings suggest that CBD may offer a safer and more effective therapeutic alternative for managing ASD-related symptoms. En ligne : https://doi.org/10.1002/aur.70151 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=578 [article] Comparative Analysis of Cannabidiol and Risperidone on Behavioral and Neurochemical Outcomes, and Neurodevelopment Markers in a Zebrafish Model of Embryonic Exposure to Sodium Valproate [texte imprimé] / Karla C.M. COSTA, Auteur ; Tamires A.V. BRIGANTE, Auteur ; Pedro H. C. LIRIO, Auteur ; Gabriel G. FERNANDES, Auteur ; Franciele F. SCARANTE, Auteur ; Davi S. SCOMPARIN, Auteur ; Rafael R. FERREIRA, Auteur ; Maria A. VICENTE, Auteur ; Flavia R. ABE, Auteur ; Francisco S. GUIMARÃES, Auteur ; Jaime E. C. HALLAK, Auteur ; Jose A. CRIPPA, Auteur ; Danielle P. DE OLIVEIRA, Auteur ; Alline C. CAMPOS, Auteur . - p.2368-2381. Langues : Anglais (eng) in Autism Research > 18-12 (December 2025) . - p.2368-2381 Mots-clés : autism spectrum disorder  cannabidiol  endocannabinoids  lipid peroxidation  risperidone  zebrafish Index. décimale : PER Périodiques Résumé : ABSTRACT Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication deficits, repetitive behaviors, and sensory abnormalities. Sodium valproate (VPA) exposure during embryonic development is a well-established preclinical model for ASD, leading to increased oxidative stress in the developing brain, including lipid peroxidation, which affects cell proliferation and organization. This study aimed to investigate the potential therapeutic effects of cannabidiol (CBD) and risperidone (RISP) in reversing ASD-like behaviors and associated neurobiological alterations induced by embryonic VPA exposure in a zebrafish model. Zebrafish embryos were exposed to 125??M VPA for 2?days post-fertilization (dpf). At 3?4?dpf, embryos were treated with 0.06??M CBD or 1??M RISP. Behavioral assays were conducted to assess hyperlocomotion and aggressive behavior. At 7?dpf, lipid peroxidation levels were measured, and expression of glial fibrillary acidic protein (GFAP) and calcium/calmodulin (CaM) were analyzed to evaluate neurobiological changes. VPA exposure resulted in increased hyperlocomotion and aggression. CBD treatment effectively reversed these behaviors, while RISP showed limited efficacy. Additionally, CBD reduced lipid peroxidation and restored anandamide levels, whereas RISP did not exhibit these effects. CBD also normalized GFAP and CaM expression, indicating restoration of glial function and excitatory/inhibitory balance. CBD demonstrated a better efficacy and safety profile compared to RISP in reversing ASD-like behaviors and associated neurobiological alterations in the zebrafish model. These findings suggest that CBD may offer a safer and more effective therapeutic alternative for managing ASD-related symptoms. En ligne : https://doi.org/10.1002/aur.70151 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=578

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