The serotonergic and alpha-1 adrenergic receptor modulator ACH-000029 ameliorates anxiety-like behavior in a post-traumatic stress disorder model

Azevedo, H., Ferreira, M., Mascarello, A., Osten, P., Werneck Guimaraes, C. R. (December 2019) The serotonergic and alpha-1 adrenergic receptor modulator ACH-000029 ameliorates anxiety-like behavior in a post-traumatic stress disorder model. Neuropharmacology, 164. p. 107912. ISSN 0028-3908

Abstract

Post-traumatic stress disorder (PTSD) is a severe chronic mental illness that develops in individuals exposed to life-threatening trauma and is characterized by hyperarousal, flashbacks and nightmares. The serotonergic (5-HT) and noradrenergic (NE) systems are deeply involved in the pathogenesis of PTSD. We have previously reported a novel anxiolytic compound, ACH-000029, that modulates 5-HT and alpha1-adrenergic receptors and induces acute anxiolytic-like effects in rodents. Here, we investigated the potential of ACH-000029 to prevent anxiety-like behavior in the single prolonged stress (SPS) PTSD model. Mice were subjected to the SPS procedure, followed by a 7-day treatment with ACH-000029 and, for comparison, with the alpha1-adrenergic antagonist prazosin. Animals were behaviorally assessed using social interaction, elevated plus maze and open field tests. Interestingly, treatment with ACH-000029 but not with prazosin ameliorated the SPS-induced sociability impairment and anxiety-like behavior. The brain-wide c-fos mapping, used as a surrogate for brain activity, indicated the brain structures that were altered by SPS and putatively involved in the anxiolytic-like effect of ACH-000029. The SPS protocol produced long-lasting impairment of regions involved in stress-anxiety response, such as the amygdala, prefrontal cortex, globus pallidus and superior colliculus. ACH-000029 treatment reversed the SPS-induced c-fos changes in the globus pallidus, lateral septum and entorhinal cortex and exclusively modulated c-fos levels in subregions from the retrosplenial cortex, cerebellum, superior colliculus and ventromedial hypothalamus. These results support the hypothesis that the dual regulation of 5-HT and alpha1-adrenergic receptors is required to alleviate PTSD symptoms and suggest a possible role of ACH-000029 as a PTSD treatment.

Item Type:	Paper
Subjects:	diseases & disorders > mental disorders > anxiety disorders bioinformatics diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > mental disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal organism description > animal behavior organism description > animal > mammal organism description > animal > mammal > rodent > mouse bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > norepinephrine bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > serotonin organism description > animal behavior > stress
CSHL Authors:	Osten, Pavel
Communities:	CSHL labs > Osten lab
Depositing User:	Adrian Gomez
Date:	13 December 2019
Date Deposited:	18 Dec 2019 19:04
Last Modified:	01 Feb 2024 20:13
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/38775

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