The serotonergic and alpha-1 adrenergic receptor modulator ACH-000029 ameliorates anxiety-like behavior in a post-traumatic stress disorder model. (1st March 2020)

• Record Type: Journal Article
• Authors: Azevedo, Hatylas; Ferreira, Marcos; Mascarello, Alessandra; Osten, Pavel; Werneck Guimarães, Cristiano Ruch
• Is Part Of: Neuropharmacology. Volume 164(2020)
• Publication Date: 2020-03-01
• Subjects: Post-traumatic stress disorder -- Noradrenaline -- Serotonin -- Single prolonged stress -- ACH-000029 -- C-fos mapping; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2019.107912
• Languages: English
• ISSNs: 0028-3908

Abstract

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 α1-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 α1-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 α1-adrenergic receptors is required to alleviate PTSD symptoms and suggest a possible role of ACH-000029 as a PTSD treatment. Highlights: ACH-000029 reduced anxiety-like behavior in the single-prolonged stress (SPS) model. ACH-000029 reversed sociability impairment induced by the SPS protocol. ACH-000029 regulated SPS-induced c-fos levels in brain areas involved in anxiety response. The dual modulation of 5-HT and α1-adrenergic receptors may alleviate PTSD symptoms.