Adjunctive treatment with brexpiprazole and escitalopram reduces behavioral stress responses and increase hypothalamic NPY immunoreactivity in a rat model of PTSD-like symptoms

Hagit Cohen; Joseph Zohar; Zeev Kaplan; Jørn Arnt

doi:10.1016/j.euroneuro.2017.11.017

Adjunctive treatment with brexpiprazole and escitalopram reduces behavioral stress responses and increase hypothalamic NPY immunoreactivity in a rat model of PTSD-like symptoms

Hagit Cohen, Joseph Zohar, Zeev Kaplan, Jørn Arnt

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

The study explored effects of brexpiprazole (partial D₂/5-HT_1A agonist, 5-HT_2A and α_1B/2C-adrenoceptor antagonist) in rats exposed to predator scent stress (PSS), a proposed model of PTSD-like phenotype. Brexpiprazole (3.0 mg/kg, PO), escitalopram (5.0 mg/kg, IP) and their combination were administered twice daily for 14 days, starting 14 days after exposure to PSS or sham-PSS, shortly after a situational stress reminder. One day after last treatment behavioral responsivity was assessed. Brexpiprazole+escitalopram-treated rats spent more time in open arms, entered open arms more often and exhibited a lower anxiety index in the elevated plus maze than vehicle-treated, PSS-exposed rats. Adjunct brexpiprazole+escitalopram treatment reduced startle amplitude, compared with vehicle-treated, PSS-exposed rats. Treatment with either drug alone did not attenuate anxiety-like behaviors following PSS exposure. Use of cut-off behavioral criteria confirmed that adjunct treatment shifted prevalence of PSS-exposed rats from extreme towards minimal behavioral responders. One day following behavioral tests, brains were prepared for immunohistochemical analysis of number of BDNF-positive cells and of NPY-positive cells/fibers. PSS exposure decreased BDNF levels in hippocampus, but this was not affected by drug treatments. PSS exposure decreased number of NPY positive cells/fibers in paraventricular and arcuate nuclei of hypothalamus. Adjunct treatment with brexpiprazole+escitalopram increased NPY in PSS- and sham-exposed rats. Treatment with brexpiprazole alone had no effects, while treatment with escitalopram alone increased NPY in the arcuate nucleus of PSS-exposed rats. In conclusion, treatment with brexpiprazole+escitalopram may be an effective intervention for the attenuation of PTSD-like stress responses, which in part may be mediated by activating NPY function.

Original language	English
Pages (from-to)	63-74
Number of pages	12
Journal	European Neuropsychopharmacology
Volume	28
Issue number	1
DOIs	https://doi.org/10.1016/j.euroneuro.2017.11.017
State	Published - 1 Jan 2018

Keywords

Animal model
Brexpiprazole
Escitalopram
Neuropeptide Y
Posttraumatic stress disorder

ASJC Scopus subject areas

Pharmacology
Neurology
Clinical Neurology
Psychiatry and Mental health
Biological Psychiatry
Pharmacology (medical)

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10.1016/j.euroneuro.2017.11.017

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title = "Adjunctive treatment with brexpiprazole and escitalopram reduces behavioral stress responses and increase hypothalamic NPY immunoreactivity in a rat model of PTSD-like symptoms",

abstract = "The study explored effects of brexpiprazole (partial D2/5-HT1A agonist, 5-HT2A and α1B/2C-adrenoceptor antagonist) in rats exposed to predator scent stress (PSS), a proposed model of PTSD-like phenotype. Brexpiprazole (3.0 mg/kg, PO), escitalopram (5.0 mg/kg, IP) and their combination were administered twice daily for 14 days, starting 14 days after exposure to PSS or sham-PSS, shortly after a situational stress reminder. One day after last treatment behavioral responsivity was assessed. Brexpiprazole+escitalopram-treated rats spent more time in open arms, entered open arms more often and exhibited a lower anxiety index in the elevated plus maze than vehicle-treated, PSS-exposed rats. Adjunct brexpiprazole+escitalopram treatment reduced startle amplitude, compared with vehicle-treated, PSS-exposed rats. Treatment with either drug alone did not attenuate anxiety-like behaviors following PSS exposure. Use of cut-off behavioral criteria confirmed that adjunct treatment shifted prevalence of PSS-exposed rats from extreme towards minimal behavioral responders. One day following behavioral tests, brains were prepared for immunohistochemical analysis of number of BDNF-positive cells and of NPY-positive cells/fibers. PSS exposure decreased BDNF levels in hippocampus, but this was not affected by drug treatments. PSS exposure decreased number of NPY positive cells/fibers in paraventricular and arcuate nuclei of hypothalamus. Adjunct treatment with brexpiprazole+escitalopram increased NPY in PSS- and sham-exposed rats. Treatment with brexpiprazole alone had no effects, while treatment with escitalopram alone increased NPY in the arcuate nucleus of PSS-exposed rats. In conclusion, treatment with brexpiprazole+escitalopram may be an effective intervention for the attenuation of PTSD-like stress responses, which in part may be mediated by activating NPY function.",

keywords = "Animal model, Brexpiprazole, Escitalopram, Neuropeptide Y, Posttraumatic stress disorder",

author = "Hagit Cohen and Joseph Zohar and Zeev Kaplan and J{\o}rn Arnt",

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Adjunctive treatment with brexpiprazole and escitalopram reduces behavioral stress responses and increase hypothalamic NPY immunoreactivity in a rat model of PTSD-like symptoms. / Cohen, Hagit; Zohar, Joseph; Kaplan, Zeev et al.
In: European Neuropsychopharmacology, Vol. 28, No. 1, 01.01.2018, p. 63-74.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Adjunctive treatment with brexpiprazole and escitalopram reduces behavioral stress responses and increase hypothalamic NPY immunoreactivity in a rat model of PTSD-like symptoms

AU - Cohen, Hagit

AU - Zohar, Joseph

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AU - Arnt, Jørn

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AB - The study explored effects of brexpiprazole (partial D2/5-HT1A agonist, 5-HT2A and α1B/2C-adrenoceptor antagonist) in rats exposed to predator scent stress (PSS), a proposed model of PTSD-like phenotype. Brexpiprazole (3.0 mg/kg, PO), escitalopram (5.0 mg/kg, IP) and their combination were administered twice daily for 14 days, starting 14 days after exposure to PSS or sham-PSS, shortly after a situational stress reminder. One day after last treatment behavioral responsivity was assessed. Brexpiprazole+escitalopram-treated rats spent more time in open arms, entered open arms more often and exhibited a lower anxiety index in the elevated plus maze than vehicle-treated, PSS-exposed rats. Adjunct brexpiprazole+escitalopram treatment reduced startle amplitude, compared with vehicle-treated, PSS-exposed rats. Treatment with either drug alone did not attenuate anxiety-like behaviors following PSS exposure. Use of cut-off behavioral criteria confirmed that adjunct treatment shifted prevalence of PSS-exposed rats from extreme towards minimal behavioral responders. One day following behavioral tests, brains were prepared for immunohistochemical analysis of number of BDNF-positive cells and of NPY-positive cells/fibers. PSS exposure decreased BDNF levels in hippocampus, but this was not affected by drug treatments. PSS exposure decreased number of NPY positive cells/fibers in paraventricular and arcuate nuclei of hypothalamus. Adjunct treatment with brexpiprazole+escitalopram increased NPY in PSS- and sham-exposed rats. Treatment with brexpiprazole alone had no effects, while treatment with escitalopram alone increased NPY in the arcuate nucleus of PSS-exposed rats. In conclusion, treatment with brexpiprazole+escitalopram may be an effective intervention for the attenuation of PTSD-like stress responses, which in part may be mediated by activating NPY function.

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Adjunctive treatment with brexpiprazole and escitalopram reduces behavioral stress responses and increase hypothalamic NPY immunoreactivity in a rat model of PTSD-like symptoms

Abstract

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