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
AU - Kaplan, Zeev
AU - Arnt, Jørn
N1 - Publisher Copyright:
© 2017 Elsevier B.V. and ECNP
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
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.
KW - Animal model
KW - Brexpiprazole
KW - Escitalopram
KW - Neuropeptide Y
KW - Posttraumatic stress disorder
UR - http://www.scopus.com/inward/record.url?scp=85039801438&partnerID=8YFLogxK
U2 - 10.1016/j.euroneuro.2017.11.017
DO - 10.1016/j.euroneuro.2017.11.017
M3 - Article
AN - SCOPUS:85039801438
VL - 28
SP - 63
EP - 74
JO - European Neuropsychopharmacology
JF - European Neuropsychopharmacology
SN - 0924-977X
IS - 1
ER -
