Targeting the Oxytocin System to Ameliorate Early Life Depressive-Like Behaviors in Maternally-Separated Rats

Abstract

Oxytocin (OXT) -"the love hormone"has been involved in the anti-depressant activity of some selective serotonin reuptake inhibitors (SSRIs). The exact mechanism underlying the OXT pathway in depression is not fully clear. This study aimed to investigate the effect of OXT analogue, carbetocin (CBT) and the SSRI, escitalopram (ESCIT) on depressive-like behaviors following maternal separation (MS). It is worthy to mention that intranasal CBT has been approved by FDA for Prader-Willi syndrome. Adolescent Wistar albino maternally-separated rats were given CBT, (100 μg/animal/day via inhalation route), and, ESCIT, (20 mg kg -1 , po) either alone or in combination for 7 days. Repeated 3-h MS demonstrated increased immobility time in forced swim test (FST) and decreased locomotor activity in open field test. MS elevated plasma level of adrenocortico-trophic hormone (ACTH) but notably reduced plasma OXT, with no effect on hippocampal OXT-R expression. Following MS, hippocampal contents of 5hydroxytryptamine receptors (5HT1A-R), serotonin transporter (SERT) were increased. CBT and ESCIT corrected the behavioral dysfunction in FST and suppressed the high levels of ACTH. Additionally, both treatments boosted OXT level, reduced 5HT1A-R and normalized SERT contents, which reflects increased availability of serotonin. Finally, CBT markedly ameliorated the histopathological damage induced by MS and suppressed the increased glial fibrillary acidic protein. CBT and ESCIT manage depressive-like behavior by positively affecting serotonergic and oxytocinergic systems. Targeting OXT system -using CBT-ameliorated depressive like behaviors induced by maternal separation most probably via enhancing OXT plasma levels, attenuating hormonal ACTH and restoring the expression of hippocampal oxytocin and serotonin mechanisms.

Early Life Stress Induces Different Behaviors in Adolescence and Adulthood May Related With Abnormal Medial Prefrontal Cortex Excitation/Inhibition Balance

“…In our MS model, rats exhibited anxiety-like behaviors in adolescence ( Figures 1B–E ), which is consistent with other studies that used the same animal model ( Banqueri et al, 2017 ; Auth et al, 2018 ). Studies have shown that MS results in an elevated stress response and depressive-like behavior in adolescent rats, which is consistent with our study ( Yang et al, 2016 ; Hu et al, 2017 ; Kim H. B. et al, 2020 ; Abdelwahab et al, 2021 ). Additionally, our results showed that MS rats exhibited depressive-like behavior in adulthood ( Figures 1F,G ), which confirmed the findings of previous studies showing that MS leads to depression in adulthood ( Arborelius et al, 2004 ; Vetulani, 2013 ; Masrour et al, 2018 ; Ruiz et al, 2018 ).…”

Retraction: Improved cognition impairment by activating cannabinoid receptor type 2: Modulating CREB/BDNF expression and impeding TLR-4/NFκBp65/M1 microglia signaling pathway in D-galactose-injected ovariectomized rats

“…� Panel B appears similar to Fig 5B in [2]. � Panel D appears similar to Fig 6E in [2] with the exception of an area in the center of the panels which appears different.…”

“…Owing to the concerns about similarities with previously published content [2], published in 2021 by The Pharmaceutical Society of Japan [2], which is not offered under a CC BY license, Figs 4C, 5B-5D, 5G-5H, 6D and 6K-6L are excluded from this article's [1] license. At the time of retraction, the article [1] was republished to note these exclusions in the legends of Figs 4-6 and the article's copyright statement.…”

Therapeutic uses of oxytocin in stress-related neuropsychiatric disorders

“…The regulation of serotonergic function and HPA axis may mediate the antidepressant mechanism of OXT. Increased the expression of 5-hydroxytryptamine receptors and serotonin transporter of hippocampus correlated with oxytocin levels in a MS induced animal model of depression [ 129 ]. But OXT exerted a synergistic function of antidepressant efficacy, such as increasing SSRI sensitivity by regulating Integrin β3 (ITGB3) and Close homolog of L1 protein (CHL1) in BDNF expression [ 130 ].…”