Effects of oxytocin on prosocial behavior and the associated profiles of oxytocinergic and corticotropin-releasing hormone receptors in a rodent model of posttraumatic stress disorder

Abstract

Background: Traumatic experience may lead to various psychological sequelae including the unforgettable trauma-associated memory as seen in posttraumatic stress disorder (PTSD), with a mechanism of impaired fear extinction due to biological imbalance among hypothalamic-pituitary-adrenal (HPA) axis and fear circuit areas such as medial prefrontal cortex (mPFC), hippocampus, and amygdala. Recently the impaired sociability seen in PTSD patients received great attention and the involvement of oxytocin (OXT) mediation is worth being investigated. This study examined whether the trauma-altered prosocial behavior can be modulated by OXT manipulation and its relationship with corticotropin-releasing hormone (CRH) signaling.

Methods: Male rats previously exposed to a single prolonged stress (SPS) were evaluated for their performance in social choice test (SCT) and novel object recognition test (NORT) following the introduction of intranasal oxytocin (OXT) and OXT receptor antagonist atosiban (ASB). OXT receptors (OXTR) and CRH receptors (CRHR1, CRHR2) were quantified in both protein and mRNA levels in medial prefrontal cortex (mPFC), hippocampus, and amygdala.

Results: SPS reduced inclination of rats staying at the sociable place with performing less prosocial contacts. OXT can amend the deficit but this effect was blocked by ASB. Expression of OXTR became reduced following SPS in mPFC and amygdala, the latter exhibited higher therapeutic specificity to OXT. Expression of CRHR1 appeared more sensitive than CRHR2 to SPS, higher CRHR1 protein levels were found in mPFC and amygdala.

Conclusion: Psychological trauma-impaired sociability is highly associated with OXT signaling pathway. Intranasal OXT restored both the SPS-impaired prosocial contacts and the SPS-reduced OXTR expressions in mPFC and amygdala. OXT may have therapeutic potential to treat PTSD patients with impaired social behaviors.

Keywords: Corticotropin-releasing hormone; Fear circuit areas; Oxytocin; Posttraumatic stress disorder, Prosocial behavior, Single prolonged stress..

Fig. 1

Flow chart of experimental procedures (a) and design of the social choice test (b). Arrowheads refer to the point of drug intervention, and drugs are also given during habituation periods. SPS: single prolonged stress; SCT: social choice test; NORT: novel object recognition test

Fig. 2

The staying Time of rats in the zone 1 (a), zone 2 (b), and zone 3 (c) of social choice test (SCT). SPS and drugs (OXT and ASB) did not affect the staying time in zone 1 (a). OXT reversed the SPS-increased of staying time in zone 2, but this could also be blocked by ASB (b). OXT reversed the SPS-induced decrease of staying time in zone 3, but this could be blocked by ASB (C). SPS = single prolonged stress, VEH = vehicle, OXT = oxytocin, ASB = atosiban. Bars represent mean ± SEM, **p < 0.01, ***p < 0.001, compared with Control-Veh; #p < 0.05, ##p < 0.01, compared with Control-OXT; ^@p < 0.05, ^@@p < 0.01, compared with SPS-OXT; ^&p < 0.05, compared with SPS-ASB/OXT. N = 6

Fig. 3

The social contacting time (a) and its percentage in zone 3 (b) of social choice test (SCT). OXT reversed SPS-induced attenuation of contact time with the restrained rat, but this could be blocked by ASB (A-B). SPS = single prolonged stress, VEH = vehicle, OXT = oxytocin, ASB = atosiban. Bars represent mean ± SEM, *p < 0.05, ***p < 0.001, compared with Control-Veh; #p < 0.05, ###p < 0.001, compared with Control-OXT; ^@p < 0.05, ^@@@p < 0.001, compared with SPS-OXT. N = 6

Fig. 4

The novel object recognition test (NORT). SPS and drugs (OXT and ASB) did not affect the time percentage for recognizing a novel object. SPS = single prolonged stress, VEH = vehicle, OXT = oxytocin, ASB = atosiban. Bars represent mean ± SEM. N = 6

Fig. 5

The OXTR mRNA levels and protein expressions in the mPFC, hippocampus, and amygdala. SPS reduced the OXT mRNA level in the mPFC, hippocampus, and amygdala, but only the mPFC OXTR mRNA level can be reversed by OXT administration (a-c). OXT reversed the SPS-decreased OXT protein expressions in the mPFC and amygdala, and these effects can be blocked by ASB (D, F). SPS and drugs (OXT and ASB) did not affect the hippocampus OXT protein expression (E). SPS = single prolonged stress, VEH = vehicle, OXT = oxytocin, ASB = atosiban, OXTR = oxytocin receptor. Bars represent mean ± SEM, *p < 0.05, **p < 0.01, ***p < 0.001, compared with Control-Veh; ##p < 0.01, ###p < 0.001, compared with Control-OXT; ^@p < 0.05, ^@@p < 0.01, ^@@@p < 0.001, compared with SPS-OXT. N = 5 for the mRNA levels (A-C); N = 4 for the protein expressions (d-f)

Fig. 6

The CRHR1 mRNA levels and protein expressions in the mPFC, hippocampus, and amygdala. OXT reversed the SPS-elevated the hippocampus CRHR1 mRNA level, but SPS and drugs (OXT and ASB) did not affect the CRHR1 mRNA level in mPFC and amygdala (a-c). SPS increased the CRHR1 protein expressions in the mPFC and amygdala, but only the mPFC CRHR1 protein expressions could reverse by OXT (d, f). SPS and drugs (OXT and ASB) did not affect the hippocampus CRHR1 protein expression (E). SPS = single prolonged stress, VEH = vehicle, OXT = oxytocin, ASB = atosiban, OXTR = oxytocin receptor. Bars represent mean ± SEM; *p < 0.05, **p < 0.01, compared with Control-Veh; ##p < 0.01, compared with Control-OXT; ^&&p < 0.01, compared with SPS-OXT. N = 5 for the mRNA levels (a-c); N = 4 for the protein expressions (d-f)

Fig. 7

The CRHR2 mRNA levels and protein expressions in the mPFC, hippocampus, and amygdala. OXT could decrease SPS-increased mPFC CRHR2 mRNA level, and this effect could be blocked by ASB (a). OXT and ASB reduced the hippocampus CRHR2 mRNA level in SPS rats (b). SPS and drugs (OXT and ASB) did not affect the CRHR2 mRNA level in amygdala (C). SPS and drugs (OXT and ASB) did not affec the CRHR2 protein expressions in the mPFC, hippocampus, and amygdala, excepting ASB reduced hippocampus CRHR2 expression (D-F). SPS = single prolonged stress, VEH = vehicle, OXT = oxytocin, ASB = atosiban, OXTR = oxytocin receptor. Bars represent mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.01, compared with Control-Veh; ##p < 0.01, ###p < 0.001, compared with Control-OXT. N = 5 for the mRNA levels (A-C); N = 4 for the protein expressions (d-f)