Abstract
Posttraumatic stress disorder (PTSD) is a trauma-induced mental disorder characterized by fear extinction abnormalities, which involve biological dysfunctions among fear circuit areas in the brain. Oxytocin (OXT) is a neuropeptide that regulates sexual reproduction and social interaction and has recently earned specific attention due to its role in adjusting neurobiological and behavioral correlates of PTSD; however, the mechanism by which this is achieved remains unclear. The present study aimed to examine whether the effects of OXT on traumatic stress-induced abnormalities of fear extinction (specifically induced by single prolonged stress (SPS), an animal model of PTSD) are associated with pro-inflammatory cytokines. Seven days after SPS, rats received intranasal OXT 40 min before a cue-dependent Pavlovian fear conditioning-extinction test in which rats’ freezing degree was used to reflect the outcome of fear extinction. We also measured mRNA expression of IL-1β, IFN-γ, and TNF-α in the medial prefrontal cortex (mPFC), hippocampus, and amygdala at the end of the study, together with plasma oxytocin, corticosterone, IL-1β, IFN-γ, and TNF-α, to reflect the central and peripheral changes of stress-related hormones and cytokines after SPS. Our results suggested that intranasal OXT effectively amends the SPS-impaired behavior of fear extinction retrieval. Moreover, it neurochemically reverses the SPS increase in pro-inflammatory cytokines; thus, IL-1β and IFN-γ can be further blocked by the OXT antagonist atosiban (ASB) in the hippocampus. Peripheral profiles revealed a similar response pattern to SPS of OXT and corticosterone (CORT), and the SPS-induced increase in plasma levels of IL-1β and TNF-α could be reduced by OXT. The present study suggests potential therapeutic effects of OXT in both behavioral and neuroinflammatory profiles of PTSD.
Highlights
Posttraumatic stress disorder (PTSD) is a mental disorder characterized by fear memory abnormalities in individuals who have previously experienced a traumatic event [1,2]
The underlying mechanism of PTSD remains unsolved, yet it should primarily involve the excessive feedback of the hypothalamus (HT)–pituitary–adrenal (HPA) axis [1,7] as well as a biological imbalance among the fear circuit areas in the brain, namely the medial prefrontal cortex, hippocampus, and amygdala [7,8,9]
A human image study suggested that this is possibly because oxytocin modulates impairments associated with cognitive deficits in domains such as working memory and executive control—which are functions executed via the prefrontal cortex, the impairment of which is highly prevalent among individuals with PTSD [13]
Summary
Posttraumatic stress disorder (PTSD) is a mental disorder characterized by fear memory abnormalities in individuals who have previously experienced a traumatic event [1,2]. The underlying mechanism of PTSD remains unsolved, yet it should primarily involve the excessive feedback of the hypothalamus (HT)–pituitary–adrenal (HPA) axis [1,7] as well as a biological imbalance among the fear circuit areas in the brain, namely the medial prefrontal cortex (mPFC), hippocampus, and amygdala [7,8,9]. With such complicated pathological attributes, treatment of PTSD is difficult and truly effective treatments have not yet been reported [10]. Oxytocin may exert some effects on PTSD-associated behaviors in connection with abnormalities of fear circuit areas, yet the underlying mechanism by which this is achieved remains unclear
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