Sex-Related Predisposition to Post-Traumatic Stress Disorder Development-The Role of Neuropeptides

Abstract

Post-traumatic stress disorder (PTSD) is characterized by re-experiencing a traumatic event, avoidance, negative alterations in cognitions and mood, hyperarousal, and severe functional impairment. Women have a two times higher risk of developing PTSD than men. The neurobiological basis for the sex-specific predisposition to PTSD might be related to differences in the functions of stress-responsive systems due to the interaction between gonadal hormones and stress peptides such as corticotropin-releasing factor (CRF), orexin, oxytocin, and neuropeptide Y. Additionally, in phases where estrogens levels are low, the risk of developing or exacerbating PTSD is higher. Most studies have revealed several essential sex differences in CRF function. They include genetic factors, e.g., the CRF promoter contains estrogen response elements. Importantly, sex-related differences are responsible for different predispositions to PTSD and diverse treatment responses. Fear extinction (the process responsible for the effectiveness of behavioral therapy for PTSD) in women during periods of high endogenous estradiol levels (the primary form of estrogens) is reportedly more effective than in periods of low endogenous estradiol. In this review, we present the roles of selected neuropeptides in the sex-related predisposition to PTSD development.

Keywords: CRF; PTSD; neuropeptide Y; orexin; oxytocin; sex differences.

Figure 1

Changes in the activities of neuropeptides and their receptors in brain structures regulating cognition and the stress response that are responsible for the development of PTSD in women compared to men. The corticolimbic circuitry that mediates emotional responses to negative stimuli is shown in blue. The locus coeruleus norepinephrine system that initiates arousal responses to stress is shown in red. The HPA axis that regulates the neuroendocrine responses to stress is shown in green. Negative feedback (marked with green lines) is reduced in females and may further increase the release of glucocorticoids. —females; —males; ACTH—adrenocorticotropic hormone; CORT—cortisol; CRF- corticotropin-releasing hormone; CRF1, CRF2—CRF receptors type 1 and 2; OX1R, OX2R—orexin receptors type 1 and 2; NPY—neuropeptide Y; Y1R—NPY receptor type 1; Y1R-NPY—binding of NPY to the Y1R receptor, ↑—increase; ↓—decrease. The figure was adapted from Matchett et al. [95]. The permission has been obtained and there is no copyright issue.