Posttraumatic Stress Disorder (PTSD) is an anxiety disorder which can develop as a result of exposure to a traumatic event and is associated with significant functional impairment. Family and twin studies have found that risk for PTSD is associated with an underlying genetic vulnerability and that more than 30% of the variance associated with PTSD is related to a heritable component. Using a fear conditioning model to conceptualize the neurobiology of PTSD, three primary neuronal systems have been investigated – the hypothalamic-pituitary-adrenal axis, the locus coeruleus-noradrenegic system, and neurocircuitry interconnecting the limbic system and frontal cortex. The majority of the initial investigations into main effects of candidate genes hypothesized to be associated with PTSD risk have been negative, but studies examining the interaction of genetic polymorphisms with specific environments in predicting PTSD have produced several positive results which have increased our understanding of the determinants of risk and resilience in the aftermath of trauma. Promising avenues of inquiry into the role of epigenetic modification have also been proposed to explain the enduring impact of environmental exposures which occur during key, often early, developmental periods on gene expression. Studies of PTSD endophenotypes, which are heritable biomarkers associated with a circumscribed trait within the more complex psychiatric disorder, may be more directly amenable to analysis of the underlying genetics and neural pathways and have provided promising targets for elucidating the neurobiology of PTSD. Knowledge of the genetic underpinnings and neuronal pathways involved in the etiology and maintenance of PTSD will allow for improved targeting of primary prevention amongst vulnerable individuals or populations, as well as timely, targeted treatment interventions.

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Corticotropin-releasing factor (CRF) is the major physiological regulator of the hypothalamic-pituitary-adrenal (HPA) axis and serves to coordinate the mammalian endocrine, autonomic, and behavioral responses to stress. Considerable literature from clinical and preclinical data suggests that hypersecretion of hypothalamic and/or extrahypothalamic CRF systems is a major factor in the pathogenesis of affective and anxiety disorders. Based on this premise, a CRF 1 receptor antagonist has been hypothesized to possess anxiolytic and/or antidepressant properties. In this study, an acute dose of the lipophilic CRF 1 receptor antagonist 3-[6-(dimethylamino)-4-methyl-pyrid-3-yl]-2,5-dimethyl-N,N-dipropyl-pyrazolo[2,3-a]pyrimidin-7-amine (R121919), administered i.v. to rats with surgically implanted jugular cannula 60 min before a 5-min restraint stress, dose dependently attenuated peak plasma adrenocorticopin hormone (ACTH) and corticosterone concentrations by 91 and 75%, respectively. In a second study, acute administration of R121919 reduced measures of anxiety in a rodent defensive withdrawal paradigm. R121919 dose dependently decreased latency to exit the tube, and total time spent in the tube 60 min after a single subcutaneous administration. In addition, the ACTH and corticosterone response to novelty was decreased by 82 and 97%, respectively, at the 10-mg/kg dose of R121919. In another study, this dose was associated with approximately an 85% occupancy of the CRF 1 receptor in the cortex measured 75-min postsubcutaneous injection. These data confirm that R121919 acts as a CRF 1 receptor antagonist in vivo, attenuates HPA axis responsivity, and possesses anxiolytic properties.

Military sexual trauma (MST) is reported by 20-40% of female veterans. The purpose of this study of female veterans referred for MST treatment was to examine the relationships between lifetime trauma (physical, sexual, and psychological) and posttraumatic stress disorder (PTSD), depression, physical health, and quality of life using retrospective cross-sectional data from medical records. Of the 135 participants, 95.4% reported at least one trauma in addition to MST, most notably sexual abuse as adult civilians (77.0%) and as children (52.6%). PTSD, depression, and sleep difficulty rates were clinically significant. Chronic pain (66.4%) was associated with childhood abuse, physical health, sleep difficulties, and coping. Integrating mental and physical health treatment is necessary to treat MST and PTSD in female veterans.