Cortisol and PTSD: Animal experiments and clinical perspectives

Abstract

A fundamental issue in the psychobiology of a traumatic experience is how circulatingstress hormones are implicated in the pathogenesis of posttraumatic stress disorder(PTSD) (Pitman 1989; Gilbertson 2002; Ohtani et al. 2004). This issue is importantbecause the onset and progression of the disorder appears to be facilitatedby a low circulating Cortisol tone (Yehuda 2002). Hence the hypothesis was proposedthat the "development of PTSD is facilitated by a failure to contain the biologicalstress response at the time of the trauma. As a result a cascade of centralstress reactions may lead to intrusive recollections of the event, avoidance of remindersof the event, and symptoms of hyperarousal," (Yehuda 2002). Indeed corticotropin-releasing hormone (CRH) levels in the cerebrospinal fluid are high in theface of low circulating Cortisol concentrations. This suggests that inadequate Cortisolfeedback in the brain may be implicated in PTSD.In this chapter, we address the question why Cortisol action is inadequate to containcentral stress reactions to traumatic events. The action exerted by Cortisol in thebrain is mediated by high affinity mineralocorticoid receptor (MR) and the loweraffinity glucocorticoid receptor (GR) (de Kloet et al. 1998). The two receptor systemsoperate in neural networks as a binary control mechanism in the regulation ofsignaling cascades underlying distinct domains of emotional and cognitive processes(Oitzl and de Kloet 1992; de Kloet et al. 1999). By operating as a dual controlmechanism, MR and GR are considered to be an interface between genetic and traumaticinputs that shape the organism's ability to cope with stressors. It is conceivable,therefore, that an imbalance in MR-mediated and GR-mediated actions is asignificant factor in the development of a phenotype vulnerable to the precipitationof PTSD. A prominent example of such a vulnerable phenotype is the newborn infant,as will be illustrated for the rat and mouse.