, 1997 and Roozendaal et al., 2009). Stressors activate the HPA-axis through the release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus (PVN) of the hypothalamus. When CRH reaches the anterior pituitary gland, it elicits adrenocorticotropic hormone (ACTH) release, which prompts glucocorticoid synthesis in the adrenal glands. Finally, glucocorticoids are released into the bloodstream where they travel and bind to receptors throughout the body and brain (McEwen et al., 1986,

de Kloet, 2004 and Sapolsky et al., 2000). Glucocorticoid release follows a slower time course than rapidly released catecholamines, peaking Compound Library 10–20 min after the onset of stress exposure (Sapolsky et al., 2000). Glucocorticoids are often characterized as a recovery hormone that adapts an organism to the neurophysiological changes that occur during stress (Lupien et al., 2007). Collectively, these two systems interact and function in a complementary manner to mobilize energy and help an organism cope with stressful experiences. Despite the inability of peripheral catecholamines to cross the blood–brain barrier, noradrenaline is projected throughout

the brain by way of the locus coeruleus (LC). The LC serves as the brain’s primary source of noradrenaline and shares reciprocal connections with brain regions that are critical to the acquisition and regulation of conditioned fear, such BIBW2992 mouse as the amygdala, hippocampus and PFC (Benarroch, 2009). The high proportion of noradrenaline receptors in the amygdala and PFC render these brain regions Cediranib (AZD2171) especially sensitive to the effects of stress (McEwen et al., 1986). Circulating glucocorticoids can influence brain function by readily crossing the blood–brain barrier and binding to high-affinity mineralocorticoid and low-affinity glucocorticoid receptors distributed throughout the amygdala, hippocampus and prefrontal cortex (Joels et al., 2012 and Lupien et al., 2007). The effects

of glucocorticoids include dampening glucose transport within cortical neurons and glia cells, which may further influence brain function by diminishing processing and amplifying the effects of early catecholamine release by slowing their clearance from synaptic space (Grundemann et al., 1998, Ferry et al., 1999 and Roozendaal et al., 2002). The release of glucocorticoids is controlled through negative feedback mechanisms housed within the PFC, suggesting that this region is targeted both for glucocorticoid binding under stress and for the regulation of glucocorticoid release (Diorio et al., 1993). Consistent with this, both chronic exposure to stress and affective psychopathology have been shown to be related to deficits in HPA regulation and inhibition (Cacioppo et al., 1998, Nyklicek et al., 2005 and Radley et al., 2006). Learning to respond appropriately to cues that signal danger is critical to survival and can facilitate adaptive behavior.