NE, on the other hand, is one of the principal mediators of autonomic stress responses through both central and peripheral mechanisms. The majority of CNS NE is derived from neurons of the locus ceruleus (LC) that project to various brain regions involved in the stress response, including the prefrontal MK-0457 research buy cortex, amygdala, hippocampus, hypothalamus, periaqueductal grey, and thalamus. In addition, there is evidence for a feed-forward circuit connecting the amygdala and hypothalamus with the LC, in which CRH and NE interact to increase fear conditioning and encoding of emotional Inhibitors,research,lifescience,medical memories, enhance arousal and vigilance, and integrate

endocrine and autonomic responses to stress. Like other stress pathways, this cascade is inhibited by glucocorticoids,18 which serve as a “brake” for the system. In the periphery, stress-induced sympathetic nervous system activation results in the release of NE and epinephrine from Inhibitors,research,lifescience,medical the adrenal medulla, increased release of NE from sympathetic nerve endings, and changes in blood flow to Inhibitors,research,lifescience,medical a variety of organs as needed for fight-or-flight behavior. The NE effects arc mediated via postsynaptic α1 β1 , and β2, receptors, whereas another

NE-activated receptor, the α2 receptor serves as a presynaptic autoreceptor inhibiting NE release. Because of its multiple roles in regulating arousal and autonomic Inhibitors,research,lifescience,medical stress responses, as well as promoting the encoding of emotional memories, NE has been a central focus of many studies investigating the pathophysiology of PTSD. A cardinal feature of patients with PTSD is sustained hyperactivity of the autonomic sympathetic branch of the autonomic nervous system, as evidenced by elevations in heart rate, blood pressure, skin conductance, and other psychophysiological measures. Accordingly, increased urinary excretion of catecholamines, and their metabolites, has been documented in combat Inhibitors,research,lifescience,medical veterans, abused women, and children with PTSD. In addition, patients with PTSD exhibit increased heart rate, blood pressure, and NE responses to traumatic reminders.

Decreased platelet α2 receptor binding further suggests NE hyperactivity in PTSD.19,20 Administration of the α2 receptor antagonist yohimbine, which increases NE release, induces flashbacks and increased autonomic Linifanib (ABT-869) responses in patients with PTSD.21 Serial sampling revealed sustained increases in CSF NE concentrations and increased CSF NE responses to psychological stressors in PTSD:22,23 Taken together, there is an abundance of evidence that NF, accounts for certain classic aspects of PTSD symptomatology, including hyperarousal, heightened startle, and increased encoding of fear memories.20 Interestingly, prospective studies have shown that increased heart rate and peripheral epinephrine excretion at the time of exposure to trauma predict subsequent development of PTSD.