, 1999). (However, some chronic stress paradigms may produce a “giving up” pattern of stress response, reducing CRF receptor expression and instead inducing opioid inhibition of LC firing (Chaijale et al., 2013) – see Valentino and Van Bockstaele, 2014). Chronic stress also increases the expression of the NE synthetic Neratinib nmr enzymes tyrosine hydroxylase and dopamine beta hydroxylase within NE neurons

and axons both rat (Melia et al., 1992, Miner et al., 2006 and Fan et al., 2013) and primate (Bethea et al., 2013). This strengthening of the NE system with chronic stress likely leads to the exacerbation of detrimental alpha-1 receptor actions in the stressed PFC. Increased NE release in other brain regions may also contribute to symptoms of PTSD such as hypervigilance and altered sleep, e.g. via alpha-1 receptor stimulation in thalamus (McCormick et al., 1991). NE alpha-1 receptor stimulation also increases acetylcholine release (Tzavara et al., 2006), which drives REM sleep (Hobson, 1992), that may contribute to increased nightmares

in PTSD. Thus normalizing NE actions and restoring the alpha-2A vs. alpha-1 receptor balance may be especially important for treating stress disorders in humans. Underlying differences in catecholamines MEK activation appear to predispose individuals for PTSD vs. resilience when faced with a traumatic stress. The relationship between genotype and stress reactivity has been seen most clearly with the catecholamine catabolic enzyme, COMT (catechol-O-methyltransferase), where a common polymorphism at amino acid 158 substitutes native valine (Val) for methionine (Met), weakening enzyme activity and increasing catecholamine availability. As mentioned above, laboratory

studies of stress reactivity have shown that subjects with higher baseline catecholamine availability (i.e. those with COMT Met–Met genotype) show impaired dlPFC function under conditions of acute, moderate stress, while those with lower baseline catecholamines (i.e. those with COMT Val genotype) can actually perform better than control conditions following acute modest stress (Qin et al., 2012), thus demonstrating the catecholamine “inverted-U” dose–response (Arnsten et al., 2012). This relationship second can also be seen clinically, with increased incidence of PTSD in those with the COMT Met genotype, including the incidence of PTSD in those exposed to genocide (Kolassa et al., 2010 and Boscarino et al., 2012). The Met158 COMT genotype has been related to greater fear response, and to increased epigenetic changes in the gene that may further reduce enzyme availability and compound the effects of stress (Norrholm et al., 2013). Similar effects have been seen with nontraumatic stressors, where gene alterations that increase catecholamine availability have been related to increased rates of distress (Desmeules et al., 2012) and depression or anxiety (Lacerda-Pinheiro et al., 2014).