For example, variations in early life maternal care can determine individual sensitivity of this feedback through epigenetic mechanisms that determine glucocorticoid receptor expression (Weaver et al., 2004). Although feedback inhibition of the HPA axis by glucocorticoids is critical in restraining the endocrine limb of the stress response, neural circuits underlying other CFTR activator limbs of the stress response are not similarly regulated. For example, whereas glucocorticoids

inhibit corticotropin-releasing factor (CRF) mRNA expression in neurons of the paraventricular hypothalamic nucleus that initiate anterior pituitary adrenocorticotropin release, they increase CRF mRNA in neurons of the amygdala and bed nucleus of the stria terminalis that are thought to underlie behavioral aspects of the stress response (Makino et al., 1994a and Makino et al., 1994b). Given the complexity of stress circuitry, there are likely to be multiple mechanisms for counter-regulation of different components of the stress response. Identifying these mechanisms can guide strategies to prevent or treat stress-related neuropsychiatric diseases. Mechanisms for counteracting stress are also potential points at which individual differences can be expressed and thus can be determinants of stress vulnerability and/or resilience. One mechanism for counteracting stress responses is through stress-elicited engagement of neuromodulators

SKI-606 that act in opposition to “pro-stress” systems or neuromediators. Some neuromediators that have been characterized as opposing stress include neuropeptide Y, endocannabinoids, urocortins and endogenous opioids (Bowers et al., 2012, Crowe et al., 2014, Gunduz-Cinar et al., 2013, Heilig and Thorsell, 2002, Hillard, 2014, Kozicz, 2007 and Reul and Holsboer, 2002). This review presents the locus coeruleus (LC)-norepinephrine (NE) system

as a model stress-response system that is co-regulated by the opposing not influences of the pro-stress mediator, CRF and the opioid neuropeptide, enkephalin during acute stress. We begin with a brief description of the anatomical and physiological characteristics of the LC-NE system with respect to its role in behavioral and cognitive aspects of the stress response (additional detail on anatomical and physiological characteristics of the LC-NE system are reviewed in (Aston-Jones et al., 1995)). This is followed by a discussion of CRF as the orchestrator of the stress response and a neurotransmitter that activates the LC-NE system in response to stress. Endogenous opioids are introduced as “anti-stress” mediators that co-regulate the LC in a manner that opposes CRF. The adaptive nature of maintaining a balance between CRF and endogenous opioid influences in the LC is emphasized. Individual factors that can tip this balance to result in pathology or determine vulnerability are discussed.