Chronic cold stress sensitizes brain noradrenergic reactivity and noradrenergic facilitation of the HPA stress response in Wistar Kyoto rats

Many psychiatric disorders, including depression, post-traumatic stress disorder and other anxiety disorders, result from an interaction between genetic factors and exposure to a sufficiently sensitizing environmental stressor. The inbred Wistar Kyoto (WKY) rat strain has been proposed as a model of stress vulnerability, exhibiting an exaggerated hypothalamic-pituitary-adrenal (HPA) response to stress and susceptibility to gastric ulceration. Previously, we showed that stress-activation of the brain noradrenergic system was deficient in WKY rats, and they lacked noradrenergic facilitation of the HPA response in the lateral bed nucleus of the stria terminalis (BSTL), compared to outbred Sprague-Dawley (SD) controls. Deficient modulatory function of the noradrenergic system may contribute to the stress susceptibility of WKY rats. Thus, we investigated the influence of a sensitizing stimulus, chronic intermittent cold exposure, on neuroendocrine and noradrenergic stress reactivity, and on noradrenergic facilitation of the HPA response in these two strains. Chronic cold exposure (7 days, 4 h/day, 4°C) potentiated activation of the HPA axis by acute immobilization stress, assessed by measuring plasma adrenocorticotropic hormone (ACTH), in both strains, although to a greater extent in WKY rats, and enhanced stress-induced norepinephrine (NE) release in BSTL of WKY but not SD rats. We then compared the influence of chronic cold exposure on noradrenergic modulation of the HPA stress response in BSTL, by measuring changes in acute stress-induced elevation of plasma ACTH after microinjecting the α₁-adrenoreceptor antagonist benoxathian into the BSTL. As shown previously, benoxathian attenuated stress-induced ACTH secretion in control SD but not control WKY rats. After chronic cold, the ACTH response to acute stress was attenuated by benoxathian administration into BSTL of both strains, such that the WKY response was not different from that of SD rats. Thus, chronic cold not only sensitized the release of NE in BSTL of WKY rats, but also restored noradrenergic facilitation of their already-elevated HPA response. Such functional sensitization of a previously-deficient facilitatory system may be one mechanism whereby exposure to repeated or severe stress may induce pathologic dysregulation of the stress response in susceptible individuals, resulting in psychiatric illness.