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Chronic Intermittent Cold Stress Sensitises the Hypothalamic-Pituitary-Adrenal Response to a Novel Acute Stress by Enhancing Noradrenergic Influence in the Rat Paraventricular Nucleus


David Morilak, Department of Pharmacology, MC 7764, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA (e-mail:


Chronic intermittent cold stress sensitises activation of the hypothalamic-pituitary-adrenal (HPA) axis by novel acute stress. We have shown that enhanced noradrenergic function in limbic forebrain contributes to HPA sensitisation. In the present study, we investigated whether chronic intermittent cold also induced changes in noradrenergic function in the paraventricular nucleus (PVN), the primary mediator of the HPA stress response. Rats were exposed to chronic intermittent cold (7 days, 6 h per day, 4 °C). On the day after final cold exposure, there were no differences in baseline plasma ACTH, but the peak ACTH response to 30 min of acute immobilisation stress was greater in cold-stressed rats compared to controls. Bilateral microinjection of the α1-adrenergic receptor antagonist benoxathian into the PVN reduced acute stress-induced adrenocorticotrophic hormone (ACTH) levels by approximately 25% in controls. Furthermore, in cold-stressed rats, all of the sensitisation of the ACTH response was blocked by benoxathian, to a level comparable to benoxathian-treated controls. In a second study using microdialysis to measure norepinephrine release in the PVN, there were no differences in either baseline or acute stress-induced increases in norepinephrine release in the PVN of cold-stressed rats compared to controls. Thus, in a third study, we tested potential alterations in postsynaptic α1-receptor sensitivity after chronic cold stress. Dose-dependent activation of ACTH secretion by microinjection of the α1-adrenergic receptor agonist, phenylephrine, into the PVN was significantly enhanced in cold-stressed rats compared to controls. Thus, the sensitised HPA response to acute stress after chronic intermittent cold exposure is at least partly attributable to an enhanced response to α1-adrenergic receptor activation in the PVN. Chronic stress-induced plasticity in the acute stress response may be important for stress adaptation, but may also contribute to pathophysiological conditions associated with stress. Thus, understanding the neural mechanisms underlying such adaptations may help us understand the aetiology of such disorders, and contribute to the future development of more effective treatment or prevention strategies.