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Ji Hye Park 1 Article
Effects of Chronic Repetitive Restraint Stress on Acute and Long-Term Changes in Plasma Corticosterone Levels and Hypothalamic Neuronal Nitric Oxide Synthase Activity in Rats
Ji Hye Park, Inhwan Lim, Seoul Lee
STRESS. 2020;28(4):285-291.   Published online December 31, 2020
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Abstract PDF

Immobilization as restraint stress is recognized as a psychologically stressful event. The stress responses alter both neuroendocrine and neurochemistry in an acute and long-term manner. We investigated whether the effect of chronic repetitive restraint stress could elicit levels of corticosterone and related neurochemical alterations.


Nine-week-old Sprague-Dawley rats (the stressed group) were subjected to restraint stress in a hemi-cylindrical apparatus nocturnally in seven consecutive days. The handled control group was a sustained-controlled husbandry, and the stressed group was returned to the same home cage immediately after daily restraint sessions. On day 14, all subjects were sacrificed and neurochemical assessment was performed. Plasma corticosterone levels were measured on days 1, 7, and 14 following a 7-day recovery period. The activity of exploration was measured on day 5 of the stress session for 5 min to expose the novel open field. On day 14, tyrosine hydroxylase, c-fos, and NADPH-diaphorase immunohistochemistry was performed in the locus coeruleus and hypothalamic PVN (paraventricular nucleus) in the brain, respectively.


The repetitive restraint stress elicits a retarded growth pattern and lowers locomotive activity at the acute phase. During the stressed session, higher levels of plasma corticosterone and nNOS (neuronal nitric oxide synthase) activity in the hypothalamus. Furthermore, the upregulated changes were prolonged seven days after the stress-free recovery period, chronically.


Chronic repetitive restraint stress may acutely alter neuroendocrine and behavioral changes via the hypothalamic-pituitary-adrenal axis, and its phenomenon is sustained as a physiological maladaptation, depending on neurochemical alterations related to hypothalamic nNOS activity.