Corticotropin-Releasing-Hormone (CRH) is the principal secretagogue for plasma ACTH and corticosterone secretion and plays an important role in coordinating a variety of physiological and behavioral responses to stress. To explore whether there is a rapid change in the secretory response of the hypothalamic CRH neuron during acute stress, we report here a study of the effects of KCl and norepinephrine (NE) on CRH release in vitro from rat hypothalami explanted after 5, 30, 60, and 120 minutes of immobilization. We also measured the plasma levels of ACTH, beta-endorphin, corticosterone, prolactin, GH, and TSH at these intervals. As the duration of immobilization increased, KCl and NE-induced CRH release in vitro progressively fell. After reaching a maximal rise after 30 minutes of immobilization, plasma ACTH, beta-endorphin, and prolactin progressively fell in plasma, whereas corticosterone remained elevated up to 120 minutes; TSH and GH secretion rapidly declined and remained suppressed. Taken together, these data suggest that during immobilization stress, the responsiveness of the hypothalamic CRH neuron rapidly falls, owing either to CRH depletion and/or desensitization to NE, and this is paralleled by a concomitant decrease in pituitary-adrenal responsiveness.