INCREASED PLASMA ACTH RESPONSES TO STRESS IN NONHANDLED COMPARED WITH HANDLED RATS REQUIRE BASAL LEVELS OF CORTICOSTERONE AND ARE ASSOCIATED WITH INCREASED LEVELS OF ACTH SECRETAGOGUES IN THE MEDIAN-EMINENCE

Postnatal handling of rat pups is known to alter permanently hypothalamic-pituitary-adrenal (HPA) responses to a wide variety of stressors. As adults, handled (H) and nonhandled (NH) animals also differ in sensitivity to the delayed negative-feedback effects of glucocorticoids on stress-induced HPA activity. However, it is not understood how handling alters neuroendocrine responses to stressful stimuli, and how differences in feedback sensitivity might account for changes in HPA activity both during and following stress. In the present studies, plasma ACTH responses to both restraint and ether stress were significantly greater in NH compared with H animals. Administration of 100 mug/kg corticosterone (B) immediately prior to restraint stress significantly decreased subsequent plasma ACTH responses to restraint to the same extent in H and NH animals, suggesting that H and NH animals do not differ in glucocorticoid fast feedback. H and NH animals adrenalectomized (ADX) 5 d prior to testing did not differ in plasma ACTH responses to restraint stress, demonstrating that the differences between the groups are dependent upon the presence of circulating B. However, the handling effect was apparent in ADX animals provided with a low level of B replacement (approximately 5-6 mug/dl). B replacement significantly decreased plasma ACTH levels under both basal conditions and in response to restraint stress in H/ADX rats. In contrast, although B replacement also decreased basal ACTH levels in ADX/NH rats, there were no differences in plasma ACTH responses to restraint between NH/ADX and NH/ADX + B animals. Thus, plasma ACTH responses to restraint were significantly greater in ADX-B/NH compared with ADX + B/H rats. Thus, a low level of B replacement was able to restore the difference between H and NH animals in plasma ACTH responses to stress. This finding shows that the differences between H and NH animals in HPA responses to stress can occur independently of stress-induced elevations in plasma B levels. Finally, we found that resting state levels of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) in the median eminence were significantly higher in NH animals compared with H animals. Taken together, these findings suggest that H and NH animals differ in delayed negative feedback, and that this difference occurs in response to low levels of B and is reflected in differential rates of CRH and AVP synthesis in hypothalamic neurons. Assuming that the difference in ACTH secretagogues exists in readily releasable storage pools in the median eminence, this would mean that any stress-induced neural signal that activates hypothalamic CRH/AVP neurons would result in a greater release of CRH and/or AVP in NH animals, leading to a larger ACTH response, and a larger and more prolonged increase in plasma B. Thus, differences between H and NH animals in HPA activity both during and following stress can occur under a variety of stressful conditions and independently of the stress-induced increase in plasma B. These findings are also consistent with earlier findings of increased hippocampal glucocorticoid receptor density in the H animals.