NEUROENDOCRINE AND IMMUNOCYTOCHEMICAL DEMONSTRATIONS OF DECREASED HYPOTHALAMO-PITUITARY-ADRENAL AXIS RESPONSIVENESS TO RESTRAINT STRESS AFTER LONG-TERM SOCIAL-ISOLATION

We have studied the effects of long-term social isolation of male Wist ar rats, after early weaning (16 days), on the activity of the hypotha lamo-pituitary-adrenal (HPA) axis. In addition to studying basal HPA a ctivity, the response of the HPA axis to 15 min of immobilization stre ss was examined. Plasma corticosterone concentrations were measured, a nd the relative weights of adrenal glands, thymus, and testes were obt ained, the latter to check whether gonadal function was affected by th e isolation paradigm. Moreover, we carried out a quantitative immunohi stochemical study of pituitary ACTH and its hypothalamic secretagogues : CRF, arginine vasopressin (AVP), and oxytocin (OT), both at the leve l of the synthesizing cell bodies in the hypothalamic paraventricular nucleus and of the releasing fibers in the median eminence (ME). Body weight and daily consumption of food and water were not altered, but s ocial isolation caused a reduction in plasma corticosterone levels, bo th under basal and stress-stimulated conditions; this was correlated w ith an increased thymus weight, without affecting adrenal or testicula r weights. The immunohistochemical study revealed that isolation cause d a smaller increase in the number of ACTH-immunoreactive cells in the pars distalis of the anterior pituitary after exposure to restraint s tress, as compared with control animals. This result indicates that fe wer corticotrophs were activated by restraint stress in isolated anima ls, such cells being smaller and exhibiting a smaller ACTH-immunoreact ive area than in control animals. Isolated animals also showed an in c rease in the content of CRF-ir fibers in the ME and a smaller decrease in the neuropeptide immunoreactivity after stress than that observed in control animals. This result could indicate a reduced release of CR F into the portal vasculature in response to acute stress and may part ially explain the reduced activation of corticotrophs observed in the pituitary of isolated animals. However, no changes were found in the c ontent of CRF, AVP, or OT within the paraventricular nucleus, nor of t he AVP or OT content in the ME. The results of this study show that lo ng-term social isolation after early weaning caused a hypofunction of the HPA axis in the adult rat. This hypofunction was particularly evid ent after exposure to an acute stressor, suggesting a desensitization of this axis to stressful stimuli.