AbstractLipocortin 1 (LC1: also called annexin 1) was first described as a putative second messenger protein for the anti‐inflammatory steroids in peripheral tissues. In the present study,in vitroandin vivomethods were used to examine its potential role within the hypothalamus as a mediator of the regulatory actions of the glucocorticoids on the hypothalamo‐pituitary‐adrenocortical axis of the rat.In thein vitrostudies, the effects of human recombinant LC1 (hu‐r‐LC1) on the concomitant release of the two major corticotrophin‐releasing factors (CRF‐41 and arginine vasopressin, AVP) from isolated hypothalami removed from chronically adrenalectomized rats were compared with those of dexamethasone in the presence and absence of appropriate secretagogues, namely phospholipase A2(PLA2), interleukin‐6 (IL‐6) and a non‐specific depolarizing agent, K+(56 mM). The spontaneous release of CRF‐41in vitrowas unaffected by either hu‐r‐LC1 (5 to 100 ng/ml) or dexamethasone (1 μM). Both compounds however reduced the release of the neuropeptide evoked by IL‐6 (5 ng/ml) but failed to modify the secretory responses to PLA2(25 U/ml) or K+(56 mM). Dexamethasone (1 μM) had no effect on the basal release of AVP but effectively blocked the secretion of the peptide induced by either IL‐6 (10 ng/ml) or PLA2(25 U/ml). In complete contrast, hu‐r‐LC1 (5 to 100 ng/ml) stimulated the release of AVP and potentiated the secretory responses to IL‐6 (10 ng/ml) and PLA2(25 U/ml) but not to K+(56 mM). The hypothalamic responses to PLA2stimulation (25 U/ml) were associated with significant (P<0.01) increases in prostaglandin E2release which, in some instances, were potentiated by hu‐r‐LC1 (5 to 20 ng/ml).In vivo, administration of histamine (0.6 mg/100 g body wt, ip) produced significant (P<0.01) increases in the serum corticosterone concentration and in the hypothalamic LC1 content. Neither hu‐r‐LC1 (0.6 to 1.2 μg) nor a polyclonal anti‐LC1 antibody (3 μl, diluted 1:200), injected intracerebroventricularly (icv), influenced either the resting serum corticosterone concentration or the hypersecretion of the steroid evoked by histamine stress. A lower dose of the recombinant protein (0.3 μg icv) also failed to alter basal corticosterone release but, in contrast to the higher doses, potentiated the pituitary‐adrenocortical responses to histamine.The results suggest that LC1 may contribute to some aspects of peptide release in the hypothalamus but that its actions are not