HYPOTHALAMIC PGE(2) AND CAMP PRODUCTION AND ADRENOCORTICAL ACTIVATIONFOLLOWING INTRAPERITONEAL ENDOTOXIN INJECTION - IN-VIVO MICRODIALYSISSTUDIES IN LEWIS AND FISCHER RATS

Inflammatory disease-susceptible Lewis (LEW) rats exhibit reduced gluc ocorticoid release in response to inflammatory and neurotransmitter st imuli, compared to histocompatible Fischer (F/344) rats. This compromi sed hypothalamo-pituitary-adrenal (HPA) axis activity has been ascribe d to a primary defect in hypothalamic corticotrophin-releasing factor- 41 (CRF) secretion, possibly caused by abnormal signal transduction in the CRF neuron. In the present study, we have used in vivo microdialy sis to asses the role of hypothalamic prostaglandin E2 (PGE2) and cycl ic adenosine monophosphate (cAMP) in endotoxin-mediated HPA axis activ ation in adult hyporesponsive LEW and hyperresponsive F/344 rats. Basa l plasma corticosterone concentration was significantly higher in F/34 4 relative to LEW rats; however, the basal levels of PGE2 and cAMP, re covered from microdialysis probes in the anterior hypothalamus, were s ignificantly greater in the LEW rat. Lipopolysaccharide (LPS) (200 mug /kg) caused a time-dependent increase in corticosterone secretion, the magnitude of which was markedly greater in the F/344 rat. Both LEW an d F/344 rats displayed a similar PGE2 profile in response to LPS, alth ough in absolute terms the response was more pronounced in LEW rats. L PS caused a dose-related increase in cAMP production in the LEW rat an d comparison with F/344 animals, following the 200 mug/kg dose of LPS, revealed a larger and more prolonged cAMP response in the LEW strain. Simultaneous administration of indomethacin (50 mg/kg) with LPS (200 mug/kg) in the LEW rat completely blocked the PGE2 and cAMP responses to the toxin and whilst the corticosterone response to LPS was signifi cantly attenuated at 140 min, no difference was apparent by 240 min. H ence, PGE2 and cAMP participate in the hypothalamic response to endoto xin-mediated adrenocortical activation in both LEW and F/344 adult rat s but the steroid and second messenger profiles are strain-specific. T he cAMP response to LPS appears to depend on products of arachidonic a cid metabolism, such as PGE2, and hence basal and stimulated productio n of these mediators may be effected by the steroid milieu.