FUNCTIONAL CIRCUITRY IN THE BRAIN OF IMMUNE-CHALLENGED RATS - PARTIALINVOLVEMENT OF PROSTAGLANDINS

This study investigated the role of prostaglandins (PGs) on the neuron al activity and the transcription of corticotropin-releasing factor (C RF) in the brain of conscious immune-challenged rats. Intravenous (i.v .) administration of indomethacin, an inhibitor of PG synthesis, was p erformed prior to and after the intraperitoneal (i.p.) injection of di fferent doses [250 mu g, 25 mu g, and 2.5 mu g/100 g body weight (b.w. )] of the immune activator lipopolysaccharide (LPS). Systemic administ ration of the high and middle doses of LPS caused a robust and widespr ead induction of both immediate-early genes (IEGs), c-fos and nerve gr owth factor-inducible gene B (NGFI-B) mRNAs, whereas injection of the low dose selectively triggered c-fos expression within the sensorial c ircumventricular organs. Pretreatment with indomethacin did not preven t c-ibs transcription in the rat brains challenged with the high dose of LPS at 3 hours postinjection. Inhibition of PG formation was more e ffective for interruption of the neuronal activation in animals inject ed with 25 mu g LPS/100 g b.w., although the influence depended on the structures and the groups of activated cells. Indeed, PG inhibition s ignificantly altered LPS-induced c-fos mRNA expression in the medial p reoptic area/organum vasculosum of the lamina terminalis, the perivent ricular nucleus, the paraventricular nucleus of the hypothalamus (PVN) , and the ventrolateral medulla (VLM) but not in many other regions, i ncluding the subfornical organ, the central nucleus of the amygdala, t he arcuate nucleus/median eminence, the parabrachial nucleus, the chor oid plexus, and the nucleus of the solitary tract (NTS). In the hypoth alamic PVN, inhibition of both c-fos and NGFI-B transcripts by indomet hacin was also associated to an abolished influence of the endotoxin o n the transcription of neuroendocrine CRF; induction of CRF primary tr anscript by the middle dose of LPS was selective to the PVN and was co mpletely blocked by pretreatment with indomethacin. Moreover, a large number of tyrosine hydroxylase (TH)immunoreactive neurons of the VLM ( A1/C1) and the NTS (A2/C2) were positive for c-fos mRNA in immune-chal lenged rats, an effect that was largely prevented by indomethacin in t he VLM but not in the NTS. These results indicate that the role of PGs in mediating the stimulatory influence of the acute-phase response de pends on the severity of the systemic stressful situation, the brain r egions, and the cell groups as well as the activated target genes. (C) 1997 Wiley-Liss, Inc.