Prepro-TRH 178-199 inhibits histamine- or restraint stress-induced activation of corticotropin releasing hormone production in rat hypothalamus

Under restraint stress conditions, prepro-thyrotropin releasing hormone (TRH) 178-199 suppresses adrenocorticotropic hormone (ACTH) secretion from the rat pituitary, which indicates that prepro-TRH 178-199 is a candidate endogenous corticotropin releasing inhibitory factor (CRIF). Restraint stress also activates the release of hypothalamic neuronal histamine, which increases both the expression of CRH mRNA in the paraventricular nucleus (PVN) and plasma concentrations of ACTH. The aim of this study was to determine whether prepro-TRH 178-199 modulates histamine- or restraint stress-induced activation of corticotropin releasing hormone (CRH) in the rat hypothalamus. Infusion of prepro-TRH 178-199 into the third cerebroventricle (i3vt) at a dose of 6 μg/kg significantly decreased the amount of CRH in the PVN, as compared to vehicle-treated controls (p < 0.05), but did not affect the CRH amount in other hypothalamic regions. Restraint stress increased the amount of CRH in the PVN and ventromedial hypothalamic nucleus (VMH), as compared to non-restrained controls (p < 0.05); this was attenuated by pretreatment with i3vt infusion of prepro-TRH 178-199 (p < 0.05). I3vt infusion of histamine (270 nmol/rat) suppressed cumulative food consumption over 24 h, increased plasma ACTH concentrations, and increased the content of CRH in the PVN, as compared to vehicle-treated controls (p < 0.05 for each); these effects were attenuated by pretreatment with prepro-TRH 178-199 (p < 0.05). These results suggest that prepro-TRH 178-199 may regulate ACTH secretion by affecting basal and histamine- or stress-induced synthesis and/or secretion of CRH and ACTH by modulating histaminergic input to the PVN and VMH.