Miragaya JR, Harris RB. Antagonism of corticotrophin-releasing factor receptors in the fourth ventricle modifies responses to mild but not restraint stress. Am J Physiol Regul Integr Comp Physiol 295: R404-R416, 2008. First published June 11, 2008 doi:10.1152/ajpregu.00565.2007.-Repeated restraint stress (RRS; 3 h of restraint on 3 consecutive days) in rodents produces temporary hypophagia, but a long-term downregulation of body weight. The mild stress (MS) of an intraperitoneal injection of saline and housing in a novel room for 2 h also inhibits food intake and weight gain, but the effects are smaller than for RRS. Previous exposure to RRS exaggerates hypophagia, glucocorticoid release, and anxiety-type behavior caused by MS. Here we tested the involvement of brain stem corticotrophin-releasing factor receptors (CRFR) in mediating energetic and glucocorticoid responses to RRS or MS and in promoting stress hyperresponsiveness in RRS rats. Administration of 1.3 nmol ␣hCRF(9-41), a nonspecific CRFR antagonist, exaggerated hypophagia and weight loss in both RRS and MS rats, whereas 0.26 nmol had no effect in RRS or MS rats. In contrast, 2 nmol of the nonspecific antagonist astressin had no effect on weight loss or hypersensitivity to subsequent MS in RRS rats, but blocked weight loss and inhibition of food intake caused by MS alone. MS rats infused with 3 nmol antisauvagine-30, a CRFR2 antagonist, did not lose weight in the 48 h after MS, but 0.3 nmol did not prevent weight loss in MS rats. These data suggest that inhibition of food intake and weight loss induced by RRS or by MS involve different pathways, with hindbrain CRFR mediating the effect of MS on body weight and food intake. Hindbrain CRFR do not appear to influence stressinduced corticosterone release in RRS rats. brain stem; ␣hCRF(9-41); astressin; antisauvagine-30; rats THE NEUROPEPTIDE CORTICOTROPHIN releasing factor (CRF) and its homologues urocortin (Ucn), Ucn II and Ucn III, have been identified as initiators of behavioral and physiological responses to stress (4, 50). CRF has two G protein-coupled receptor subtypes: CRFR1 and CRFR2 (8, 43), and CRFR2 presents two variants (CRFR2 and CRFR2␣). CRFR2␣ prevails in neural tissue (31), whereas CRFR2 is expressed in areas such as heart, gastrointestinal tract, arterioles, and muscle (26,31). Studies with knockout and transgenic mice suggest that CRFR2 mediate behavioral responses (2-4, 38) to stress, including inhibition of food intake and body weight loss (14,37,38,45), whereas CRFR1 appears to be more important in controlling activity of the hypothalamic-pituitary-adrenal (HPA) axis and anxiety behaviors (40,47). Many sites in the brain are involved in the initial response to a stressor and multiple sites express CRFR. Nuclei that have been demonstrated to control food intake or energy expenditure (18,55,56) and also express CRFR1 and/or CRFR2 include the dorsomedial, arcuate, paraventricular, lateral, and ventromedial nuclei of the hypothalamus, the area postrema, the nucleus of the solitary tract,...
