Reduction of Stress-Induced Behavior by Antagonism of Corticotropin-Releasing Hormone 2 (CRH₂) Receptors in Lateral Septum or CRH₁Receptors in Amygdala

Abstract

Although corticotropin-releasing hormone (CRH), a regulator of stress responses, acts through two receptors (CRH1 and CRH2), the role of CRH2 in stress responses remains unclear. Knock-out mice without the CRH2 gene exhibit increased stress-like behaviors. This profile could result either directly from the absence of CRH2 receptors or indirectly from developmental adaptations. In the present study, CRH2 receptors were acutely blocked by alpha-helical CRH (alpha(h)CRH, CRH1/CRH2 antagonist; 0, 30, 100, and 300 ng) infusion into the lateral septum (LS), which abundantly expresses CRH2 but not CRH1 receptors. Freezing, locomotor activity, and analgesia were tested after infusion. Intra-LS alpha(h)CRH blocked shock-induced freezing without affecting activity or pain responses; infusions into lateral ventricle or nucleus of the diagonal band had no effects. The same behavioral profile was obtained with d-Phe-CRH((12-41)) (100 ng), another CRH1/CRH2 antagonist. A selective CRH1 antagonist (NBI27914), in doses that reduced freezing on intra-amygdala (central nucleus) infusion (0, 0.2, and 1.0 microg), did not affect freezing when infused into the LS. Ex vivo autoradiography revealed that binding of [125I]sauvagine, a mixed CRH1/CRH2 agonist, was prevented in the LS by previous intra-LS infusion of alpha(h)CRH but not NBI27914. In vitro studies demonstrated that [125I]sauvagine binding in the LS could be inhibited by a CRH1/CRH2 antagonist but not by the selective CRH1 receptor antagonist, confirming that in the LS, alpha(h)CRH antagonized exclusively CRH2 receptors. Acute antagonism of CRH2 receptors in the LS thus produces a behaviorally, anatomically, and pharmacologically specific reduction in stress-induced behavior, in contrast to results of recent knock-out studies, which induced congenital and permanent CRH2 removal. CRH2 receptors may thus represent a potential target for the development of novel CRH system anxiolytics.

Predator threat induces behavioral inhibition, pituitary-adrenal activation and changes in amygdala CRF-binding protein gene expression

“…Future studies will determine if CRF 2 receptor expression is altered in other brain regions, for example the lateral septum and the bed nucleus of the stria terminalis, that have been implicated in CRF-dependent stress responses (Erb and Stewart, 1999;Bakshi et al, 2002) and also express higher levels of CRF 2 receptors.…”

Neuropeptide binding reflects convergent and divergent evolution in species-typical group sizes

“…Incubation concentrations and durations for each peptide were: 125 I-SG, 30 pM for 60 min; 125 I-VIP, 50 pM for 90 min; and linear 125 I-V 1a antagonist, 50 pM for 75 min. Concentrations were selected through pilot testing using a range of concentrations from the literature, and are similar to those used in previous investigations (e.g., Hof et al, 1991;Young et al, 1999;Bakshi et al, 2002). For 125 I-SG binding, slides were then rinsed 2 × 4 min in icecold Tris-MgCl 2 buffer, dipped in distilled water and dried under a cool stream of air.…”

Intermale aggression in corticotropin-releasing factor receptor 1 deficient mice

“…Within the CNS and elsewhere, CRF acts primarily on CRFR1 [4,35,41], but can activate with less efficacy CRF receptor 2 (CRFR2) [22,39]. CRF related peptides, urocortin (Ucn) 1 and Ucn 3, can also elicit different aspects of fear and anxiety (behavioral manifestations of stress) by acting within specific brain regions [3,18,23]. Ucn 1 and Ucn 3 may be the primary ligands for CRFR2, but Ucn 1 can also activate with lesser efficacy CRFR1 [24,25,31,39].…”