Reduction of stress-induced behavior by antagonism of corticotropin-releasing hormone 2 (CRH2) receptors in lateral septum or CRH1 receptors in amygdala.
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.
Bakshi
Vaishali P
VP
Department of Psychiatry, University of Wisconsin, Madison, Wisconsin 53719, USA. vbakshi@facstaff.wisc.edu
Smith-Roe
Stephanie
S
Newman
Sarah M
SM
Grigoriadis
Dimitri E
DE
Kalin
Ned H
NH
D029845:Amphibian Proteins; D000679:Amygdala / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001667:Binding, Competitive / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage; D004333:Drug Administration Routes; D006727:Hormone Antagonists / Q000008:administration & dosage; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D036361:Peptide Hormones; D010455:Peptides / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020665:Septum of Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013312:Stress, Physiological / Q000188:drug therapy*; D000099052:CRF Receptor, Type 1
D029845:Amphibian Proteins; C101531:CRF receptor type 2; D006727:Hormone Antagonists; D036361:Peptide Hormones; D010455:Peptides; D018019:Receptors, Corticotropin-Releasing Hormone; C069206:alpha helical corticotropin-releasing hormone; D000099052:CRF Receptor, Type 1; C025727:sauvagine; D003346:Corticotropin-Releasing Hormone