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The Journal of Neuroscience, April 1, 2002, 22(7):2926-2935

Reduction of Stress-Induced Behavior by Antagonism of Corticotropin-Releasing Hormone 2 (CRH₂) Receptors in Lateral Septum or CRH₁ Receptors in Amygdala

Vaishali P. Bakshi¹, Stephanie Smith-Roe², Sarah M. Newman¹, Dimitri E. Grigoriadis³, and Ned H. Kalin¹

¹ Department of Psychiatry, University of Wisconsin, Madison, Wisconsin 53719, ² Department of Environmental Toxicology, Oregon State University, Corvallis, Oregon 97330, and ³ Neurocrine Biosciences Inc., San Diego, California 92121

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 -helical CRH (hCRH, 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 hCRH 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 µg), 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 hCRH 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, hCRH 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.

Key words: CRF; anxiety; corticotropin-releasing hormone; corticotropin-releasing factor; defensive behavior; freezing; behavioral inhibition

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2272926-10$05.00/0

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