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The Journal of Neuroscience, July 21, 2004, 24(29):6545-6552; doi:10.1523/JNEUROSCI.5760-03.2004

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Behavioral/Systems/Cognitive
Corticotropin-Releasing Factor Receptors CRF₁ and CRF₂ Exert Both Additive and Opposing Influences on Defensive Startle Behavior

Victoria B. Risbrough,¹ Richard L. Hauger,^2,3 Amanda L. Roberts,⁴ Wylie W. Vale,⁵ and Mark A. Geyer^1,2,3

Departments of ¹Neurosciences and ²Psychiatry, University of California, San Diego, La Jolla, California 92093-0804, ³Veterans Affairs Healthcare System and Department of Psychiatry, University of California, San Diego, La Jolla, California 92093-0603, ⁴Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, and ⁵Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037

The corticotropin-releasing factor (CRF) receptors (CRF₁ and CRF₂) are crucial mediators of physiological and behavioral responses to stress. In animals, CRF₁ appears to primarily mediate CRF-induced anxiety-like responses, but the role of CRF₂ during stress is still unclear. Here we report the effects of CRF₁ and CRF₂ on the magnitude and plasticity of defensive startle responses in mice. Startle plasticity is measured by inhibition of startle by sensory stimuli, i.e., prepulse inhibition (PPI), and is disrupted in patients with panic or posttraumatic stress disorders in which CRF neurotransmission may be overactive. Pharmacological blockade of CRF₁ reversed both CRF-induced increases in startle and CRF-induced deficits in PPI. CRF₂ blockade attenuated high-dose but not low-dose CRF-induced increases in startle and reduced PPI. Conversely, activation of CRF₂ enhanced PPI. CRF had no effect on startle and increased PPI in CRF₁ knock-out mice. These data indicate that CRF receptors act in concert to increase the magnitude of defensive startle yet in opposition to regulate the flexibility of startle. These data support a new model of respective CRF receptor roles in stress-related behavior such that, although both receptors enhance the magnitude of defensive responses, CRF₁ receptors contravene, whereas CRF₂ receptors enhance, the impact of sensory information on defensive behavior. We hypothesize that excessive CRF₁ activation combined with reduced CRF₂ signaling may contribute to information processing deficits seen in panic and posttraumatic stress disorder patients and support CRF₁-specific pharmacotherapy.

Key words: CRH; antisauvagine-30; NBI-30775; R121919; urocortin; anxiety

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Received Dec 31, 2003; revised June 7, 2004; accepted June 7, 2004.

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