Corticotropin-Releasing Factor Receptors CRF1and CRF2Exert Both Additive and Opposing Influences on Defensive Startle Behavior

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Abstract
The corticotropin-releasing factor (CRF) receptors (CRF1and CRF2) are crucial mediators of physiological and behavioral responses to stress. In animals, CRF1appears to primarily mediate CRF-induced anxiety-like responses, but the role of CRF2during stress is still unclear. Here we report the effects of CRF1and CRF2on 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 CRF1reversed both CRF-induced increases in startle and CRF-induced deficits in PPI. CRF2blockade attenuated high-dose but not low-dose CRF-induced increases in startle and reduced PPI. Conversely, activation of CRF2enhanced PPI. CRF had no effect on startle and increased PPI in CRF1knock-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, CRF1receptors contravene, whereas CRF2receptors enhance, the impact of sensory information on defensive behavior. We hypothesize that excessive CRF1activation combined with reduced CRF2signaling may contribute to information processing deficits seen in panic and posttraumatic stress disorder patients and support CRF1-specific pharmacotherapy.

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