Abstract
Rationale
Hypersecretion of corticotropin releasing factor (CRF) has been implicated in both severe anxiety disorders and major depression. Although the role of the CRF1 receptor in the anxiogenic effects of CRF is well supported, the role of CRF2 receptors in anxiety-like behaviors is less clear. In rats, CRF increases the acoustic startle reflex (ASR) via its action in the extended amygdala, providing a putative measure of CRF-mediated anxiogenic activity.
Objective
To characterize the effect of CRF on ASR in mice and determine the respective roles of CRF1 and CRF2 receptors in CRF-potentiated ASR.
Methods
The present study examined: (1) the time course and dose response functions for the effects of human/rat (h/r)-CRF (0.02–0.6 nmol, ICV (intracerebroventricular)) on ASR in two inbred strains of mice; (2) the effects of the CRF1 receptor antagonist NBI-30775 (20 mg/kg, intraperitoneal) and the CRF2 receptor antagonist Antisauvagine-30 (1–10 nmol, ICV) on CRF-potentiated ASR and (3) the effects of the CRF2 receptor agonist urocortin 2 (0.2–6 nmol, ICV) on ASR in mice.
Results
h/r-CRF significantly increased ASR in mice in a time-dependent manner with maximal efficacy at the 0.2 and 0.6 nmol doses. 129S6/SvEvTac mice exhibited a slightly increased duration of action and lower minimal effective dose threshold for CRF effects on ASR compared to C57BL/6J mice. Both selective CRF1 and CRF2 antagonists attenuated h/r-CRF-potentiated ASR without affecting acoustic startle when given alone. The selective CRF2 receptor agonist urocortin 2 increased ASR (1 and 2 nmol), albeit with less efficacy than the non-selective CRF receptor agonist h/r-CRF.
Conclusions
Both CRF1 and CRF2 receptors appear to contribute to the h/r-CRF-induced increases in ASR in mice. These data support the hypothesis that both receptors contribute to the anxiogenic effects of CRF.
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Acknowledgements
The authors thank Drs. Dimitri Grigoriadis and Alan Foster of Neurocrine Biosciences for the CRF antagonists and their helpful comments and suggestions throughout the experimental and manuscript processes. We thank Frank Dautzenberg for his constructive review of the manuscript and Margaret Joppa for invaluable instruction on ICV injections. We are also grateful to Jonathon Stroebel, Sara Tehrani, Sorana Caldwell, and Katrina Paumier for technical assistance. This research was supported by the US Veterans Affairs VISN 22 Mental Illness Research, Education, and Clinical Center (MIRECC; M.A.G. and R.L.H.), a VA Merit Review grant (R.L.H.), a MERCK NEP fellowship and an NIMH National Research Service Award (V.B.R.), and the National Institute on Drug Abuse [DA02925 (M.A.G.) and DA13769–01 (R.L.H.)].
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Risbrough, V.B., Hauger, R.L., Pelleymounter, M.A. et al. Role of corticotropin releasing factor (CRF) receptors 1 and 2 in CRF-potentiated acoustic startle in mice. Psychopharmacology 170, 178–187 (2003). https://doi.org/10.1007/s00213-003-1535-6
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DOI: https://doi.org/10.1007/s00213-003-1535-6