Background
Women are twice as likely as men to suffer from stress-related affective disorders.
Corticotropin-releasing factor (CRF) is an important link between stress and mood,
in part through its signaling in the serotonergic dorsal raphe (DR). Development of
CRF receptor-1 (CRFr1) antagonists has been a focus of numerous clinical trials but
has not yet been proven efficacious. We hypothesized that sex differences in CRFr1
modulation of DR circuits might be key determinants in predicting therapeutic responses
and affective disorder vulnerability.
Methods
Male and female mice received DR infusions of the CRFr1 antagonist, NBI 35965, or
CRF and were evaluated for stress responsivity. Sex differences in indices of neural
activation (cFos) and colocalization of CRFr1 throughout the DR were examined. Whole-cell
patch-clamp electrophysiology assessed sex differences in serotonin neuron membrane
characteristics and responsivity to CRF.
Results
Males showed robust behavioral and hypothalamic-pituitary-adrenal axis responses to
DR infusion of NBI 35965 and CRF, whereas females were minimally responsive. Sex differences
were also found for both CRF-induced DR cFos and CRFr1 co-localization throughout
the DR. Electrophysiologically, female serotonergic neurons showed blunted membrane
excitability and divergent inhibitory postsynaptic current responses to CRF application.
Conclusions
These studies demonstrate convincing sex differences in CRFr1 activity in the DR,
where blunted female responses to NBI 35965 and CRF suggest unique stress modulation
of the DR. These sex differences might underlie affective disorder vulnerability and
differential sensitivity to pharmacologic treatments developed to target the CRF system,
thereby contributing to a current lack of CRFr1 antagonist efficacy in clinical trials.
Key Words
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Article info
Publication history
Published online: December 02, 2013
Accepted:
October 16,
2013
Received in revised form:
September 26,
2013
Received:
July 1,
2013
Footnotes
Authors ARH and AVR contributed equally to this work.
Identification
Copyright
© 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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- Intersections of Sex and Corticotropin-Releasing FactorBiological PsychiatryVol. 75Issue 11
- PreviewSince its original identification and characterization in 1981 by Vale et al. (1), corticotropin-releasing factor (CRF)—now also called corticotropin-releasing hormone—has been intimately linked with stress regulation and conditioned fear and anxiety. For example, knockout of the CRF receptor 1 (CRFr1) has anxiolytic effects (2,3), while CRF overexpression increases conditioned fear (4). With the increasing availability of highly selective tools, roles for CRF in discrete cell populations have also been established.
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