Elsevier

Biological Psychiatry

Volume 75, Issue 11, 1 June 2014, Pages 873-883
Biological Psychiatry

Archival Report
Sex Differences in Corticotropin-Releasing Factor Receptor-1 Action Within the Dorsal Raphe Nucleus in Stress Responsivity

https://doi.org/10.1016/j.biopsych.2013.10.013Get rights and content

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.

Section snippets

Subjects

A total of 268 adult male and female littermate mice were used for all experiments. Mice were maintained under a 12-hour light/dark cycle with ad libitum access to food and water. For behavioral experiments and electrophysiological studies, C57Bl/6:129S/J F1 hybrid mice were obtained from the Jackson Laboratory (Bar Harbor, Maine) or bred in house. For CRFr1 colocalization studies, mice with fluorescent-labeled CRFr1 containing neurons were generated as previously described (39). Mice received

DR Infusions of NBI 35965 or CRF Preferentially Alter Male Corticosterone Production

The 5-HT output from the DR has modulatory activity on the hypothalamic-pituitary-adrenal (HPA) axis 34, 35. The CRF regulation of DR neurons could therefore influence HPA responsiveness. Thus, we assessed the effect of CRFr1 antagonism within the DR on the corticosterone response to restraint stress (Figure 1). The NBI significantly blunted corticosterone levels in males (F1,9 = 7.085, p = .026). The effect of NBI was manifested as a reduction in the rise time from 0 to 30 min before restraint

Discussion

Stress-mediated affective disorders display significant sex differences in incidence and treatment efficacy 1, 56. The CRFr1 is a key mediator of neuroendocrine and behavioral stress responses, in part through signaling in the 5-HTergic DR 27, 28, 29, 30. Because there are known sex differences in the DR, dysregulation of 5-HTergic signaling might to contribute to increased disease risk in females 57, 58. Development of CRFr1 small molecule antagonists has been a major focus in clinical trials

References (84)

  • D.M. Nielsen et al.

    Antidepressant-like activity of corticotropin-releasing factor type-1 receptor antagonists in mice

    Eur J Pharmacol

    (2004)
  • D.H. Overstreet et al.

    Antidepressant effects of citalopram and CRF receptor antagonist CP-154,526 in a rat model of depression

    Eur J Pharmacol

    (2004)
  • M. Carlsson et al.

    A regional study of sex differences in rat brain serotonin

    Prog Neuropsychopharmacol Biol Psychiatry

    (1988)
  • S.K. Wood et al.

    Cellular adaptations of dorsal raphe serotonin neurons associated with the development of active coping in response to social stress

    Biol Psychiatry

    (2013)
  • J.L. Lukkes et al.

    Corticotropin-releasing factor 1 and 2 receptors in the dorsal raphe differentially affect serotonin release in the nucleus accumbens

    Eur J Pharmacol

    (2008)
  • L.F. Faulconbridge et al.

    Caudal brainstem delivery of ghrelin induces fos expression in the nucleus of the solitary tract, but not in the arcuate or paraventricular nuclei of the hypothalamus

    Brain Res

    (2008)
  • J.A. Rosecrans

    Differences in brain area 5-hydroxytryptamine turnover and rearing behavior in rats and mice of both sexes

    Eur J Pharmacol

    (1970)
  • R. Hiroi et al.

    Estrogen selectively increases tryptophan hydroxylase-2 mRNA expression in distinct subregions of rat midbrain raphe nucleus: Association between gene expression and anxiety behavior in the open field

    Biol Psychiatry

    (2006)
  • D.H. Kim et al.

    Intracerebroventricular injection-induced increase in plasma corticosterone levels in the mouse: A stress model

    J Pharmacol Toxicol Methods

    (1998)
  • P.E. Sawchenko et al.

    The distribution and cells of origin of serotonergic inputs to the paraventricular and supraoptic nuclei of the rat

    Brain Res

    (1983)
  • A. Neufeld-Cohen et al.

    Chronic activation of corticotropin-releasing factor type 2 receptors reveals a key role for 5-HT1A receptor responsiveness in mediating behavioral and serotonergic responses to stressful challenge

    Biol Psychiatry

    (2012)
  • A.J. Dunn et al.

    Physiological and behavioral responses to corticotropin-releasing factor administration: Is CRF a mediator of anxiety or stress responses?

    Brain Res Brain Res Rev

    (1990)
  • J.K. Abrams et al.

    Serotonergic systems associated with arousal and vigilance behaviors following administration of anxiogenic drugs

    Neuroscience

    (2005)
  • K.A. Allers et al.

    Neurochemical and anatomical identification of fast- and slow-firing neurones in the rat dorsal raphe nucleus using juxtacellular labelling methods in vivo

    Neuroscience

    (2003)
  • T. Kapitany et al.

    The citalopram challenge test in patients with major depression and in healthy controls

    Psychiatry Res

    (1999)
  • L.D. Van de Kar

    Neuroendocrine aspects of the serotonergic hypothesis of depression

    Neurosci Biobehav Rev

    (1989)
  • A.W. Zobel et al.

    Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated

    J Psychiatr Res

    (2000)
  • R.C. Kessler et al.

    Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication

    Arch Gen Psychiatry

    (2005)
  • W. Vale et al.

    Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin

    Science

    (1981)
  • R.E. Sutton et al.

    Corticotropin releasing factor produces behavioural activation in rats

    Nature

    (1982)
  • M.P. Stenzel-Poore et al.

    Overproduction of corticotropin-releasing factor in transgenic mice: A genetic model of anxiogenic behavior

    J Neurosci

    (1994)
  • P. Timpl et al.

    Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1

    Nat Genet

    (1998)
  • K.E. Habib et al.

    Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates

    Proc Natl Acad Sci U S A

    (2000)
  • M.B. Muller et al.

    Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress

    Nat Neurosci

    (2003)
  • M.E. Keck et al.

    The high-affinity non-peptide CRH1 receptor antagonist R121919 attenuates stress-induced alterations in plasma oxytocin, prolactin, and testosterone secretion in rats

    Pharmacopsychiatry

    (2003)
  • M. Paez-Pereda et al.

    Corticotropin releasing factor receptor antagonists for major depressive disorder

    Expert Opin Investig Drugs

    (2011)
  • T. Deak et al.

    The impact of the nonpeptide corticotropin-releasing hormone antagonist antalarmin on behavioral and endocrine responses to stress

    Endocrinology

    (1999)
  • G. Griebel et al.

    4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylp henyl)ethyl]5-methyl-N-(2-propynyl)-1, 3-thiazol-2-amine hydrochloride (SSR125543A), a potent and selective corticotrophin-releasing factor(1) receptor antagonist. II. Characterization in rodent models of stress-related disorders

    J Pharmacol Exp Ther

    (2002)
  • S. Lelas et al.

    Anxiolytic-like effects of the corticotropin-releasing factor1 (CRF1) antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyr imidine] administered acutely or chronically at doses occupying central CRF1 receptors in rats

    J Pharmacol Exp Ther

    (2004)
  • E.M. Jutkiewicz et al.

    The effects of CRF antagonists, antalarmin, CP154,526, LWH234, and R121919, in the forced swim test and on swim-induced increases in adrenocorticotropin in rats

    Psychopharmacology (Berl)

    (2005)
  • G.F. Koob et al.

    Update on corticotropin-releasing factor pharmacotherapy for psychiatric disorders: A revisionist view

    Neuropsychopharmacology

    (2012)
  • R.J. Valentino et al.

    Evidence for regional heterogeneity in corticotropin-releasing factor interactions in the dorsal raphe nucleus

    J Comp Neurol

    (2001)

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    Authors ARH and AVR contributed equally to this work.

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