title: Sex differences in corticotropin-releasing factor receptor-1 action within the dorsal raphe nucleus in stress responsivity.
abstract: 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.
authors.affiliation: Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Alexis R
authors.initials: AR
authors.lastname: Howerton
authors.affiliation: Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Alison V
authors.initials: AV
authors.lastname: Roland
authors.affiliation: Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Fluharty
authors.affiliation: Department of Psychology, University at Buffalo, State University of New York, Buffalo, New York.
authors.forename: Anikò
authors.initials: A
authors.lastname: Marshall
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Chen
authors.affiliation: Department of Psychology, University at Buffalo, State University of New York, Buffalo, New York.
authors.forename: Derek
authors.initials: D
authors.lastname: Daniels
authors.affiliation: Department of Anesthesia, Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania.
authors.forename: Sheryl G
authors.initials: SG
authors.lastname: Beck
authors.affiliation: Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: tbale@vet.upenn.edu.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Bale
mesh_terms: D000073:Acenaphthenes / Q000494:pharmacology; D000818:Animals; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D065847:Dorsal Raphe Nucleus / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006728:Hormones / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists / Q000037:antagonists & inhibitors*; D012737:Sex Factors; D013315:Stress, Psychological / Q000378:metabolism*; D000099052:CRF Receptor, Type 1
chemical_list: C504986:6-cyclopropylmethyl-2-(2,4-dichlorophenyl)-7-ethyl-4-methyl-7,8-dihydro-6H-1,3,6,8a-tetraazaacenaphthylene; D000073:Acenaphthenes; D006728:Hormones; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone
keywords: CRF receptor-1; Corticotropin releasing factor; GABA; dorsal raphe nucleus; parvalbumin; serotonin; sex; stress