Reduction of fear-potentiated startle by benzodiazepines in C57BL/6J mice

Kiersten S. Smith, Edward G. Meloni, Karyn M. Myers, Ashlee Van't Veer, William A. Carlezon, Uwe Rudolph

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale: Anxiety disorders affect 18% of the United States adult population annually. Recent surges in the diagnosis of posttraumatic stress disorder (PTSD) from combat-exposed veterans have prompted an urgent need to understand the pathophysiology underlying this debilitating condition. Objectives: Anxiety and fear responses are partly modulated by gamma aminobutyric acid type A (GABAA) receptor-mediated synaptic inhibition; benzodiazepines potentiate GABAergic inhibition and are effective anxiolytics. Many genetically modified mouse lines are generated and/or maintained on the C57BL/6J background, a strain where manipulation of anxiety-like behavior using benzodiazepines is difficult. Fear-potentiated startle (FPS), a test of conditioned fear, is a useful preclinical tool to study PTSD-like responses but has been difficult to establish in C57BL/6J mice. Methods: We modified several FPS experimental parameters and developed a paradigm to assess conditioned fear in C57BL/6J mice. The 6-day protocol consisted of three startle Acclimation days, a Pre-Test day followed by Training and Testing for FPS. Subject responses to the effects of three benzodiazepines were also examined. Results: C57BL/6J mice had low levels of unconditioned fear assessed during Pre-Test (15-18%) but showed robust FPS (80-120%) during the Test session. Conditioned fear responses extinguished over repeated test sessions. Administration of the benzodiazepines alprazolam (0.5 and 1 mg/kg, i.p.), chlordiazepoxide (5 and 10 mg/kg, i.p.), and diazepam (1, 2, and 4 mg/kg, i.p.) significantly reduced FPS to Pre-Test levels. Conclusions: We used a modified and pharmacologically-validated paradigm to assess FPS in mice thereby providing a powerful tool to examine the neurobiology of PTSD in genetic models of anxiety generated on the C57BL/6J background.

Original languageEnglish (US)
Pages (from-to)697-706
Number of pages10
JournalPsychopharmacology
Volume213
Issue number4
DOIs
StatePublished - Feb 2011
Externally publishedYes

Keywords

  • Anxiety
  • Benzodiazepine
  • C57BL/6J mice
  • Chlordiazepoxide
  • Diazepam
  • Fear-potentiated startle

ASJC Scopus subject areas

  • Pharmacology

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