The benzodiazepine alprazolam dissociates contextual fear from cued fear in humans as assessed by fear-potentiated startle

Biol Psychiatry. 2006 Oct 1;60(7):760-6. doi: 10.1016/j.biopsych.2005.11.027. Epub 2006 Apr 21.


Background: The startle reflex is potentiated by aversive states. It has been proposed that phasic startle potentiation to a threat cue and sustained startle potentiation to contextual stimuli reflect distinct processes mediated by different brain structures. The present study tested the hypothesis that alprazolam would reduce the sustained startle potentiation to contextual threats but not the startle potentiation to a threat cue.

Methods: Sixteen healthy subjects received each of four treatments: placebo, .5 mg of alprazolam, 1 mg of alprazolam, and 50 mg of diphenhydramine (Benadryl) in a crossover design. Participants were exposed to three conditions, including one in which predictable aversive shocks were signaled by a cue, a second in which shocks were administered unpredictably, and a third condition in which no shocks were anticipated. Acoustic startle were delivered regularly across conditions.

Results: Phasic startle potentiation to the threat cue in the predictable condition was not affected by alprazolam. In contrast, the sustained increase in startle in the predictable and unpredictable conditions was reduced significantly by the high dose of alprazolam.

Conclusions: Startle responses to an explicit threat cue and to an aversive context are psychopharmacologically distinct, suggesting that they may represent functionally dissociable aversive states.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Intramural

MeSH terms

  • Acoustic Stimulation
  • Adult
  • Alprazolam / pharmacology*
  • Analysis of Variance
  • Anti-Anxiety Agents / pharmacology*
  • Anxiety / psychology
  • Association Learning / drug effects
  • Conditioning, Classical / drug effects*
  • Cross-Over Studies
  • Diphenhydramine / pharmacology
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Environment
  • Fear / drug effects*
  • Fear / psychology
  • Female
  • Humans
  • Hypnotics and Sedatives / pharmacology
  • Male
  • Reference Values
  • Reflex, Startle / drug effects*


  • Anti-Anxiety Agents
  • Hypnotics and Sedatives
  • Diphenhydramine
  • Alprazolam