The Benzodiazepine Alprazolam Dissociates Contextual Fear from Cued Fear in Humans as Assessed by Fear-potentiated Startle

Mood and Anxiety Disorder Program, National Institutes of Mental Health, Bethesda, Maryland 20892-2670, USA.
Biological Psychiatry (Impact Factor: 10.26). 11/2006; 60(7):760-6. DOI: 10.1016/j.biopsych.2005.11.027
Source: PubMed


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

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    • "Broadly, predictable threat elicits a phasic response to an identifiable stimulus (labeled fear), while unpredictable threat elicits a generalized feeling of apprehension not associated with a clearly identifiable source (labeled anxiety;Davis, 1998;Barlow, 2000). These two types of threat have been shown to elicit qualitatively distinct aversive states (Davis, 1998;Davis et al., 2010;Grillon et al., 2006), and have overlapping , yet separable neural correlates (Alvarez et al., 2011;Davis, 2006). In order to assess fear and anxiety responses separately, Grillon and colleagues developed the NPU-threat paradigm (Grillon et al., 2004;Schmitz and Grillon, 2012). "
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    ABSTRACT: Heightened sensitivity to threat is a characteristic feature of panic disorder (PD). It is also a factor that is considered to be central to PD but not major depressive disorder (MDD) - a related disorder that commonly co-occurs with PD. However, sensitivity to threat is a broad construct and it is unclear whether individuals with PD exhibit heightened initial threat reactivity, impairments in modulating their threat responding over time, or both. It is also unclear how these different facets of threat responding apply to predictable and/or unpredictable threat. The aim of the current study was to examine whether there are differences in initial threat reactivity and the time course of threat responding during predictable and unpredictable threat-of-shock in 186 adults with: 1) current PD and no history of depression (i.e., PD-only), 2) current MDD and no history of an anxiety disorder (i.e., MDD-only), 3) current comorbid PD and MDD, or 4) no lifetime history of psychopathology (i.e., controls). Threat responding was assessed using an electromyography startle paradigm. Relative to controls, individuals in the three psychopathology groups exhibited heightened initial threat reactivity to predictable and unpredictable threat and did not differ from each other. Multilevel mixed model analyses indicated that those with PD evidenced less of a decline over time in startle responding during unpredictable threat relative to those without PD. Those with MDD displayed a greater slope of decline in startle responding during predictable threat compared with those without MDD. The pattern of results suggests that there may be conceptual differences between measures of initial threat reactivity and time course of threat responding. Moreover, time course of threat responding, not initial threat reactivity, may differentiate PD from MDD. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jul 2015 · International Journal of Psychophysiology
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    • "The startle data appear in Table 3 (top). As in our previous studies and consistent with our a priori hypotheses (see, eg, Grillon et al, 2006, 2009a, 2013), we examined fear and anxiety separately. Fear-potentiated startle was operationally defined as the increased startle magnitude from ITI to the threat cue in P and anxiety-potentiated startle was operationally defined as the increased ITI startle magnitude from N to U. Fear-potentiated startle was analyzed using a two-way Stimulus Type (ITI, cue) Â Treatment (placebo, alprazolam, low-GSK, and high-GSK) rANOVA. "
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    ABSTRACT: Fear to predictable threat and anxiety to unpredictable threat reflect distinct processes mediated by different brain structures, the central nucleus of the amygdala and the bed nucleus of the stria terminalis (BNST), respectively. The present study tested the hypothesis that the corticotropin releasing factor (CRF1) antagonist GSK561679 differentially reduces anxiety but increases fear in humans. Thirty one healthy females received each of four treatments, placebo, 50 mg GSK561679 (low-GSK), 400 mg GSK561679 (high-GSK), and 1 mg alprazolam in a crossover design. Participants were exposed to three conditions during each of the four treatments. The three conditions included one in which predictable aversive shocks were signaled by a cue, a second during which shocks were administered unpredictably, and a third condition without shock. Fear and anxiety were assessed using the acoustic startle reflex. High-GSK had no effect on startle potentiation during unpredictable threat (anxiety) but increased startle potentiation during the predictable condition (fear). Low-GSK did not affect startle potentiation across conditions. Consistent with previous findings, alprazolam reduced startle potentiation during unpredictable threat but not during predictable threat. The increased fear by high-GSK replicates animal findings and suggests a lift of the inhibitory effect of the bed nucleus of the stria terminalis (BNST) on the amygdala by the CRF1 antagonist.Neuropsychopharmacology accepted article preview online, 28 November 2014. doi:10.1038/npp.2014.316.
    Full-text · Article · Nov 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "Dissociations in findings between physiological (startle) and subjective (shock expectancy or fearfulness ratings) measures have been found in many previous studies (Grillon et al., 2006; Heitland et al., 2012, 2013; Kindt et al., 2009). However, it is usually the case in studies looking at a neurobiological manipulation (e.g., the administration of a pharmacological substance), or genetics, that physiological measures are more sensitive than subjective measures. "
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    ABSTRACT: In everyday life, aversive events are usually associated with certain predictive cues. Normally, the acquisition of these contingencies enables organisms to appropriately respond to threat. Presence of a threat cue clearly signals ‘danger’, whereas absence of such cues signals a period of ‘safety’. Failure to identify threat cues may lead to chronic states of anxious apprehension in the context in which the threat has been imminent, which may be instrumental in the pathogenesis of anxiety disorders.
    Full-text · Article · Nov 2014 · International Journal of Psychophysiology
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