Acute Hydrocortisone Treatment Increases Anxiety but Not Fear in Healthy Volunteers: A Fear-Potentiated Startle Study

Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-2670, USA.
Biological psychiatry (Impact Factor: 9.47). 03/2011; 69(6):549-55. DOI: 10.1016/j.biopsych.2010.12.013
Source: PubMed

ABSTRACT The debilitating effects of chronic glucocorticoids excess are well-known, but comparatively little is understood about the role of acute cortisol. Indirect evidence in rodents suggests that acute cortisone could selectively increase some forms of long-duration aversive states, such as "anxiety," but not relatively similar, briefer aversive states, such as "fear." However, no prior experimental studies in humans consider the unique effects of cortisol on anxiety and fear, using well-validated methods for eliciting these two similar but dissociable aversive states. The current study examines these effects, as instantiated with short- and long-duration threats.
Healthy volunteers (n = 18) received placebo or a low (20 mg) or a high (60 mg) dose of hydrocortisone in a double-blind crossover design. Subjects were exposed repeatedly to three 150-sec duration conditions: no shock; predictable shocks, in which shocks were signaled by a short-duration threat cue; and unpredictable shocks. Aversive states were indexed by acoustic startle. Fear was operationally defined as the increase in startle reactivity during the threat cue in the predictable condition (fear-potentiated startle). Anxiety was operationally defined as the increase in baseline startle from the no shock to the two threat conditions (anxiety-potentiated startle).
Hydrocortisone affected neither baseline nor short-duration, fear-potentiated startle but increased long-duration anxiety-potentiated startle.
These results suggest that hydrocortisone administration in humans selectively increases anxiety but not fear. Possible mechanisms implicated are discussed in light of prior data in rodents. Specifically, hydrocortisone might increase anxiety via sensitization of corticotrophin-releasing hormones in the bed nucleus of the stria terminalis.

Download full-text


Available from: Daniel S Pine, Aug 26, 2015
1 Follower
  • Source
    • "anxiety) without affecting the acute, short-term threat response (i.e. fear) [Grillon et al., 2011]. Moreover, evidence showing that glucocorticoids induce approach motivation [Putman et al., 2010a,b], aggression [B€ ohnke et al., 2010] and active stressbehaviors [Thaker et al., 2009], suggests that glucocorticoids particularly drive active fight-flight behaviors and might not be anxiolytic per se. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Evolution has provided us with a highly flexible neuroendocrine threat system which, depending on threat imminence, switches between active escape and passive freezing. Cortisol, the "stress-hormone", is thought to play an important role in both fear behaviors, but the exact mechanisms are not understood. Using pharmacological functional magnetic resonance imaging we investigated how cortisol modulates the brain's fear systems when humans are under virtual-predator attack. We show dissociated neural effects of cortisol depending on whether escape from threat is possible. During inescapable threat cortisol reduces fear-related midbrain activity, whereas in anticipation of active escape cortisol boosts activity in the frontal salience network (insula and anterior cingulate cortex), which is involved in autonomic control, visceral perception and motivated action. Our findings suggest that cortisol adjusts the human neural threat system from passive fear to active escape, which illuminates the hormone's crucial role in the adaptive flexibility of fear behaviors. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Human Brain Mapping 08/2015; DOI:10.1002/hbm.22918 · 6.92 Impact Factor
  • Source
    • "In contrast to this gender effect, exposure to a stress manipulation (elevating both the sympathetic and the glucocorticoid stress response) facilitated cue fear conditioning in men but not in women (Zorawski et al., 2005, 2006; Jackson et al., 2006). Furthermore, a high dose of hydrocortisone (60 mg) exclusively enhanced context fear conditioning in both sexes, while leaving cue fear conditioning unaffected (Grillon et al., 2011). Finally, delay eyeblink conditioning is impaired in men and women after a stress manipulation (TSST; Wolf et al., 2009), whereas trace eyeblink conditioning is improved by a stress manipulation (CPT; Duncko et al., 2007) as well as by cortisol (2 mg, administered intravenously; Kuehl et al., 2010), but also by a cortisol inhibitor (1500 mg metyrapone; Nees et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Memories for emotionally arousing and fearful events are generally well retained. From the evolutionary point of view this is a highly adaptive behavioral response aimed to remember relevant information. However, fearful memories can also be inappropriately and vividly (re)expressed, such as in posttraumatic stress disorder. The memory formation of emotionally arousing events is largely modulated by hormones, peptides, and neurotransmitters which are released during and after exposure to these conditions. One of the core reactions in response to a stressful situation is the rapid activation of the autonomic nervous system, which results in the release of norepinephrine in the brain. In addition, stressful events stimulate the hypothalamus-pituitary-adrenal axis which slowly increases the release of glucocorticoid hormones from the adrenal glands. Here we will review how glucocorticoids and norepinephrine regulate the formation of fearful memories in rodents and humans and how these hormones can facilitate the storage of information by regulating excitatory synapses.
    Frontiers in Behavioral Neuroscience 10/2011; 5:62. DOI:10.3389/fnbeh.2011.00062 · 4.16 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The threat of predictable and unpredictable aversive events was developed to assess short-duration (fear) and long-duration (anxiety) aversive states in humans. A typical experiment consists of three conditions: a safe condition (neutral (N)), during which participants are safe from aversive stimuli, and two threat conditions-one in which aversive events are administered predictably (P) (i.e., signaled by a threat cue), and one in which aversive stimuli are administered unpredictably (U). During the so-called NPU-threat test, ongoing change in aversive states is measured with the startle reflex. The NPU-threat test has been validated in pharmacological and clinical studies and can be implemented in children and adults. Similar procedures have been applied in animal models, making the NPU-threat test an ideal tool for translational research. The procedure is relatively short (35 min), simple to implement and generates consistent results with large effect sizes.
    Nature Protocol 02/2012; 7(3):527-32. DOI:10.1038/nprot.2012.001 · 8.36 Impact Factor
Show more