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: 10.26). 03/2011; 69(6):549-55. DOI: 10.1016/j.biopsych.2010.12.013
Source: PubMed


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.

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    • "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. "
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    • "d stress hormone ( e . g . , cortisol ) function within the hypothalamic - pituitary - adrenal axis ( Fara - velli et al . , 2012 ; Stetler & Miller , 2011 ) . Grillon and colleagues examined the impact of placebo - con - trolled hydrocortisone ( i . e . , natural or synthetic corti - sol used as a medication ) administration on startle response ( Grillon et al . , 2011 ) . Guided by a theoreti - cal model , these investigators separated short dura - tion fear - potentiated startle 2 from long duration anxiety - potentiated startle . 3 Fear - potentiated startle has been primarily linked to signaling in the central amygdala , whereas anxiety - potentiated startle has been associated with signaling in t"

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    • "This may have been caused by relative small n size. Another explanation could be that the current dose of hydrocortisone employed was 20 mg as opposed to 60 mg that Grillon and colleagues employed (Grillon et al., 2011). Also, we did not observe altered baseline FPS startle responding (i.e., as measured on trials in between context presentation), in contrast with one study who found heightened FPS due to cortisol (Buchanan et al., 2001). "
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    ABSTRACT: At the core of anxiety disorders is the inability to use contextual information to modulate behavioral responses to potentially threatening events. Models of the pathogenesis of anxiety disorders incorporate stress and concomitant stress hormones as important vulnerability factors, while others emphasize sex as an important factor. However, translational basic research has not yet investigated the effects of stress hormones and sex on the ability to use contextual information to modulate responses to threat. Therefore, the purpose of the present study was threefold: first, we aimed at developing an experimental paradigm specifically capable of capturing contextual modulation of the expression of fear. Second, we tested whether cortisol would alter the contextualization of fear expression. Third, we aimed at assessing whether alterations in contextualization due to cortisol were different for men and women. Healthy participants (n = 42) received placebo or hydrocortisone (20 mg) prior to undergoing a newly developed differential contextual fear-conditioning paradigm. The results indicated that people rapidly acquire differential contextual modulation of the expression of fear, as measured by fear potentiated startle (FPS) and skin conductance responses (SCR). In addition, cortisol impaired the contextualization of fear expression leading to increased fear generalization on FPS data in women. The opposite pattern was found in men. Finally, as assessed by SCR, cortisol impaired differential conditioning in men. The results are in line with models suggesting heightened vulnerability in women for developing anxiety disorders after stressful events.
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