Although evidence suggests that chronic as well as acute glucocorticoids are anxiogenic in animals (2
), much remains to be learned about their emotional effects in humans. A key question is whether cortisol sensitizes anxiety or is involved in its termination. The present results indicate that cortisol increases anxiety. Specifically, we examined the effect of acute hydrocortisone treatment on two types of potentiated startle responses, fear-potentiated startle evoked by a short-duration threat cue and anxiety-potentiated startle associated with longer-duration contextual threat. Results showed that the high dose of hydrocortisone (60 mg) increased anxiety-potentiated startle without affecting fear-potentiated startle. The results showing that cortisol increases aversive states are consistent with the observation that increased endogenous cortisol levels are associated with negative affect and with animal (33
) and human (34
) data showing an anxiogenic effect of cortisol on potentiated startle.
That glucocorticoids are anxiogenic is also in line with findings that blockade of glucocorticoid synthesis reduces anxiety in humans. Indeed, the preclinical finding that inhibition of steroid synthesis reduces both corticosterone levels and anxiety in rats exposed to a predator (cat) (35
) has prompted similar investigations in humans. The effect of the cortisol synthesis inhibitor metyrapone was evaluated in patients with panic disorders. In one study, metyrapone nonsignificantly reduced anxiety symptoms in the healthy comparison group (36
). In another study, which used a panicogenic carbon dioxide challenge, metyrapone modestly reduced anxiety during the period that preceded the panicogenic challenge in the patients without affecting the panic symptoms to the challenge itself, suggesting a differential effect of cortisol on fear and generalized anxiety symptoms (37
). These results are consistent with the present findings that hydrocortisone increased anxiety but not fear.
These findings point to an anxiogenic effect of hydrocortisone, but contradictory results have been reported. Hydrocortisone decreases negative mood (38
), but null effect (40
) as well as increased negative mood (7
) have also been found. One possibility is that hydrocortisone lessens negative mood during mild stressors, but this effect might be subtle and dose-dependent (38
). A relatively low dose of hydrocortisone (30 mg) affects fear conditioning, decreasing it in male subjects and increasing it in female subjects (45
). A reanalysis of our data did not reveal any trend for a gender effect on anxiety responses. It is possible that hydrocortisone did not affect the expression of fear per se in these conditioning studies but influenced any of the multitudes of processes involved in conditioning, such as attention, learning, and memory. This latter interpretation is consistent with findings that cortisol decreases phobic symptoms and might improve symptoms of post-traumatic stress disorder (9
)—not by alleviating the expression of fear per se but by preventing the retrieval of “vivid and excessive stimulus-associated fear memory” that led to the phobic/traumatic response (9
). If cortisol indirectly reduces (or increases) fear and anxiety by interfering with emotional memory processes, such a reduction would not be expected in our study because fear and anxiety induction did not rely on memory. Indeed, the study was explicitly designed to examine the expression of fear and anxiety as opposed to aversive learning and memory; each safe and threat condition was clearly signaled to the subjects on a monitor. It is thus possible that cortisol affects multiple emotional processes; cortisol might both impair emotional memory retrieval and increase the expression of anxiety, the former effect being more likely at low doses, and the latter one being more likely at high doses.
What are the potential mechanisms for the cortisol-induced increase in anxiety-potentiated startle? The present study was based on the premise (see introductory text) that: 1) anxiety is mediated by activation of CRH receptors in the BNST (17
), and 2) cortisol increases extrahypothalamic CRH (16
). Cortisol and CRH might have worked together to enhance anxiety, cortisol potentiating the effect of CRH in the BNST. This interpretation is supported by findings that corticosterone administered in the BNST increases anxiety-like behaviors in the rat (16
). Accordingly, the failure of cortisol to affect fear-potentiated startle to the threat cue is consistent with the finding that cued fear-potentiated startle in rodents is not affected by CRH (19
An alternative possibility is that cortisol influenced brain areas involved in the processing of contextual cues, as opposed to explicit threat cues. Because the hippocampus is rich in glucocorticoid receptors and is essential for contextual processing, this structure might be involved in the present findings. In fact, prior studies have found a selective effect of corticosterone on cue and context conditioning in rodents, possibly due to increased cortisol-induced excitability of the hippocampus (49
). A better comprehension of glucocorticoid effects will require an understanding of the effect of this steroid hormone on various constituents of aversive states.
Little is known about the effect of cortisol on startle in humans. Consistent with our results, past studies showed no significant modulation of baseline startle of 4 days of prednisone treatment (160 mg/day) (50
) or acute treatment with cortisol (5 mg, 20 mg) compared with placebo (40
). These two studies also showed no effect of cortisol on the modulation of startle by affective picture. These results suggest that, within the range of doses studied so far, cortisol does not affect baseline startle and potentiated response to mildly aversive stimuli but increases the potentiation of startle to more evocative and long-lasting threats.
The present results need to be interpreted in the context of its strengths and limitations. The main strength of this study is its reliance on a robust translational approach with a well-developed and well-proven procedure. One limitation is the relatively small sample size. However, this sample size is similar to or greater than that of our previous psychopharmacological studies (29
). In addition, we used a within-subjects design, which improves statistical power. Another limitation was that the effect of hydrocortisone on potentiated startle was not found with the subjective anxiety data. Reports of dissociation between objective measures and subjective reports are frequent in drug studies (51
). The most likely reason for the differential effect of hydrocortisone on physiological and subjective reports in the present study is that startle was used to probe anxiety online, whereas the subjective anxiety measures were retrospective. Subtle differences in responding might have been affected by the passage of time and by the complexity of the design. Finally, it is highly likely that startle potentiation and subjective reports reflect the influence of different structures, subjective report being more cortically mediated than startle.
This study found that acute hydrocortisone increased anxiety without affecting fear. These results raise concerns as to the use of cortisol to treat anxiety (9
). Cortisol might reduce fear by interfering with retrieval of emotional memory (9
), but it might also increase the expression of anxiety. There is growing evidence from animal studies that activation of CRH receptors in the BNST mediates sustained anxiety. Increased anxiety in the present study could therefore be due to a potentiation of CRH activity in the BNST by cortisol. This hypothesis, however, cannot be tested in humans. A significant advantage of our experimental model is its cross-species nature. Future studies in animals should examine the role of acute glucocorticoids in sustained anxiety states and, more particularly, whether any effect is dependent on CRH activity.