Glucocorticoid-induced enhancement of extinction-from animal models to clinical trials

Abstract

Extensive evidence from both animal model and human research indicates that glucocorticoid hormones are crucially involved in modulating memory performance. Glucocorticoids, which are released during stressful or emotionally arousing experiences, enhance the consolidation of new memories, including extinction memory, but reduce the retrieval of previously stored memories. These memory-modulating properties of glucocorticoids have recently received considerable interest for translational purposes because strong aversive memories lie at the core of several fear-related disorders, including post-traumatic stress disorder and phobias. Moreover, exposure-based psychological treatment of these disorders relies on successful fear extinction. In this review, we argue that glucocorticoid-based interventions facilitate fear extinction by reducing the retrieval of aversive memories and enhancing the consolidation of extinction memories. Several clinical trials have already indicated that glucocorticoids might be indeed helpful in the treatment of fear-related disorders.

Keywords: Clinical trials; Fear-related disorders; Glucocorticoids; Memory.

Fig. 1

Glucocorticoid-induced enhancement of extinction. According to this model, glucocorticoids reduce the retrieval of aversive memories and thus curtail the expression of fear. A reduction of aversive memories may also support fear extinction: Experiencing reduced fear in otherwise fearful situations is likely to support fear extinction processes by promoting non-fearful, corrective experiences. Further, glucocorticoids enhance the consolidation of extinction memory

Fig. 2

Role of the endocannabinoid system in regulating glucocorticoid effects on memory consolidation. Glucocorticoids, released during emotionally arousing situations, bind to a membrane-bound GR, and activate the intracellular cAMP/PKA signaling cascade. This triggers the release of endocannabinoids, particularly anandamide (AEA). Anandamide then activates CB1 receptors on GABAergic interneurons and thereby inhibits GABA release. This subsequently disinhibits norepinephrine (NE) release and increases the excitability of pyramidal neurons within the basolateral amygdala. This overall increases the sensitivity of basolateral amygdala neurons to the effects of norepinephrine and results in an increased activation of the cAMP (cyclic adenosine monophosphate) / PKA (protein kinase A) pathway and phosphorylation of the transcription factor CREB (cAMP response-element binding) protein. These stress hormone effects in the basolateral amygdala are required for enhancement of memory for emotionally arousing experiences by influencing information storage processes in other brain regions. Adapted from Atsak et al., Neuropsychopharmacology,

Fig. 3

Stress before extinction learning reduced the return of fear in a renewal paradigm. The renewal test compared the mean skin conductance response (SCR) to the conditioned stimuli (CS+) in both contexts A (acquisition context) and B (extinction context). The control group (left panel; n = 20) showed renewal of the extinguished fear response (** P < .001: the response to the previously extinguished CS+ in context A is higher than in context B), the stress (socially evaluated cold pressor test 25–30 min before extinction learning) group (right panel; n = 20) showed no renewal. These results suggest a stronger and more generalized extinction memory in the stress group. Error bars represent SEM and thus between-subject variance. CS+, conditioned stimulus. Adapted from (Meir Drexler et al. 2018)

Fig. 4

Glucocorticoids enhance extinction-based psychotherapy. a VR exposure to fear of heights. b Adding cortisol to VR exposure results in reductions of self-reported fear of heights (measured with Acrophobia Questionnaire, range 0–120) at posttreatment and at follow-up. VR exposure took place on 3 treatment sessions between pretreatment and posttreatment assessment. Cortisol (20 mg) was administered 1 h before each VR exposure session. Values are depicted as mean and SEM. Asterisks (*, P < 0.05) indicate significant differences between the placebo- and cortisol group at a certain time point. Adapted from (de Quervain et al. 2011)