Abstract
BackgroundConditioning of physiological responses can be achieved by repeatedly pairing a previously neutral conditioned stimulus with the administration of a pharmacologically salient unconditioned stimulus. This type of conditioning has been effective for specific immune and endocrine responses, but results with regard to conditioning of cortisol, a key stress-regulatory parameter, are currently unclear. This paper describes a pharmacological conditioning design, optimized for the examination of effects of cortisol conditioning under both basal conditions and in response to stress.MethodsA double-blind randomized controlled conditioning paradigm aimed at conditioning of cortisol is conducted in 48 healthy female volunteers. During the acquisition phase, a gustatory stimulus (conditioned stimulus) is paired with hydrocortisone (100 mg, capsulated, unconditioned stimulus) three times before being administered together with placebo during three evocation sessions. To investigate possible effects of cortisol conditioning in response to stress, participants are exposed to the Trier Social Stress Test during the third evocation session. Primary outcome measure of this study is the mean area under the curve of salivary cortisol during the first two evocation sessions. As secondary outcomes, self-reported affect and stress as well as alpha-amylase are investigated. A pilot study was conducted to ensure that this design is feasible to be used in a larger study.DiscussionThis study design provides an innovative opportunity to examine the conditioning of cortisol under basal conditions and in response to stress. Also, the possible effect of cortisol conditioning on secondary outcomes of self-reported affect and alpha-amylase can be investigated. If cortisol could successfully be conditioned, this would be of conceptual relevance, showing that hypothalamic pituitary adrenal (HPA) axis regulation can be influenced by associative learning processes. Eventually, this could also have important clinical implications for understanding and treating stress-related disorders in which HPA axis dysregulation might play a role.Trial registrationNederlands Trial Register, NTR4651. Registered on 29 July 2014
Highlights
Conditioning of physiological responses can be achieved by repeatedly pairing a previously neutral conditioned stimulus with the administration of a pharmacologically salient unconditioned stimulus
The current study design aims to build on previous research, using hydrocortisone as unconditioned stimulus (UCS), and examining conditioned responses under basal conditions, and in response to psychosocial stress
After the acquisition phase and before the evocation phase, there is a drug washout period of 4 days to ensure measurements in the evocation phase are not influenced by residues of hydrocortisone or suppression of the hypothalamic pituitary adrenal (HPA) axis that might result from hydrocortisone treatment
Summary
The study protocol has been approved by the medical research ethics committee of the Leiden University Medical Center (LUMC; P14-020, NL47105.058.14). A saliva sample for cortisol and alpha-amylase measurement is taken and the participant is asked to sit still for a 5 min recording of heart rate and skin conductance (T-10) After this baseline measurement, participants are administered a placebo pill paired with the same distinctively tasting beverage as used in the acquisition sessions (T0). Sample size In order to gain insight into the effect size of the group difference in basal cortisol after conditioning (primary outcome measures) that could be expected when conditioning with hydrocortisone, a pilot study was conducted using a similar design as in the current study This pilot study in 10 female participants (7 receiving hydrocortisone in the acquisition phase and 3 receiving placebo) found a difference (Δm) in the AUCg of cortisol during the first 2 evocation sessions of 6.14 with a weighted standard deviation of 11.68, resulting in an effect size of d = 0.53. The acquisition sessions of the current study were limited to a baseline measurement of salivary cortisol and the standardized administration of CS and UCS, in order to significantly reduce participant burden
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