Conditioning cortisol in humans: design and pilot study of a randomized controlled trial

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 2014Electronic supplementary materialThe online version of this article (10.1186/s40814-018-0382-5) contains supplementary material, which is available to authorized users.

Brain and cortisol responses to smoking cues are linked in tobacco‐smoking individuals

“…Such a reduction in cortisol may be directly related to drug use, as acute administration of nicotine 63,64 and cigarette smoking 17 increase cortisol concentrations. Drug‐paired cues also induce a cortisol response, 65 which is consistent with a number of studies showing that neuroendocrine function can be classically conditioned in humans 66–69 . Although we did not observe a cue‐induced rise in cortisol at the group level, the individual variability in cortisol responsiveness in our sample was sufficient to yield an association with brain activity.…”

“…Drug-paired cues also induce a cortisol response, 65 which is consistent with a number of studies showing that neuroendocrine function can be classically conditioned in humans. [66][67][68][69] Although we did not observe a cueinduced rise in cortisol at the group level, the individual variability in cortisol responsiveness in our sample was sufficient to yield an association with brain activity. The link between drug cues and cortisol is clinically relevant as greater amounts of cue-induced cortisol release are linked to poorer treatment outcomes.…”

Cellular Signaling Pathways as Plastic, Proto-cognitive Systems: Implications for Biomedicine

“…Explorations of this are necessary to find what internal biological processes can be conditioned besides the ones already found. For example, the immune and endocrine systems can be conditioned, and the type of paired environmental cue had a significant effect on the strength of the conditioning [139][140][141][142].…”

Human Pharmacological Conditioning of the Immune and Endocrine System: Challenges and Opportunities

“…If cortisol could be conditioned, this may have clinical implications for these disorders, but conditioned effects under basal circumstances may not generalize to the cortisol stress response, which is particularly important in this regard (Putman & Roelofs, 2011). In a pilot study in 10 participants (Tekampe et al, 2014;Tekampe, van Middendorp, Sweep, et al, 2017), hydrocortisone (UCS) was paired with a distinctively tasting beverage (CS) 3 times on consecutive days during the acquisition phase. In the evocation phase, again consisting of 3 sessions on 3 consecutive days, the CS was administered paired with a placebo.…”

“…The pilot study showed the feasibility of the design and preliminary results indicated that conditioning with cortisol may affect cortisol levels under basal circumstances as well as in exposure to psychosocial stress. Particularly after exposure to stress, the conditioned participants additionally appeared to have a lower negative affective response compared to subjects in the placebo group (Tekampe et al, 2014;Tekampe, van Middendorp, Sweep, et al, 2017). This might be a first indication that some effects of pharmacological conditioning specifically become apparent by applying challenges during evocation.…”