Harnessing associative learning paradigms to optimize drug treatment

Hadamitzky, Martin; Schedlowski, Manfred

doi:10.1016/j.tips.2022.03.002

Cited by 8 publications

(9 citation statements)

References 46 publications

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“…Combining OLP with psychological interventions such as conditioning or observational learning, both empirically proven to contribute to placebo effects, 12 , 15 , 21 represents a promising avenue of future research and may extend the longevity of a short-term OLP treatment. In classical conditioning, unconditioned stimuli (eg, a drug) are frequently combined with conditioned stimuli (eg, an OLP capsule), resulting in a newly acquired response in which the placebo alone can elicit behaviors that resemble the drug's response.…”

Section: Discussionmentioning

confidence: 99%

“…In classical conditioning, unconditioned stimuli (eg, a drug) are frequently combined with conditioned stimuli (eg, an OLP capsule), resulting in a newly acquired response in which the placebo alone can elicit behaviors that resemble the drug's response. 15 , 21 Such an approach does not necessitate the use of deception, and preliminary research suggests that conditioning may help to sustain OLP efficacy. In a recent trial, conditioned OLP provided as an additional analgesic therapy reduced opioid intake in acute postoperative pain.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

No long-term effects after a 3-week open-label placebo treatment for chronic low back pain: a 3-year follow-up of a randomized controlled trial

Kleine-Borgmann¹,

Dietz²,

Schmidt³

et al. 2022

Pain

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

No long-term effects after a 3-week open-label placebo treatment for chronic low back pain: a 3-year follow-up of a randomized controlled trial

Kleine-Borgmann¹,

Dietz²,

Schmidt³

et al. 2022

Pain

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“…Despite these advances, further research in basic and clinical science is urgently required for adequate and reliable application of conditioned immunosuppression for patients in need of sufficient treatment. Moreover, it is important to investigate whether this phenomenon generalizes across various drug categories, such as analgesics or antidepressants (Hadamitzky & Schedlowski, 2022).…”

Section: Remaining Challenges and Outlookmentioning

confidence: 99%

“…The reproducible protocol of conditioned immunosuppression in rats (Basic Protocol 1) constitutes a reliable tool to gain further insights into the underlying mechanisms and pathways of brain‐to‐immune communication. Given that its applicability has also been shown for humans (Goebel et al., 2002), conditioned immunopharmacological effects may be implemented as controlled drug‐dose reduction strategies supporting the efficacy of medical treatments for patients’ benefit (Hadamitzky & Schedlowski, 2022).…”

Section: Introductionmentioning

confidence: 99%

Taste‐Associative Learning in Rats: Conditioned Immunosuppression with Cyclosporine A to Study the Neuro‐Immune Network

et al. 2022

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The pharmacological effects of an immunosuppressive drug, such as cyclosporine A (CsA), can be learned and retrieved by humans and animals when applying associative learning paradigms. This principle is based on Pavlovian conditioning, in which repeated presentation of an "unconditioned stimulus" (US; here, the drug CsA) is paired with exposure to a "conditioned stimulus" (CS; here, the novel taste of saccharin). Re-exposure to the CS at a later time leads to an avoidance behavior. Concomitantly, using this paradigm, animals exposed to the CS (saccharin) display immunosuppression, reflected by reduced splenic T-cell proliferation and diminished interleukin-2 and interferonγ expression and release in ex vivo cultured splenocytes, mimicking the pharmacological effects of the US (CsA). Notably, this paradigm of taste-immune associative learning demonstrates the impressive abilities of the brain to detect and store information about an organism's immunological status and to retrieve this information, thereby modulating immunological functions via endogenous pathways. Moreover, conditioned pharmacological effects, obtained by means of associative learning, have been successfully implemented as controlled drugdose reduction strategies as a supportive treatment option to optimize pharmacological treatment effects for patients' benefit. However, our knowledge about the underlying neurobiological and immunological mechanisms mediating such learned immunomodulatory effects is still limited. A reliable animal model of taste-immune associative learning can provide novel insights into peripheral and central nervous processes. In this article, we describe protocols that focus on the basic taste-immune associative learning paradigm with CsA and saccharin in rats, where conditioned peripheral immunosuppression is determined in ex vivo cultured splenocytes. The behavioral protocol is reliable and adaptable and may pave the road for future studies using taste-immune associative learning paradigms to gain deeper insight into brain-to-immune-system communication.

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“…Importantly, this phenomenon has been shown to be inducible in healthy humans (Goebel et al 2002 ) and could be successfully added to the standard therapy with CsA or tacrolimus in renal transplant patients, thereby amplifying the immunosuppressive effects (Kirchhof et al 2018 ). Based on these reports, it has been hypothesised that taste-immune associative learning protocols may be implemented as supportive therapeutic strategies in clinical contexts to maximize the patients´ therapeutic benefit (Albring et al 2014 ; Hadamitzky and Schedlowski 2022 ).…”

Section: Introductionmentioning

confidence: 99%

The Effects of Fingolimod (FTY720) on Leukocyte Subset Circulation cannot be Behaviourally Conditioned in Rats

Jakobs,

Hörbelt-Grünheidt,

Hadamitzky

et al. 2024

J Neuroimmune Pharmacol

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Suppression of immune functions can be elicited by behavioural conditioning using drugs such as cyclosporin A or rapamycin. Nevertheless, little is known about the underlying mechanisms and generalisability of this phenomenon. Against this background, the present study investigated whether the pharmacological properties of fingolimod (FTY720), an immunosuppressive drug widely applied to treat multiple sclerosis, can be conditioned in rats by means of taste-immune associative learning. For this purpose, a conditioned taste avoidance paradigm was used, pairing the presentation of a novel sweet drinking solution (saccharin or sucrose) as conditioned stimulus (CS) with therapeutically effective doses of FTY720 as unconditioned stimulus (US). Subsequent re-exposure to the CS at a later time point revealed that conditioning with FTY720 induced a mild conditioned taste avoidance only when saccharin was employed as CS. However, on an immunological level, neither re-exposure with saccharin nor sucrose altered blood immune cell subsets or splenic cytokine production. Despite the fact that intraperitonally administered FTY720 could be detected in brain regions known to mediate neuro-immune interactions, the present findings show that the physiological action of FTY720 is not inducible by mere taste-immune associative learning. Whether conditioning generalises across all small-molecule drugs with immunosuppressive properties still needs to be investigated with modified paradigms probably using distinct sensory CS. Moreover, these findings emphasize the need to further investigate the underlying mechanisms of conditioned immunomodulation to assess the generalisability and usability of associative learning protocols as supportive therapies in clinical contexts. Graphical Abstract

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Harnessing associative learning paradigms to optimize drug treatment

Cited by 8 publications

References 46 publications

No long-term effects after a 3-week open-label placebo treatment for chronic low back pain: a 3-year follow-up of a randomized controlled trial

No long-term effects after a 3-week open-label placebo treatment for chronic low back pain: a 3-year follow-up of a randomized controlled trial

Taste‐Associative Learning in Rats: Conditioned Immunosuppression with Cyclosporine A to Study the Neuro‐Immune Network

The Effects of Fingolimod (FTY720) on Leukocyte Subset Circulation cannot be Behaviourally Conditioned in Rats

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