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A18 – Extinction and reconsolidation of behaviorally conditioned anti-proliferative and anti-metabolic effects: mechanisms and potential clinical relevance

Manfred Schedlowski, Martin Hadamitzky

Based on our established taste-immune paradigm in rats employing the immunosuppressive drug cyclosporine A (CsA), we will investigate extinction and reconsolidation of behavioral conditioned immune responses of immunomodulating compounds with distinct cell signaling pathways (rapamycin, methotrexate), Moreover, we will employ DREADDs to analyze the role of brain structures steering these learning processes, and will analyze the potential clinical relevance of learned immunomodulation employing a tumor model as well as a model of chronic inflammatory autoimmune disease.

Guiding questions of A18:

  • Are learned immune responses restricted to calcineurin inhibitors such as CsA or does conditioning with other immunomodulating drugs and distinct cell signaling pathways such as RAPA or MTX operate under similar mechanisms?
  • Which brain areas mediate learning and extinction processes of conditioned immunopharmacological effects?
  • Can extinction of the learned immunopharmacological effects of RAPA and MTX be inhibited by administering sub- or low-therapeutic drug doses during retrieval as reminder cues concomitantly with the CS?
  • Are behaviorally conditioned anti-proliferative (RAPA) and anti-metabolic effects (MTX) of clinical relevance by interfering with disease progression in animal models of tumor growth and inflammatory autoimmune diseases?

Martin Hadamitzky

Projektleiter A18

Universität Duisburg-Essen

Manfred Schedlowski

Projektleiter A18

Universität Duisburg-Essen

Laura Heiß-Lueckemann

Postdoc A18

Universität Duisburg-Essen

Marie Jakobs

Doktorandin A18

Universität Duisburg-Essen

Yasmin Salem

Doktorandin A18

Universität Duisburg-Essen

10 project-relevant publications

Hadamitzky M, Bösche K, Engler A, Schedlowski M, Engler H (2015) Extinction of conditioned taste aversion is related to the aversion strength and associated with c-fos expression in the insular cortex. Neuroscience. 303: 34–41.

Hadamitzky M, Bösche K, Wirth T, Buck B, Beetz O, Christians U, Schniedewind B, Lückemann L, Güntürkün O, Engler H, Schedlowski M (2016) Memory-updating abrogates extinction of learned immunosuppression. Brain Behav Immun. 52: 40–48.

Hadamitzky M, Engler H, Schedlowski M (2013) Learned immunosuppression: extinction, renewal, and the challenge of reconsolidation. J Neuroimmune Pharmacol. 8(1): 180–188.

Hadamitzky M, Orlowski K, Schwitalla JC, Bösche K, Unteroberdorster M, Bendix I, Engler H, Schedlowski M (2016) Transient inhibition of protein synthesis in the rat insular cortex delays extinction of conditioned taste aversion with cyclosporine A. Neurobiol Learn Mem. 133: 129–135.

Lückemann L, Bösche K, Engler H, Schwitalla J-C, Hadamitzky M, Schedlowski M (2016) Pre-exposure to the unconditioned or conditioned stimulus does not affect learned immunosuppression in rats. Brain Behav Immun. 51: 252–257.

Pacheco-Lopez G, Niemi M-B, Kou W, Harting M, Fandrey J, Schedlowski M (2005) Neural substrates for behaviorally conditioned immunosuppression in the rat. J Neurosci. 25(9): 2330–2337.

Pacheco-Lopez G, Riether C, Doenlen R, Engler H, Niemi M-B, Engler A, Kavelaars A, Heijnen CJ, Schedlowski M (2009) Calcineurin inhibition in splenocytes induced by pavlovian conditioning. FASEB J. 23(4): 1161–1167.

Schedlowski M, Enck P, Rief W, Bingel U (2015) Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: Implications for Clinical Trials and Clinical Practice. Pharmacol Rev. 67(3): 697–730.

Schedlowski M, Pacheco-Lopez G (2010) The learned immune response: Pavlov and beyond. Brain Behav Immun. 24(2): 176–185.

Tuerkmen A, Bösche K, Lückemann L, Engler H, Schedlowski M, Hadamitzky M (2016) Rats taste-aversive learning with cyclosporine a is not affected by contextual changes. Behav Brain Res. 312: 169–173.