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Calcineurin inhibition in splenocytes induced by pavlovian conditioning

Gustavo Pacheco-López^*,1,2, Carsten Riether^*,1, Raphael Doenlen^*, Harald Engler^*,, Maj-Britt Niemi^*, Andrea Engler^*, Annemieke Kavelaars, Cobi J. Heijnen and Manfred Schedlowski

^* Department of Psychology and Behavioral Immunobiology, Institute for Behavioral Sciences, ETH Zurich, Zurich, Switzerland;

Division of Medical Psychology and Behavioral Immunobiology, Medical Faculty, University of Duisburg-Essen, Essen, Germany; and

Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, Utrecht, The Netherlands

²Correspondence: Institute for Behavioral Sciences, Psychology and Behavioral Immunobiology, TUR B21.1, Turnerstrasse 1, 8092 Zurich, Switzerland. E-mail: pacheco{at}ifv.gess.ethz.ch

Pavlovian conditioning is one of the major neurobiological mechanisms of placebo effects, potentially influencing the course of specific diseases and the response to a pharmacological therapy, such as immunosuppression. In our study with behaviorally conditioned rats, a relevant taste (0.2% saccharin) preceded the application of the immunosuppressive drug cyclosporin A (CsA), a specific calcineurin (CaN) inhibitor. Our results demonstrate that through pavlovian conditioning the particular pharmacological properties of CsA can be transferred to a neutral taste, i.e., CaN activity was inhibited in splenocytes from conditioned rats after reexposure to the gustatory stimulus. Concomitant immune consequences were observed on ex vivo mitogenic challenge (anti-CD3). Particularly, Th1-cytokine, but not Th2-cytokine, production and cell proliferation were impeded. Appropriate pharmacological and behavioral controls certify that all these changes in T-lymphocyte reactivity are attributable to mere taste reexposure. Furthermore, the underlying sympathetic-lymphocyte interaction was revealed modeling the conditioned response in vitro. CaN activity in CD4⁺ T lymphocytes is reduced by β-adrenergic stimulation (terbutaline), with these effects antagonized by the β-adrenoreceptor antagonist nadolol. In summary, CaN was identified as the intracellular target for inducing conditioned immunosuppression by CsA, contributing to our understanding of the intracellular mechanisms behind "learned placebo effects."—Pacheco-López, G., Riether, C., Doenlen, R., Engler, H., Niemi, M.-B., Engler, A., Kavelaars, A., Heijnen, C. J., Schedlowski, M. Calcineurin inhibition in splenocytes induced by pavlovian conditioning.

Key Words: cyclosporin A • immunosuppression • associative learning • placebo • taste