Calcineurin inhibition in splenocytes induced by pavlovian conditioning.
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 beta-adrenergic stimulation (terbutaline), with these effects antagonized by the beta-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
Gustavo
G
Department of Psychology and Behavioral Immunobiology, Institute for Behavioral Sciences, ETH Zurich, Zurich, Switzerland. pacheco@ifv.gess.ethz.ch
Riether
Carsten
C
Doenlen
Raphael
R
Engler
Harald
H
Niemi
Maj-Britt
MB
Engler
Andrea
A
Kavelaars
Annemieke
A
Heijnen
Cobi J
CJ
Schedlowski
Manfred
M
D000818:Animals; D065095:Calcineurin Inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003214:Conditioning, Classical / Q000187:drug effects* / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012439:Saccharin / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects*; D013549:Sweetening Agents / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013649:Taste / Q000187:drug effects
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D013549:Sweetening Agents; D016572:Cyclosporine; D012439:Saccharin