Behavioral conditioning of anti-proliferative and immunosuppressive properties of the mTOR inhibitor rapamycin.

Suppression of immune functions can be elicited by behavioral conditioning using drugs such as cyclosporine A, cyclophosphamide, or opioids. Nevertheless, little is known regarding the conditioned actions of clinically approved immunosuppressive drugs with distinct cell signaling pathways. The present study tested the assumption to condition immunopharmacological properties of rapamycin (sirolimus), a small-molecule drug widely used as anti-tumor medication and to prevent graft rejection. For this purpose, a conditioned taste avoidance (CTA) paradigm was used, pairing the presentation of a novel taste (saccharin) as conditioned stimulus (CS) with injections of rapamycin as unconditioned stimulus (US). Subsequent re-exposure to the CS at a later time revealed that conditioning with rapamycin induced an only moderate CTA. However, pronounced conditioned immunopharmacological effects were observed, reflected by significantly reduced levels of IL-10 cytokine production and diminished proliferation of splenic CD4+ and CD8+ T cells in Dark Agouti and Fischer 344 rats. For one, these findings support earlier observations revealing that not a pronounced CTA but rather re-exposure to the CS or taste itself is essential for conditioned immunosuppression. Moreover, our results provide first evidence that the phenomenon of learned immune responses generalizes across many, if not all, small-molecule drugs with immunosuppressive properties, thereby providing the basis for employing learned immunopharmacological strategies in clinical contexts such as supportive therapy.

Behaviorally conditioned immunosuppression with cyclosporine A forms long lasting memory trace.

Behaviorally conditioned taste avoidance (CTA) paradigms using the novel taste saccharin as a conditioned stimulus (CS) and the immunosuppressive drug cyclosporine A (CsA) as unconditioned stimulus (US) demonstrate learned suppression of immune functions. However, conditioned immune responses might decrease over time depending on the period between acquisition and retrieval (retention interval). Thus, the present study investigated whether and to what extent prolonged 14- and 30-days retention intervals affect conditioned behavioral (CTA) and immune responses in rats. Our findings demonstrate that conditioned animals displayed a marked CTA after 14 and 30 days upon CS re-exposure compared to control animals. More importantly, the production of the pro-inflammatory cytokine interferon (IFN)-γ was significantly suppressed in ex vivo anti-CD3 stimulated splenocytes of conditioned animals compared to controls at both time points. These findings document that CTA paradigms using the immunosuppressive drug CsA as US form long lasting memory traces of the learned behavioral and immune responses.