VON HÖRSTEN, S. M. S. EXTON, J. VÖGE, J. WESTERMANN, M. SCHULT, E. NAGEL, R. E. SCHMIDTAND M. SCHEDLOWSKI. Cyclosporine A affects open field behavior in DA rats. PHARMACOL BIOCHEM BEHAV 60(1) 71–76, 1998.—Since the introduction of Cyclosporine A (CsA) for immunosuppression in solid-organ transplantation, the rate of allograft rejection has decreased substantially. However, treatment with CsA induces neuropsychological complications in patients, including affective disorders such as anxiety, disorientation, depression, aggression, paranoia, and apathy. These CsA-induced affective side effects cannot be extensively studied in humans. Therefore, this study investigates the effects of intraperitoneal CsA (20 mg/kg) injections on the open-field behavior of male Dark Agouti (DA) rats 1, 6, 12, and 23 h after drug administration on 3 consecutive days. CsA induced an increase in emotionality in DA rats 6 h after injection, reflected by decreased ambulatory activity in the open field and increased defecation. In addition, a decrease in rearing activity was observed 12 h after CsA administration. These behavioral alterations are discussed in the view of changes in cytokine profiles induced by CsA.

Immunosuppression induced by Cyclosporine A (CsA) can be behaviorally conditioned. It is unknown, however, whether a taste aversion paradigm using CsA as an unconditioned stimulus (UCS) induces alterations of blood leukocyte numbers and function. Results obtained by three-colour flow cytometry and granulocyte chemiluminescence response demonstrate that in conditioned rats, absolute numbers of lymphocyte subsets, including B, CD8+ T cells and CD4+ naive and memory T cells, and granulocyte numbers and function were significantly decreased. In contrast to the conditioned response, CsA treatment alone increased lymphocyte numbers and did not affect granulocyte function. Thus, our data demonstrate that behaviorally conditioned CsA effects can be monitored in the blood. In addition, results indicate that the CNS mediates the behaviorally conditioned immunosuppression by reducing the availability and function of granulocytes and lymphocytes.

The classical conditioning of immune parameters is commonly conducted within a conditioned taste aversion (CTA) paradigm. In this study, the immunosuppressive drug cyclosporine A (CsA) was investigated for its ability to produce both taste aversion to a novel stimulus and conditioned alterations in immune functioning. The paradigm comprised the pairing of a 0.2% saccharin solution (the conditioned stimulus; CS) with an intraperitoneal injection of 20 mg/kg CsA (the unconditioned stimulus; UCS). Upon saccharin re-presentation, a marked reduction in fluid consumption was observed, indicating aversion to the novel substance (=CTA). By using a single CsA/saccharin pairing the CTA lasted for one CS representation. However, by implementing three pairings, this effect could be extended for up to seven representations. No noticeable difference was recorded by adjusting the saccharin representation from every consecutive day to every second day. The most effective paradigm in creating CTA was subsequently investigated for its effectiveness in producing conditioned immune alterations. Animals were killed on the day of the third CS re-presentation, and immune functions assessed. Conditioned animals displayed a significant reduction in thymus and spleen weights. Effects on the spleen were further investigated, revealing a significantly reduced proliferative ability of isolated splenocytes to concanavalin A. These results demonstrate that the physiological effects produced by CsA are sufficiently salient to elicit CTA. Furthermore, the reduction in lymphoid organ weight and splenocyte proliferation induced by CsA are also conditionable using this paradigm. (C) 1998 Elsevier Science Inc.

Bi-directional interactions between the central nervous system (CNS) and immune system are demonstrated by the modification of immune function using behavioral conditioning. However, the mechanisms by which the CNS achieves conditioned immunomodulation are still in question. Here, we report that the immunosuppressive effects of cyclosporine A (CsA) can be behaviorally conditioned in rats using saccharin as a gustatory conditioned stimulus. The conditioned effects were compared to control groups that received CsA paired with water (sham-conditioned), CsA injection on test days (CsA-treated), and unhandled rats (untreated). In conditioned animals, the mitogen-induced lymphocyte proliferation in the spleen is significantly suppressed, and the survival time of heterotopic heart allografts prolonged. These effects are paralleled by conditioned inhibition of IL-2 and IFN-γ synthesis by splenocytes. Furthermore, the CNS-induced immunosuppression is mediated neuronally and not via the blood, since the conditioned reduction of proliferation and cytokine production is completely abrogated after surgical denervation of the spleen. Thus, during conditioning, the CNS learns to reinstate at demand a CsA-like immunosuppression via splenic innervation. This might be used as a supportive therapy for controlling immune functions.