Taste‐Associative Learning in Rats: Conditioned Immunosuppression with Cyclosporine A to Study the Neuro‐Immune Network

The pharmacological effects of an immunosuppressive drug, such as cyclosporine A (CsA), can be learned and retrieved by humans and animals when applying associative learning paradigms. This principle is based on Pavlovian conditioning, in which repeated presentation of an “unconditioned stimulus” (US; here, the drug CsA) is paired with exposure to a “conditioned stimulus” (CS; here, the novel taste of saccharin). Re‐exposure to the CS at a later time leads to an avoidance behavior. Concomitantly, using this paradigm, animals exposed to the CS (saccharin) display immunosuppression, reflected by reduced splenic T‐cell proliferation and diminished interleukin‐2 and interferon‐γ expression and release in ex vivo cultured splenocytes, mimicking the pharmacological effects of the US (CsA). Notably, this paradigm of taste‐immune associative learning demonstrates the impressive abilities of the brain to detect and store information about an organism's immunological status and to retrieve this information, thereby modulating immunological functions via endogenous pathways. Moreover, conditioned pharmacological effects, obtained by means of associative learning, have been successfully implemented as controlled drug‐dose reduction strategies as a supportive treatment option to optimize pharmacological treatment effects for patients’ benefit. However, our knowledge about the underlying neurobiological and immunological mechanisms mediating such learned immunomodulatory effects is still limited. A reliable animal model of taste‐immune associative learning can provide novel insights into peripheral and central nervous processes. In this article, we describe protocols that focus on the basic taste‐immune associative learning paradigm with CsA and saccharin in rats, where conditioned peripheral immunosuppression is determined in ex vivo cultured splenocytes. The behavioral protocol is reliable and adaptable and may pave the road for future studies using taste‐immune associative learning paradigms to gain deeper insight into brain‐to‐immune‐system communication. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC.