INITIAL INSIGHTS INTO MOLECULAR AND NEUROBIOLOGICAL UNDERPINNINGS OF SICKNESS-INDUCED NEGATIVE TREATMENT EXPECTATION IN RATS

Immunotherapy and chemotherapy are commonly associated with a wide range of psychological and somatic sickness symptoms. Due to the unpleasantness of these symptoms, many patients develop negative treatment expectations and exhibit anticipatory behavioral and physiological responses when re-exposed to treatment-related cues. Despite their broad clinical implications, the underlying molecular and neurobiological mechanisms of sickness-induced negative treatment expectations and their physiological consequences are largely unknown. Here, we present results from an animal model of endotoxin-induced sickness. Using an associative learning paradigm with rats, we paired the administration of an unfamiliar taste (saccharin) with the injection of bacterial endotoxin as a sickness-inducing agent. This resulted in the establishment of negative treatment expectation, as reflected by a conditioned taste avoidance (CTA). The strength of the CTA increased with the number of prior treatment experiences and was resistant to extinction. During acquisition, the endotoxin-induced central inflammatory response involved the insular cortex (IC), a key region for the integration of interoceptive information. Re-exposure to the taste stimulus alone elicited a significant increase in plasma corticosterone, demonstrating that sickness-associated cues can trigger fear-related physiological responses. Chemogenetic silencing of neurons in the anterior IC during acquisition did not prevent the development of CTA or CS-induced activation of the stress system. However, pharmacological treatment with the non-selective cyclooxygenase inhibitor ibuprofen during acquisition completely blocked the anticipatory stress response upon CS re-exposure. Together, these results provide initial insights into the molecular and neurobiological mechanisms underlying sickness-induced negative treatment expectations and identify prostaglandins as potential mediators of expectation-driven anticipatory responses.