EXPOSURE TO TREATMENT CONTEXT ALONE DOES NOT ELICIT CONDITIONED SICKNESS RESPONSES IN RATS

Nonspecific sickness symptoms are common negative side effects of immuno- and chemotherapy. During the course of such therapies, which typically involve repeated treatment cycles, many patients develop sickness symptoms after mere re-exposure to the treatment context. The mechanisms underlying this anticipatory nocebo response remain largely unknown and can only partially be addressed in patients. This study aimed to establish a contextual learning paradigm in rats as a translational animal model of conditioned sickness. During the acquisition phase, animals received intraperitoneal injections of endotoxin (lipopolysaccharide, LPS) as sickness-inducing stimulus and were subsequently placed in a novel context containing distinct tactile, olfactory, and visual cues. This procedure was repeated up to three times with increasing LPS doses to strengthen prior learning. In the recall phase, rats were re-exposed to the treatment context alone to test for conditioned behavioral and physiological sickness responses. During acquisition, LPS-treated animals showed robust sickness responses, including immune activation and reduced exploratory behavior. However, re-exposure to the treatment context failed to elicit conditioned sickness responses both at the behavioral or physiological level, irrespective of the number of learning trials. The difficulties to establish a successful association between treatment context and sickness may arise from the complexity of the contextual cues, from insufficient contingency awareness, or from inflammation-induced effects on affects hippocampal-dependent learning and memory.