Male and female rats exhibit comparable gaping behavior but activate brain regions differently during expression of conditioned nausea

Abstract

Twenty-five to fifty percent of patients undergoing chemotherapy will develop anticipatory nausea and vomiting (ANV), in which symptoms occur in anticipation of treatment. ANV is triggered by environmental cues and shows little response to traditional antiemetic therapy, suggesting that unique neural pathways mediate this response. Understanding the underlying neural mechanisms of this disorder is critical to the development of novel therapeutic interventions. The purpose of the present study was to identify brain areas activated during ANV and characterize sex differences in both the behavior and the brain areas activated during ANV. We used a rat model of ANV by pairing a novel context with the emetic drug lithium chloride (LiCl) to produce conditioned nausea behaviors in the LiCl-paired environment. We quantitated gaping, an analog of human vomiting, after acute or repeated LiCl in a unique environment. To identify brain regions associated with gaping, we measured c-fos activation by immunochemical staining after these same treatments. We found that acute LiCl activated multiple brain regions including the supraoptic nucleus of the hypothalamus, central nucleus of the amygdala, nucleus of the solitary tract and area postrema, none of which were activated during ANV. ANV activated c-fos expression in the frontal cortex, insula and paraventricular nucleus of the hypothalamus of males but not females. These data suggest that therapies such as ondansetron which target the area postrema are not effective in ANV because it is not activated during the ANV response. Further studies aimed at characterizing the neural circuits and cell types that are activated in the conditioned nausea response will help identify novel therapeutic targets for the treatment of this condition, improving both quality of life and outcomes for patients undergoing chemotherapy.

A new experimental rat model of nocebo‐related nausea involving double mechanisms of observational learning and conditioning

“…Our findings revealed similar activated brain regions in nocebo nausea, particularly those primarily responsible for integrating cognition, emotion, and nausea messages, such as the ACC, insula, BLA, PVN, PVT, PAG, DRD, and NTS. This was in line with a recent study that detected c‐Fos expression in different brain regions after inducing conditioned nausea in male rats, with more activated neurons in the frontal cortex, insula, and PVN 50 . The ACC and insula, the key brain regions identified in our study, could integrate emotional and cognitive stimuli to directly trigger nausea 12,51 .…”

“…This was in line with a recent study that detected c‐Fos expression in different brain regions after inducing conditioned nausea in male rats, with more activated neurons in the frontal cortex, insula, and PVN. 50 The ACC and insula, the key brain regions identified in our study, could integrate emotional and cognitive stimuli to directly trigger nausea. 12 , 51 Strong evidence also suggested that they were associated with the production of aversion emotions.…”