Timing-dependent immune modulation of learning in a long-interval rodent model of anticipatory nausea

Anticipatory nausea is a classically conditioned response to cues that have been associated with a nauseating stimulus. In rodents, anticipatory nausea can be modelled by pairing the novel cue of a distinct context with the toxic effects of lithium chloride (LiCl), which leads to anticipatory nausea responses (e.g. gaping) when exposed to the context alone. Previous work has shown that lipopolysaccharide (LPS) attenuates LiCl-induced anticipatory nausea. However, these studies use short inter-trial intervals (ITIs), which limits our understanding of how LPS attenuates LiCl-induced anticipatory nausea (e.g., through associative or non-associative mechanisms). We developed a long interval (7-day ITI) rodent model to enhance the translational relevance of anticipatory nausea research and to begin understanding the mechanisms underlying LPS effects. Adult male Long Evans rats were administered LiCl (127 mg/kg) or vehicle control (NaCl) intraperitoneally (i.p.) paired with a 30 min exposure to a distinct context for 4 conditioning trials at 7-day intervals. Rats were administered either LPS or NaCl (200 μg/kg, i.p.) immediately after the conditioning trials (post-conditioning) or LPS 90 mins prior to the conditioning trials (pre-conditioning). These trials were followed by 4 drug-free test/extinction trials. LiCl induced significant conditioned gaping responses with long ITIs. Pre-conditioning LPS robustly attenuated conditioned gaping. For post-conditioning LPS, we did not detect an attenuation using the long interval model. The use of long ITIs enabled the assessment of the temporally dependent effects of LPS on anticipatory nausea. These findings advance current models of anticipatory nausea and highlight new directions for investigating the immune modulation of nausea-related behaviours.