Abstract
Using the rat conditioned gaping model of nausea, the interoceptive insular cortex (IIC) has been identified as a critical site for the regulation of lithium chloride (LiCl)-induced nausea. Indirect evidence supports a model where serotonin (5-HT) acts on post-synaptic 5-HT3 receptors and its release is suppressed by elevating 2-arachidonylglycerol (2-AG) by monoacylglycerol lipase (MAGL) inhibition to suppress nausea. Here we directly test the hypothesis that systemic LiCl elevates 5-HT in the IIC and this is prevented by pretreatments that reduce 5-HT release. Using male Sprague-Dawley rats, LiCl (but not saline), elevated 5-HT selectively in the IIC, for 20 min after LiCl administration (127.2 mg/kg, ip). Systemic pretreatment with the MAGL inhibitor, MJN110, prevented the LiCl-induced elevation of 5-HT in the IIC. Systemic cannabidiol (CBD), which reduces LiCl-induced nausea by acting at 5-HT1A somatodendritic autoreceptors, also prevented LiCl-induced elevation of 5-HT in the IIC. Since 5-HT3 receptor agonists delivered to the IIC produce nausea, we tested and confirmed the hypothesis that, the intra-IIC administration of 5-HT3 receptor antagonist, ondansetron, but not MJN110, would prevent LiCl-induced conditioned gaping reactions produced by intra-IIC administration of the 5-HT3 receptor agonist, m-chlorophenylbiguanide (mCPBG). Finally, we demonstrate that exposure to a LiCl-paired flavor (but not a saline-paired flavor), produces elevated 5-HT release in the IIC, while rats display conditioned gaping reactions. These results confirm that LiCl-induced nausea is triggered by elevated 5-HT release in the IIC and is attenuated by treatments that reduce 5-HT availability in this region.
Significance Statement Understanding of the neurobiology of nausea has lagged behind that of the neurobiology of vomiting. Here we demonstrate for the first time that a nauseating drug produces an elevation of serotonin in the brain region that mediates nausea in humans, the interoceptive insular cortex (IIC). This elevated serotonin (and nausea) is prevented by pretreatment with a drug that elevates the endocannabinoid, 2-arachidonyl glycerol (2-AG), in this region. As well, pretreatment with the non-psychoactive cannabinoid, cannabidol, acts to reduce forebrain release of serotonin (and nausea) triggered by the nauseating drug. These results strongly suggest serotonin serves as a trigger to produce the sensation of nausea in the IIC and cannabinoids act to prevent this trigger to regulate nausea.
Footnotes
There are no conflicts of interest
Funding sources This research was supported by research grants from the Canadian Institutes of Health Research (CIHR # 1371220, 156394) and Natural Sciences and Engineering Research Council of Canada (NSERC # 290157) to LAP.
Acknowledgements: We thank the late Larry Parsons, Scripps Institute, LaJolla, for his guidance in in-vivo microdialysis/HPLC measurement of serotonin.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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