Nausea-Induced 5-HT Release in the Interoceptive Insular Cortex and Regulation by Monoacylglycerol Lipase (MAGL) Inhibition and Cannabidiol.

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 postsynaptic 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, i.p.). 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.