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 postsynaptic 5-HT(3) 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-HT(1A) somatodendritic autoreceptors, also prevented LiCl-induced elevation of 5-HT in the IIC. Since 5-HT(3) receptor agonists delivered to the IIC produce nausea, we tested and confirmed the hypothesis that the intra-IIC administration of 5-HT(3) receptor antagonist, ondansetron, but not MJN110, would prevent LiCl-induced conditioned gaping reactions produced by intra-IIC administration of the 5-HT(3) 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.