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

Aug 4, 2018eNeuro

Nausea-triggered serotonin release in the body-awareness brain area and its control by enzyme blocking and cannabidiol

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Abstract

LiCl administration (127.2 mg/kg) elevated 5-HT levels in the (IIC) of male Sprague Dawley rats for 20 minutes.

The elevation of 5-HT in the IIC was specifically induced by LiCl, not by saline.
Systemic pretreatment with the inhibitor, MJN110, prevented the LiCl-induced increase in 5-HT levels in the IIC.
Cannabidiol (CBD) also blocked the LiCl-induced rise in 5-HT in the IIC, suggesting its role in nausea reduction.
Intra-IIC administration of the 5-HT receptor antagonist ondansetron prevented nausea triggered by 5-HT receptor agonists.
A flavor paired with LiCl exposure led to increased 5-HT release in the IIC and conditioned gaping reactions in the rats.

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Using the rat conditioned gaping model of nausea, the (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-HTreceptors and its release is suppressed by elevating 2-arachidonylglycerol (2-AG) by (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-HTsomatodendritic autoreceptors, also prevented LiCl-induced elevation of 5-HT in the IIC. Since 5-HTreceptor agonists delivered to the IIC produce nausea, we tested and confirmed the hypothesis that the intra-IIC administration of 5-HTreceptor antagonist, ondansetron, but not MJN110, would prevent LiCl-induced conditioned gaping reactions produced by intra-IIC administration of the 5-HTreceptor agonist,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. 3 1A3 3 3m-

Key numbers

20 min

5-HT Elevation Duration

5-HT levels were elevated in the for this period after LiCl injection.

127.2 mg/kg

LiCl Dose

LiCl was administered at this dose to induce nausea in the rat model.

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

Abstract

Key numbers

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