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

eNeuro. 2018 Jul 31;5(4):ENEURO.0256-18.2018. doi: 10.1523/ENEURO.0256-18.2018. eCollection 2018 Jul-Aug.

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-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.

Keywords: cannabinoid; interoceptive insular cortex; microdialysis; nausea; rat; serotonin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cannabidiol / pharmacology*
  • Carbamates / pharmacology*
  • Cerebral Cortex* / drug effects
  • Cerebral Cortex* / metabolism
  • Cerebral Cortex* / physiopathology
  • Disease Models, Animal
  • Interoception*
  • Lithium Chloride / administration & dosage
  • Lithium Chloride / pharmacology*
  • Male
  • Monoacylglycerol Lipases / antagonists & inhibitors*
  • Nausea* / chemically induced
  • Nausea* / drug therapy
  • Nausea* / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / metabolism*
  • Serotonin 5-HT3 Receptor Agonists / pharmacology*
  • Serotonin 5-HT3 Receptor Antagonists / pharmacology*
  • Succinimides / pharmacology*

Substances

  • Carbamates
  • MJN110
  • Serotonin 5-HT3 Receptor Agonists
  • Serotonin 5-HT3 Receptor Antagonists
  • Succinimides
  • Cannabidiol
  • Serotonin
  • Monoacylglycerol Lipases
  • Lithium Chloride