Journal
JOURNAL OF NEUROCHEMISTRY
Volume 99, Issue 4, Pages 1164-1175Publisher
WILEY
DOI: 10.1111/j.1471-4159.2006.04173.x
Keywords
2-arachidonoylglycerol; endocannabinoid; hallucinogen; phospholipase C; phospholipase D; serotonin(2a) receptor
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Funding
- NCRR NIH HHS [C06-RR14499] Funding Source: Medline
- NIDA NIH HHS [DA02189] Funding Source: Medline
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To date, several studies have demonstrated that phospholipase C-coupled receptors stimulate the production of endocannabinoids, particularly 2-arachidonoylglycerol. There is now evidence that endocannabinoids are involved in phospholipase C-coupled serotonin 5-HT2A receptor-mediated behavioral effects in both rats and mice. The main objective of this study was to determine whether activation of the 5-HT2A receptor leads to the production and release of the endocannabinoid 2-arachidonoylglycerol. NIH3T3 cells stably expressing the rat 5-HT2A receptor were first incubated with [H-3]-arachidonic acid for 24 h. Following stimulation with 10 mu M serotonin, lipids were extracted from the assay medium, separated by thin layer chromatography, and analyzed by liquid scintillation counting. Our results indicate that 5-HT2A receptor activation stimulates the formation and release of 2-arachidonoylglycerol. The 5-HT2A receptor-dependent release of 2-arachidonoylglycerol was partially dependent on phosphatidylinositol-specific phospholipase C activation. Diacylglycerol produced downstream of 5-HT2A receptor-mediated phospholipase D or phosphatidylcholine-specific phospholipase C activation did not appear to contribute to 2-arachidonoylglycerol formation in NIH3T3-5HT(2A) cells. In conclusion, our results support a functional model where neuromodulatory neurotransmitters such as serotonin may act as regulators of endocannabinoid tone at excitatory synapses through the activation of phospholipase C-coupled G-protein coupled receptors.
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