Toward a molecular understanding of hallucinogen action
The serotonergic hallucinogens are a diverse group of chemicals that have in common their affinity for the mammalian 5-HT2A receptor. Biochemical studies have demonstrated that the 5-HT2A receptor couples to many signaling pathways, forming a complex signaling network that affects various cellular processes. The purpose of this study was to investigate 5-HT2A receptor-mediated signal transduction in an attempt to identify signaling events that are unique to hallucinogens. The first study was initiated in order to explore the effect on 5-HT2A receptor-dependent phospholipase C activation of adding a methyl group to the alpha position of the side chain of a small series of phenethylamine agonists. Because the alpha methyl group renders the phenethylamines chiral, the effect on phospholipase C activation of both (R)- and (S)-enantiomers also was assessed. Next, the discovery of 5-HT2A receptor-dependent 2-arachidonoylglycerol release is presented, along with a characterization of the signaling pathways that are involved with the production and hydrolysis of this important endocannabinoid. The production and release of 2-arachidonoylglycerol was demonstrated to be dependent on phospholipase C with no contribution coming from the 5-HT 2A receptor-dependent phospholipase D pathway. Finally, in light of the fact that 5-HT2A receptor-dependent 2-arachidonoylglycerol release was demonstrated to be phospholipase C-dependent, the pathway for the biosynthesis of the major hydrolysis product of 2-arachidonoylglycerol, arachidonic acid, was examined. Results indicate that the production and release of arachidonic acid in the cell line tested is dependent on both fatty acid amidohydrolase-catalyzed hydrolysis of 2-arachidonoylglycerol and sn2-selective diacylglycerol lipase-catalyzed hydrolysis of diacyglycerol derived from sequential phospholipase D and phosphatidic acid hydrolase activation. The data presented herein contribute to our understanding of 5-HT2A receptor-mediated signal transduction and also help to explain the results of animal studies that have demonstrated a role for endocannabinoids in certain behavioral effects that are mediated by 5-HT2A receptor activation. Given the role that the 5-HT2A receptor plays in normal and aberrant cognition, a detailed understanding of its molecular pharmacology is essential for the development of drugs that modulate its function, in order to alleviate the symptoms of central nervous system disorders such as schizophrenia, obsessive compulsive disorder, depression, and others.
Nichols, Purdue University.
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