Cellular mechanisms of serotonin 5-HT2A receptor-mediated cGMP formation: the essential role of glutamate

• Published in: Brain research Vol. 1003; no. 1-2; pp. 168 - 175
• Main Authors: REGINA, Meredith J, BUCELLI, Robert C, WINTER, Jerrold C, RABIN, Richard A
• Format: Journal Article
• Language: English
• Published: London Elsevier 02.04.2004; Amsterdam; New York, NY
• Subjects: Animals; Biological and medical sciences; Brain - cytology; Brain - drug effects; Brain - metabolism; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Cyclic GMP - metabolism; Fundamental and applied biological sciences. Psychology; Glutamic Acid - physiology; Male; N-Methylaspartate - pharmacology; PC12 Cells; Rats; Rats, Inbred F344; Receptor, Serotonin, 5-HT2A - metabolism; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - metabolism; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists - pharmacology; Vertebrates: nervous system and sense organs; 5-HT2A serotonin receptor; Rat; Rodentia; Central nervous system; 3',5'-GMP; Glutamate receptor; Frontal cortex; Glutamate; Encephalon; Vertebrata; Mammalia; Excitatory aminoacid; Neurotransmitter; NMDA receptor
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2004.01.014

The current study explores the mechanisms by which activation of serotonin(2A) (5-HT(2A)) receptors increase production of cyclic guanosine monophosphate (cGMP) in slices of rat frontal cortex. Contrary to results in cortical slices, stimulation of 5-HT(2A) receptors in cells stably expressing this serotonin receptor did not alter cGMP levels. In cortical slices, stimulation of cGMP formation by 2,5-dimethoxy-4-methylamphetamine (DOM), a 5-HT(2A/2C) receptor agonist, was blocked by tetanus toxin, a substance that prevents vesicular neurotransmitter release. However, this stimulation was not altered by tetrodotoxin, an agent that inhibits depolarization-induced neurotransmitter release. Addition of an N-methyl-d-aspartate (NMDA) receptor antagonist, d-AP-7, but not of an AMPA/kainate receptor antagonist CNQX, completely inhibited DOM-mediated cGMP production in the slices. Combined application of maximally effective concentrations of NMDA and DOM elicited a greater increase in cGMP content than either drug alone. The present study shows that 5-HT(2A) receptors do not directly stimulate cGMP formation, but rather that 5-HT(2A) receptor-mediated cGMP production is dependent on extracellular glutamate activating NMDA receptors. The results indicate that 5-HT(2A) receptor-mediated cGMP production could be at least partially attributed to potentiation of NMDA receptor-mediated cGMP formation.