Cellular mechanisms of serotonin 5-HT2A receptor-mediated cGMP formation: the essential role of glutamate.
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.
Regina
Meredith J
MJ
Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, 102 Farber Hall, State University of New York at Buffalo, Buffalo, NY 14214-3000, USA.
Bucelli
Robert C
RC
Winter
Jerrold C
JC
Rabin
Richard A
RA
D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D018698:Glutamic Acid / Q000502:physiology*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D011916:Rats, Inbred F344; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D044402:Receptor, Serotonin, 5-HT2A; D016194:Receptors, N-Methyl-D-Aspartate; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists; D018698:Glutamic Acid; D016202:N-Methylaspartate; D006152:Cyclic GMP