Cellular mechanisms of serotonin 5-HT_2A 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.