Biochemical changes associated with serotonergic hallucinogens

Elucidating the mechanisms of action of hallucinogens has become an increasingly important area of research as their abuse has grown in recent years. Although serotonin receptors appear to play a role in the behavioral effects of the phenethylamine and indoleamine hallucinogens, the signaling pathways activated by these agents are unclear. Administration of serotonin (5-hydroxytryptamine, 5-HT) was shown to increase production of the second messenger, cyclic guanosine monophosphate (cGMP), in frontal cortical slices of rat brain. The effect of 5-HT was greater than that of N-methyl-D-aspartate (NMDA), a stimulant of cGMP formation in the central nervous system. The 5-HT2A/2C receptor phenethylamine agonist, 2,5-dimethoxy-4-methylamphetamine (DOM), increased cGMP content in the slices. Additionally 8-hydroxy-2-(di- n-propylamino)tetralin (DPAT), a 5-HT1A/7 receptor agonist, also increased cGMP production. Stimulation of cGMP formation by DOM was prevented by a 5-HT2A/2C receptor antagonist, pirenperone, as well as by a 5-HT2A receptor selective antagonist, MDL100907. A 5-HT 2C receptor antagonist, SB242084, did not block the effect of DOM. Stimulation of cGMP production by DPAT was blocked by the 5-HT1A receptor antagonist, WAY100635. Stimulation of cGMP formation by serotonin could be completely prevented administration by either pirenperone or WAY100635. In summary, activation of serotonin 5-HT1A and 5-HT2A receptors increase brain cGMP levels.; Studies were undertaken to explore the mechanisms by which activation of serotonin2A (5-HT2A) receptors increase production of cGMP in slices of rat frontal cortex. Contrary to results in cortical slices, stimulation of 5-HT2A receptors in cells stably expressing this serotonin receptor did not alter cGMP levels. In cortical slices, stimulation of cGMP formation by DOM 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 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. (Abstract shortened by UMI.)...