Abstract
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. Here it is shown that administration of serotonin (5-hydroxytryptamine, 5-HT) increased cyclic guanosine monophosphate (cGMP) production 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-HT 2A/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-HT 2A/2C receptor antagonist, pirenperone, as well as by a 5-HT 2A 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-HT 1A receptor antagonist, WAY100635. Stimulation of cGMP formation by serotonin could be prevented by pirenperone orWAY100635. In summary, activation of serotonin 5-HT 1A and 5-HT 2A receptors increase brain cGMP levels.
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