Characterization of a novel effect of serotonin 5-HT1A and 5-HT2A receptors: increasing cGMP levels in rat frontal cortex.
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-HT2A receptor selective antagonist, MDL100907. A 5-HT2C 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 prevented by pirenperone or WAY100635. In summary, activation of serotonin 5-HT1A and 5-HT2A receptors increase brain cGMP levels.
Regina
Meredith J
MJ
SUNY-Buffalo, Department of Pharmacology and Toxicology, 102 Farber Hall, Buffalo, NY 14214-3000, USA.
Winter
Jerrold C
JC
Rabin
Richard A
RA
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D044402:Receptor, Serotonin, 5-HT2A; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D006152:Cyclic GMP