LSD and DOB: interaction with 5-HT2A receptors to inhibit NMDA receptor-mediated transmission in the rat prefrontal cortex.
Both the phenethylamine hallucinogen (-)-1-2, 5-dimethoxy-4-bromophenyl-2-aminopropane (DOB), a selective serotonin 5-HT2A,2C receptor agonist, and the indoleamine hallucinogen D-lysergic acid diethylamide (LSD, which binds to 5-HT1A, 1B, 1D, 1E, 1F, 2A, 2C, 5, 6, 7, dopamine D1 and D2, and alpha1 and alpha2 adrenergic receptors), but not their non-hallucinogenic congeners, inhibited N-methyl-D-aspartate (NMDA)-induced inward current and NMDA receptor-mediated synaptic responses evoked by electrical stimulation of the forceps minor in pyramidal cells of the prefrontal cortical slices. The inhibitory effect of hallucinogens was mimicked by 5-HT in the presence of selective 5-HT1A and 5-HT3 receptor antagonists. The inhibitory action of DOB, LSD and 5-HT on the NMDA transmission was blocked by the 5-HT2A receptor antagonists R-(+)-alpha-(2, 3-dimethoxyphenil)-1-[4-fluorophenylethyl]-4-piperidineme thanol (M100907) and ketanserin. However, at low concentrations, when both LSD and DOB by themselves only partially depressed the NMDA response, they blocked the inhibitory effect of 5-HT, suggesting a partial agonist action. Whereas N-(4-aminobutyl)-5-chloro-2-naphthalenesulphonamide (W-7, a calmodulin antagonist) and N-[2-[[[3-(4'-chlorophenyl)- 2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4'-methoxy-b enzenesulphonamide phosphate (KN-93, a Ca2+/CaM-KII inhibitor), but not the negative control 2-[N-4'methoxybenzenesulphonyl]amino-N-(4'-chlorophenyl)-2-propeny l-N -methylbenzylamine phosphate (KN-92), blocked the inhibitory action of LSD and DOB, the selective protein kinase C inhibitor chelerythrine was without any effect. We conclude that phenethylamine and indoleamine hallucinogens may exert their hallucinogenic effect by interacting with 5-HT2A receptors via a Ca2+/CaM-KII-dependent signal transduction pathway as partial agonists and modulating the NMDA receptors-mediated sensory, perceptual, affective and cognitive processes.
Arvanov
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VL
Department of Psychiatry and Behavioral Science, SUNY at Stony Brook, NY 11794-8790, USA.
Liang
X
X
Russo
A
A
Wang
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RY
D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006213:Hallucinogens / Q000494:pharmacology*; D008238:Lysergic Acid Diethylamide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*
D006213:Hallucinogens; D044402:Receptor, Serotonin, 5-HT2A; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine; C003943:2,5-dimethoxy-4-bromoamphetamine; D008238:Lysergic Acid Diethylamide