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-am inopropane (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 D-1 and D-2, and alpha(1 ) and alpha(2) adrenergic receptors), but not their non-hallucinogenic cong eners, inhibited N-methyl-D-aspartate (NMDA)-induced inward current and NMD A 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 recept or antagonists R-(+)-alpha-(2,3-dimethoxyphenil)-1-[4-fluorophenylethyl]-4- piperidinemethanol (M100907) and ketanserin. However, at low concentrations , when both LSD and DOB by themselves only partially depressed the NMDA res ponse, they blocked the inhibitory effect of 5-HT, suggesting a partial ago nist action. Whereas N-(4-aminobutyl)-5-chloro-2-naphthalenesulphonamide (W -7, a calmodulin antagonist) and N-[2-[[[3-(4-chlorophenyl)-2-propenyl]meth ylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4'-methoxy-benzenesulphonamide ph osphate (KN-93, a Ca2+/CaM-KII inhibitor), but not the negative control 2-[ N-4'methoxybenzenesulphonyl]amino-N-(4-chlorophenyl)-2-propenyl-N-methylben zylamine phosphate (KN-92), blocked the inhibitory action of LSD and DOB, t he selective protein kinase C inhibitor chelerythrine was without any effec t. 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 modu lating the NMDA receptors-mediated sensory, perceptual, affective and cogni tive processes.