LSD and DOB: interaction with 5‐HT2A receptors to inhibit NMDA receptor‐mediated transmission in the rat prefrontal cortex

Hallucinogenic compounds, including the phenethylamine DOB (a selective serotonin 5-HT2A,2C receptor agonist) and the indoleamine LSD (which binds to multiple serotonin, dopamine, and adrenergic receptors), inhibit NMDA receptor-mediated currents and synaptic responses in pyramidal cells of prefrontal cortical slices, while non-hallucinogenic congeners do not. This inhibition is mimicked by serotonin when 5-HT1A and 5-HT3 receptors are blocked, and is prevented by 5-HT2A receptor antagonists. At low concentrations, LSD and DOB partially depress the NMDA response and block serotonin's inhibitory effect, indicating partial agonist action. The inhibition depends on a Ca2+/calmodulin-dependent protein kinase II pathway, not protein kinase C. The findings suggest hallucinogens may alter sensory, perceptual, affective, and cognitive processes by modulating NMDA receptors through 5-HT2A receptor partial agonism.

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Abstract

Abstract Both the phenethylamine hallucinogen (–)‐1‐2,5‐dimethoxy‐4‐bromophenyl‐2‐aminopropane (DOB), a selective serotonin 5‐HT 2A,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 α 1 and α 2 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‐HT 1A and 5‐HT 3 receptor antagonists. The inhibitory action of DOB, LSD and 5‐HT on the NMDA transmission was blocked by the 5‐HT 2A receptor antagonists r ‐(+)‐α‐(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 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‐benzenesulphonamide phosphate (KN‐93, a Ca 2+ /CaM‐KII inhibitor), but not the negative control 2‐[N‐4′methoxybenzenesulphonyl]amino‐N‐(4′‐chlorophenyl)‐2‐propenyl‐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‐HT 2A receptors via a Ca 2+ /CaM‐KII‐dependent signal transduction pathway as partial agonists and modulating the NMDA receptors‐mediated sensory, perceptual, affective and cognitive processes.