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

  • Arvanov V
  • Liang X
  • Russo A
 et al. 
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Abstract

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.

Author-supplied keywords

  • 2
  • 5-Dimethoxy-4-Methylamphetamine
  • 5-Dimethoxy-4-Methylamphetamine: analogs & derivat
  • 5-Dimethoxy-4-Methylamphetamine: pharmacology
  • 5-HT2A
  • Animals
  • Electric Stimulation
  • Excitatory Postsynaptic Potentials
  • Excitatory Postsynaptic Potentials: physiology
  • Hallucinogens
  • Hallucinogens: pharmacology
  • Lysergic Acid Diethylamide
  • Lysergic Acid Diethylamide: antagonists & inhibito
  • Lysergic Acid Diethylamide: pharmacology
  • Male
  • Membrane Potentials
  • Membrane Potentials: physiology
  • N-Methyl-D-Aspartate
  • N-Methyl-D-Aspartate: antagonists & inhibitors
  • Patch-Clamp Techniques
  • Prefrontal Cortex
  • Prefrontal Cortex: drug effects
  • Prefrontal Cortex: metabolism
  • Pyramidal Cells
  • Pyramidal Cells: drug effects
  • Pyramidal Cells: physiology
  • Rats
  • Receptor
  • Receptors
  • Serotonin
  • Serotonin Agonists
  • Serotonin Agonists: pharmacology
  • Serotonin: drug effects
  • Sprague-Dawley
  • Synaptic Transmission
  • Synaptic Transmission: drug effects

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Authors

  • Viktor L Arvanov

  • Xiaofu Liang

  • Angelo Russo

  • Rex Y Wang

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