Biphasic modulatory action of the selective sigma receptor ligand SR 31742A on N-methyl-D-aspartate-induced neuronal responses in the frontal cortex.
The technique of intracellular recording was used to assess the effect of SR 31742A, a selective sigma receptor ligand, on N-methyl-d-aspartate (NMDA) and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated responses in pyramidal cells of the rat medial prefrontal cortex in vitro brain slice preparations. Bath application of SR 31742A produced a biphasic effect on NMDA responses: SR 31742A facilitated and inhibited NMDA-induced inward current at low (0.01, 0.05 and 0.1 microM) and higher (0.5, 1 and 10 microM) concentrations, respectively. The potentiating effect reached the peak (366%) at 0.1 microM, with an estimated EC50 value of 23 nM. Correspondingly, SR 31742A also produced a similar biphasic modulatory action on excitatory postsynaptic potentials or currents (EPSPs/EPSCs) evoked by electrical stimulation of the forceps minor. In contrast, SR 31742A produced a modest potentiation of AMPA responses at the concentrations from 0.01 to 1 microM. The potentiating action of SR 31742A on NMDA-receptor mediated neurotransmission may account for, at least partially, its antipsychotic and cognitive-enhancing potential, whereas the inhibitory action on NMDA responses at higher concentrations may be related to the purported neuroprotective action of sigma receptor ligands.
State University of New York at Stony Brook, Department of Psychiatry and Behavioral Science, Putnam Hall, South Campus, Stony Brook, NY 11794-8790, USA.
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D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials; D005625:Frontal Lobe / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000187:drug effects*; D014743:Videotape Recording
D014150:Antipsychotic Agents; D001381:Azepines; D008024:Ligands; D017480:Receptors, sigma; C080238:3-(hexahydroazepin-1-yl)-1-(3-chloro-4-cyclohexylphenyl)-1-propene hydrochloride; D016202:N-Methylaspartate