Biphasic modulatory action of the selective sigma receptor ligand SR 31742A on N-methyl-d-aspartate-induced neuronal responses in the frontal cortex

Abstract

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.