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Inhibition of NMDA‐receptor mediated response in the rat medial prefrontal cortical pyramidal cells by the 5‐HT3 receptor agonist SR 57227A and 5‐HT: Intracellular studies

The techniques of intracellular recording and single‐electrode voltage‐clamp were used to study the effect of serotonin (5‐HT) and the selective 5‐HT3 receptor agonist SR 57227A on N‐methyl‐D‐aspartic acid (NMDA)‐evoked responses in pyramidal cells of the rat medial prefrontal cortex (mPFC) in in vitro brain slice preparations. Bath application of 5‐HT or SR 57227A produced a concentration‐dependent inhibition of NMDA‐induced membrane depolarization, action potentials, and inward current. The depressant action of 5‐HT and SR 57227A had a slow onset and showed no signs of receptor desensitization. This action was markedly attenuated or completely blocked by the selective 5‐HT3 receptor antagonists granisetron and BRL 46470A, but not other receptor antagonists. In addition to inhibiting NMDA‐evoked responses, SR 57227A also depressed significantly pharmacologically isolated, NMDA receptor‐mediated, monosynaptic excitatory postsynaptic currents (EPSCs) elicited by electrical stimulation of the forceps minor; this inhibitory action was blocked by BRL 46470A but not other 5‐HT receptor antagonists. Perfusion of Ca2+‐free or low Ca2+ plus Cd2+ artificial cerebrospinal fluid prevented electrical stimulation‐induced EPSCs, but did not affect the inhibitory action of 5‐HT and SR 57227A. In conclusion, we demonstrate for the first time that 5‐HT and SR 57227A interact with 5‐HT3‐like receptors to produce a direct inhibitory action on NMDA receptor‐mediated response in pyramidal cells of the mPFC. Synapse 29:257–268, 1998. © 1998 Wiley‐Liss, Inc.