A pre- and postsynaptic modulatory action of 5-HT and the 5-HT2A, (2C) receptor agonist DOB on NMDA-evoked responses in the rat medial prefrontal cortex

Intracellular recordings were made from pyramidal neurons in layers V and V I of the rat medial prefrontal cortex in slice preparations to investigate the effect of the serotonin 5-HT2A,2C receptor agonist (-)-1-2,5-dimethoxy- 4-bromophenol-2-aminopropane (DOB) and 5-hydroxytryptamine (5-HT) on N-meth yl-D-aspartate (NMDA)-induced responses. Bath application of either DOB or 5-HT [in the presence of antagonists to 5-HT1A, 5-HT3 and gamma-aminobutytr ic acid (GABA) receptors] produced a concentration-dependent biphasic modul ation of the NMDA responses. They facilitated and inhibited NMDA responses at low (less than or equal to 1 mu M DOB and less than or equal to 50 mu M 5-HT) and higher concentrations, respectively. Both the facilitating and in hibitory action were blocked by the highly selective 5-HT2A receptor antago nist R-(+)-alpha-(2,3-dimethoxyphenil)-1-[4-fluorophenylethyl]-4-piperidine methanol (M100907) and the 5-HT2 receptor antagonist ketanserin, thus indic ating that both facilitation and inhibition were mediated by the activation of the 5-HT2A receptor subtype. However, the facilitating, but not inhibit ory, action of DOB showed a marked desensitization, suggesting that the fac ilitation and inhibition of NMDA responses resulted from activation of diff erent 5-HT2A receptor subtypes and/or signal-transduction pathways. Indeed, the selective PKC inhibitor chelerythrine and the Ca2+/CaM-KII inhibitor K N-93 prevented the facilitating and inhibitory action of DOB, respectively. We have generated several lines of evidence to indicate the following scen ario. Low concentrations of DOB, at presynaptic nerve terminals, markedly e nhance NMDA-induced release of excitatory amino acids (EAAs), which then ac t upon both NMDA and non-NMDA receptors to elicit inward current. The massi ve inward current masks the postsynaptic inhibitory action of DOB. At highe r concentrations, DOB inhibits the release of EAAs and discloses the postsy naptic inhibitory action.