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 VI 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-methyl-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-aminobutytric acid (GABA) receptors] produced a concentration-dependent biphasic modulation of the NMDA responses. They facilitated and inhibited NMDA responses at low (</= 1 microM DOB and </= 50 microM 5-HT) and higher concentrations, respectively. Both the facilitating and inhibitory action were blocked by the highly selective 5-HT2A receptor antagonist R-(+)-alpha-(2, 3-dimethoxyphenil)-1-[4-fluorophenylethyl]-4-piperidineme thanol (M100907) and the 5-HT2 receptor antagonist ketanserin, thus indicating that both facilitation and inhibition were mediated by the activation of the 5-HT2A receptor subtype. However, the facilitating, but not inhibitory, action of DOB showed a marked desensitization, suggesting that the facilitation and inhibition of NMDA responses resulted from activation of different 5-HT2A receptor subtypes and/or signal-transduction pathways. Indeed, the selective PKC inhibitor chelerythrine and the Ca2+/CaM-KII inhibitor KN-93 prevented the facilitating and inhibitory action of DOB, respectively. We have generated several lines of evidence to indicate the following scenario. Low concentrations of DOB, at presynaptic nerve terminals, markedly enhance NMDA-induced release of excitatory amino acids (EAAs), which then act upon both NMDA and non-NMDA receptors to elicit inward current. The massive inward current masks the postsynaptic inhibitory action of DOB. At higher concentrations, DOB inhibits the release of EAAs and discloses the postsynaptic inhibitory action.