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A pre‐ and postsynaptic modulatory action of 5‐HT and the 5‐HT 2A, 2C receptor agonist DOB on NMDA‐evoked responses in the rat medial prefrontal cortex
Author(s) -
Arvanov Viktor L.,
Liang Xiaofu,
Magro Pellegrino,
Roberts Roy,
Wang Rex Y.
Publication year - 1999
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.1999.00708.x
Subject(s) - nmda receptor , agonist , ketanserin , chelerythrine , inhibitory postsynaptic potential , 5 ht receptor , chemistry , excitatory postsynaptic potential , postsynaptic potential , glutamate receptor , serotonin , 5 ht2 receptor , neuroscience , pharmacology , receptor , protein kinase c , biology , signal transduction , biochemistry
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‐HT 2A,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‐HT 1A , 5‐HT 3 and γ‐aminobutytric acid (GABA) receptors] produced a concentration‐dependent biphasic modulation of the NMDA responses. They facilitated and inhibited NMDA responses at low (≤ 1 μ m DOB and ≤ 50 μ m 5‐HT) and higher concentrations, respectively. Both the facilitating and inhibitory action were blocked by the highly selective 5‐HT 2A receptor antagonist r ‐(+)‐α‐(2,3‐dimethoxyphenil)‐1‐[4‐fluorophenylethyl]‐4‐piperidinemethanol (M100907) and the 5‐HT 2 receptor antagonist ketanserin, thus indicating that both facilitation and inhibition were mediated by the activation of the 5‐HT 2A 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‐HT 2A receptor subtypes and/or signal‐transduction pathways. Indeed, the selective PKC inhibitor chelerythrine and the Ca 2+ /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.