STIMULATION OF SEROTONIN RELEASE IN THE RAT-BRAIN CORTEX BY ACTIVATION OF IONOTROPIC GLUTAMATE RECEPTORS AND ITS MODULATION VIA ALPHA(2)-HETERORECEPTORS

Rat brain cortex slices were used to study (1) the release of 5-hydrox ytryptamine (5-HT) induced by activation of N-methyl-D-aspartate (NMDA ) or non-NMDA receptors and (2) the alpha(2)-adrenoceptor-mediated mod ulation of NMDA-evoked 5-HT release. Cortical slices were preincubated with [H-3]5-HT in the presence of the selective noradrenaline reuptak e inhibitor, maprotiline (to avoid false labelling of noradrenergic ax on terminals), and then superfused with solution containing the 5-HT r euptake inhibitor, 6-nitroquipazine. In slices superfused with Mg2+-fr ee medium, NMDA and L-glutamate, in a concentration-dependent manner, elicited an overflow of tritium. The NMDA-evoked tritium overflow was abolished by omission of Ca2+ ions, almost completely suppressed by 1. 2 mM Mg2+ and only partly (by about 60%) inhibited by tetrodotoxin. Di zocilpine (formerly MK-801), an antagonist at the phencyclidine site w ithin the NMDA-gated channel, also decreased the NMDA-evoked overflow. The competitive NMDA receptor antagonist DL-(E)-2-amino-4-methyl-5-ph osphono-3-pentanoic acid (CGP 37849) caused a parallel shift of the NM DA concentration-response curve to the right. The NMDA-induced tritium overflow was not affected by addition of exogenous glycine but was in hibited by 5,7-dichlorokynurenic acid, an antagonist at the glycine si te of the NMDA receptor. Spermidine slightly increased the NMDA-induce d tritium overflow whereas arcaine, an antagonist at the polyamine sit e of the NMDA-receptor, caused a decrease. Ifenprodil and eliprodil, w hich exhibit different affinities for NMDA receptors composed of diffe rent subunits were highly potent (in the nanomolar range) in inhibitin g the NMDA-evoked tritium overflow. Noradrenaline reduced, whereas the alpha(2)-adrenoceptor antagonist idazoxan facilitated, the NMDA-evoke d overflow. Idazoxan shifted the concentration-response curve of norad renaline to the right. In slices superfused with solution containing 1 .2 mM Mg2+, kainic acid or (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxa zole propionic acid (AMPA) also caused a concentration-dependent overf low of tritium, which again was not completely (by about 75 and 50%, r espectively) inhibited by tetrodotoxin. The kainate-evoked tritium ove rflow was inhibited by the non-NMDA receptor antagonist 6-cyano-7-nitr oquinoxaline-2,3-dione (CNQX) but not affected by CGP 37849 or arcaine . The AMPA-evoked tritium overflow was also decreased by CNQX. It is c oncluded that activation of NMDA or non-NMDA receptors elicits a relea se of 5-HT in the rat brain cortex. The receptors are at least partly located on the serotoninergic nerve terminals. The results with ifenpr odil and eliprodil are compatible with the view that the NMDA receptor involved contains the NR2B subunit. The NMDA-evoked 5-HT release is m odulated by presynaptic alpha(2)-adrenoceptors.