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Stimulation of serotonin release in the rat brain cortex by activation of ionotropic glutamate receptors and its modulation via α2-heteroreceptors

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Abstract

Rat brain cortex slices were used to study (1) the release of 5-hydroxytryptamine (5-HT) induced by activation of N-methyl-D-aspartate (NMDA) or non-NMDA receptors and (2) the α2-adrenoceptor-mediated modulation of NMDA-evoked 5-HT release.

Cortical slices were preincubated with [3H]5-HT in the presence of the selective noradrenaline reuptake inhibitor, maprotiline (to avoid false labelling of noradrenergic axon terminals), and then superfused with solution containing the 5-HT reuptake inhibitor, 6-nitroquipazine. In slices superfused with Mg2+-free 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. Dizocilpine (formerly MK801), an antagonist at the phencyclidine site within the NMDA-gated channel, also decreased the NMDA-evoked overflow. The competitive NMDA receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849) caused a parallel shift of the NMDA concentration-response curve to the right. The NMDA-induced tritium overflow was not affected by addition of exogenous glycine but was inhibited by 5,7-dichlorokynurenic acid, an antagonist at the glycine site of the NMDA receptor. Spermidine slightly increased the NMDA-induced tritium overflow whereas arcaine, an antagonist at the polyamine site of the NMDA-receptor, caused a decrease. Ifenprodil and eliprodil, which exhibit different affinities for NMDA receptors composed of different subunits were highly potent (in the nanomolar range) in inhibiting the NMDA-evoked tritium overflow. Noradrenaline reduced, whereas the α2-adrenoceptor antagonist idazoxan facilitated, the NMDA-evoked overflow. Idazoxan shifted the concentration-response curve of noradrenaline to the right. In slices superfused with solution containing 1.2 mM Mg2+, kainic acid or (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) also caused a concentration-dependent overflow of tritium, which again was not completely (by about 75 and 50%, respectively) inhibited by tetrodotoxin. The kainate-evoked tritium overflow was inhibited by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) but not affected by CGP 37849 or arcaine. The AMPA-evoked tritium overflow was also decreased by CNQX.

It is concluded that activation of NMDA or non-NMDA receptors elicits a release of 5-HT in the rat brain cortex. The receptors are at least partly located on the serotoninergic nerve terminals. The results with ifenprodil and eliprodil are compatible with the view that the NMDA receptor involved contains the NR2B subunit. The NMDA-evoked 5-HT release is modulated by presynaptic α2-adrenoceptors.

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Authors and Affiliations

  1. Institut für Pharmakologie und Toxikologie der Universität Bonn, Reuterstrasse 2b, D-53113, Bonn, Germany

    K. Fink, V. Schmitz, C. Böing & M. Göthert

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  1. K. Fink
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  2. V. Schmitz
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  3. C. Böing
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  4. M. Göthert
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Fink, K., Schmitz, V., Böing, C. et al. Stimulation of serotonin release in the rat brain cortex by activation of ionotropic glutamate receptors and its modulation via α2-heteroreceptors. Naunyn-Schmiedeberg's Arch Pharmacol 352, 394–401 (1995). https://doi.org/10.1007/BF00172776

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  • DOI: https://doi.org/10.1007/BF00172776

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