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Release of endogenous aspartate from rat cerebellum slices and synaptosomes: inhibition mediated by a 5-HT2 receptor and by a 5-HT1 receptor of a possibly novel subtype

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Summary

The effects of 5-hydroxytryptamine (5-HT) and of a number of 5-HT receptor agonists and antagonists on the release of endogenous aspartate were investigated in rat cerebellum slices and synaptosomes depolarized with high K+. The release of endogenous aspartate evoked from slices by 35 mmol/l KCl and from synaptosomes by 15 mmol/1 KCl was strongly (about 90%) calcium-dependent. In slices the release of aspartate was inhibited by exogenous 5-HT (0.1–100 nmol/1) in a concentration-dependent manner. The indoleamine was very potent, producing 30% inhibition at 0.1 nmol/l. The effect of 10 nmol/1 5-HT was partly but maximally counteracted by ketanserin (300–1000 nmol/1), a 5-HT2 receptor antagonist, but fully blocked by 300 nmol/1 of the mixed 5-HT1/5-HT2 receptor antagonist methiothepin. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) inhibited the K+-evoked release of endogenous aspartate in a concentration-dependent manner. The effect of 8-OH-DPAT was antagonized by methiothepin, but not by ketanserin which fully antagonized the inhibition produced by DOI. In cerebellar synaptosomes the release of endogenous aspartate evoked by 15 mmol/l K+ was inhibited by exogenous 5-HT and by 8-OH-DPAT, but not by DOI. Methiothepin (100–300 nmol/1) antagonized the inhibitory effects of 100 nmol/l 5-HT or 8-OH-DPAT. However, 1000 nmol/l of various 5-HT receptor antagonists [ketanserin, methysergide, (−)-propranolol, spiperone or ICS 205–930] did not counteract the effect of 100 nmol/15-HT.

It is concluded that: (1) 5-HT projections to the rat cerebellum may exert a potent inhibitory action on the depolarization-evoked release of aspartate; (2) this inhi bition is mediated through receptors of both the 5-HT1 and the 5-HT2 type; (3) the 5-HT2 receptors appear to be sited on structures which do not survive the standard preparation of synaptosomes, while the 5-HT1 receptors are likely to be localized on Apartate-releasing nerve terminals; and (4) the 5-HT1 receptors do not conform to the pharmacological criteria defining the known subtypes of the 5-HT1-binding sites.

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Authors and Affiliations

  1. Istituto di Farmacologia e Farmacognosia, University degli Studi di Genova, Viale Cembrano 4, I-16148, Genova, Italy

    Guido Maura, Alessandra Barzizza, Susanna Folghera & Maurizio Raiteri

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  1. Guido Maura
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  2. Alessandra Barzizza
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  3. Susanna Folghera
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  4. Maurizio Raiteri
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Maura, G., Barzizza, A., Folghera, S. et al. Release of endogenous aspartate from rat cerebellum slices and synaptosomes: inhibition mediated by a 5-HT2 receptor and by a 5-HT1 receptor of a possibly novel subtype. Naunyn-Schmiedeberg's Arch Pharmacol 343, 229–236 (1991). https://doi.org/10.1007/BF00251120

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