Activation of presynaptic 5-hydroxytryptamine1-like receptors on glutamatergic terminals inhibits N-methyl-D-aspartate-induced cyclic GMP production in rat cerebellar slices.
In rat cerebellar slices, depolarization with 35 mM KCl caused increase of cyclic GMP (cGMP) production. This increase was Ca(++)-dependent, similar to the K(+)-evoked release of glutamate and aspartate in the same preparation. The K(+)-induced cGMP formation was inhibited in a concentration-dependent manner by D-(-)-2-amino-5-phosphonopentanoic acid (maximal inhibition 60-70%; IC50 = 0.019 microM) indicating the involvement of N-methyl-D-aspartate receptors probably activated by excitatory amino acids (EAAs) released by K(+)-depolarization. The cGMP production evoked by high-K+ was also potently inhibited by 5-hydroxytryptamine (5-HT; IC50 = 0.42 nM) or by 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT; IC50 = 1 nM). Methiothepin prevented the action of both 5-HT and 8-OH-DPAT. These data suggest the involvement of 5-HT1-like receptors. When added alone to the depolarized slices, methiothepin (0.03-3 microM) produced a concentration-dependent increase of cGMP suggesting that the 5-HT1-like receptors may be physiologically activated by the endogenous transmitter. Endogenous 5-HT released by (+)-fenfluramine (1 microM) or remaining in the biophase due to reuptake inhibition by citalopram (1 microM) caused reduction of cGMP compatible with a close apposition between 5-HT and EAA terminals. It can be concluded that activation (either direct or indirect) or blockade of presynaptic 5-HT1-like receptors previously found to be sited on EAA terminals in rat cerebellum where they mediate decrease of EAA release may profoundly affect the postsynaptic response elicited by EAA receptors coupled to guanylate cyclase.
Istituto di Farmacologia e Farmacognosia, Università degli Studi di Genova, Italy.
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Raiteri
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Maura
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Barzizza
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D002118:Calcium / Q000502:physiology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D015283:Citalopram / Q000494:pharmacology; D006152:Cyclic GMP / Q000096:biosynthesis*; D005277:Fenfluramine / Q000494:pharmacology; D005971:Glutamates / Q000502:physiology; D018698:Glutamic Acid; D066298:In Vitro Techniques; D008297:Male; D008719:Methiothepin / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D005971:Glutamates; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013764:Tetrahydronaphthalenes; D015283:Citalopram; D005277:Fenfluramine; D012701:Serotonin; D018698:Glutamic Acid; D008719:Methiothepin; D016202:N-Methylaspartate; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D006152:Cyclic GMP; D011188:Potassium; D002118:Calcium