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Blockade of central 5-hydroxytryptamine receptors by methiothepin

  • M. A. Monachon
  • W. P. Burkard
  • M. Jalfre
  • W. Haefely
Short Communication

Summary

Methiothepin (1-[10,11-dihydro-8-(methylthio)dibenzo[b,f] thiepin-10-yl]-4-methylpiperazine maleate), a representative of a new class of neuroleptics, is shown to be an antagonist of 5-hydroxytryptamine (5-HT) at receptors in the CNS. The neuropharmacological evidence was obtained by observing its effects on ponto-geniculo-occipital (PGO) spikes induced in curarized cats by either the benzoquinolizine Ro 4-1284 or p-chlorophenylalanine. Methiothepin a) increased the number of drug-induced spikes, b) antagonized the inhibitory action of 5-HTP and LSD on the spikas, and c) induced PGO-spikes by itself in untreated animals. The turnover of 5-HT in the rat brain was accelerated by methiothepin as indicated by virtually unaltered 5-HT levels, an increase of 5-hydroxyindole acetic acid, an enhancement of the 5-HT increase induced by a MAO inhibitor and by an increase of tryptophan levels in the brain.

Key words

Brain Serotonin PGO-Spikes Methiothepin Serotonin Antagonist 

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References

  1. Banna, N. R., Anderson, E. G.: The effect of 5-hydroxytryptamine antagonists on spinal neuronal activity. J. Pharmacol. exp. Ther. 162, 319–325 (1968).Google Scholar
  2. Bogdanski, D., Pletscher, A., Brodie, B. B., Udenfriend, S.: Identification and assay of serotonin in brain. J. Pharmacol. exp. Ther. 117, 82–88 (1956).Google Scholar
  3. Delorme, F., Froment, J. L., Jouvet, M.: Suppression du sommeil par la p-chlorométamphétamine et la p-chlorophénylalanine. C. R. Soc. Biol. (Paris) 160, 2347–2351 (1966).Google Scholar
  4. Jeannerod, M., Jouvet, M.: Effects remarquables de la réserpine sur l'activité EEG phasique ponto-géniculo-occipitale. C. R. Soc. Biol. (Paris) 159, 900–903 (1965).Google Scholar
  5. Denckla, W. D., Denwey, H. K.: The determination of tryptophan in plasma, liver and urine. J. Lab. clin. Med. 69, 161–169 (1967)Google Scholar
  6. Giacalone, E., Valzelli, L.: A method for the determination of 5-hydroxyindolyl-3-acetic acid in brain. J. Neurochem. 13, 1265–1266 (1966).Google Scholar
  7. Jalfre, M., Monachon, M.-A., Haefely, W.: Pharmacological modifications of benzoquinolizine-induced geniculate spikes. Experientia (Basel) 26, 691 (1970).Google Scholar
  8. Jalfre, M., Monachon, M.-A., Haefely, W.: Drugs and PGO-waves in the cat. First Canadian International Symposium on Sleep, Montreal, April 14, 1972 (in press).Google Scholar
  9. Jalfre, M., Monachon, M.-A. Keller, H. H., Haefely, W.: The effects of catecholamines on drug-induced geniculate spikes. First International Congress, Association for the Psychophysiological Study of Sleep, Bruges (Belgium), June 19–23, 1971 (in press).Google Scholar
  10. Keller, H. H.: Depletion of cerebral monoamines by p-chlorophenylalamine in the cat. Experientia (Basel) 28, 177 (1972).Google Scholar
  11. Nybäck, A., Sedvall, G.: Further studies on the accumulation and disappearance of catecholamines formed from tyrosine-C14 in mouse brain. Europ. J. Pharmacol. 10, 193–205 (1970).Google Scholar
  12. Pelz, K., Jirkowsky, I., Adlerová, E., Metyŝová, J., Protiva, M.: Neurotrope und psychotrope Substanzen XXV. Über die in 8-Stellung durch die Methyl-, tertbuty-methoxy-methylthio-und methansulfonylgruppe substituierten 10-(4-methylpiperazine)10,11-dihydrobenzo[b,f]thiepin-derivate. Collect. czechoslav. chem. Commun. 33, 1895–1910 (1968).Google Scholar
  13. Pletscher, A., Besendorf, H., Gey, K. F.: Depression of norepinephrine and 5-hydroxytryptamine in the brain by benzoquinolizine derivatives. Science 129, 844 (1959).Google Scholar
  14. Tagliamonte, A., Tagliamonte, P., Perez-Cruet, J., Stern, S., Gessa, G. L.: Effect of psychotropic drugs on tryptophan concentration in the rat brain. J. Pharmacol. exp. Ther. 177, 475–480 (1971).Google Scholar
  15. Tebēcis, A. K.: Antagonism of 5-hydroxytryptamine by methiothepin: microelectrophoretic studies of neurones in the lateral geniculate nucleus. Nature (in press).Google Scholar
  16. Vogt, M.: Cerebral tryptamine receptors: functional considerations. In: S. Garattini and P. A. Shore, ed.: Advances in Pharmacology, Vol. 6B, pp. 19–25. New York: Academic Press 1968.Google Scholar

Copyright information

© Springer-Verlag 1972

Authors and Affiliations

  • M. A. Monachon
    • 1
  • W. P. Burkard
    • 1
  • M. Jalfre
    • 1
  • W. Haefely
    • 1
  1. 1.Abteilung für Experimentalle MedizinF. Hoffmann-La Roche & Co.Basel

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