Skip to main content

Blockade of central 5-hydroxytryptamine receptors by methiothepin

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.

This is a preview of subscription content, access via your institution.

References

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • Jalfre, M., Monachon, M.-A., Haefely, W.: Pharmacological modifications of benzoquinolizine-induced geniculate spikes. Experientia (Basel) 26, 691 (1970).

    Google Scholar 

  • 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).

  • 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).

  • Keller, H. H.: Depletion of cerebral monoamines by p-chlorophenylalamine in the cat. Experientia (Basel) 28, 177 (1972).

    Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 

  • Tebēcis, A. K.: Antagonism of 5-hydroxytryptamine by methiothepin: microelectrophoretic studies of neurones in the lateral geniculate nucleus. Nature (in press).

  • 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 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Monachon, M.A., Burkard, W.P., Jalfre, M. et al. Blockade of central 5-hydroxytryptamine receptors by methiothepin. Naunyn-Schmiedeberg's Arch. Pharmacol. 274, 192–197 (1972). https://doi.org/10.1007/BF00501854

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00501854

Key words

  • Brain Serotonin
  • PGO-Spikes
  • Methiothepin
  • Serotonin Antagonist