, Volume 60, Issue 3, pp 281–289 | Cite as

Receptor mechanisms in increased sensitivity to serotonin agonists after dihydroxytryptamine shown by electronic monitoring of muscle twitches in the rat

  • R. Malcolm Stewart
  • Alexander Campbell
  • Günther Sperk
  • Ross J. Baldessarini
Original Investigations


Muscle twitches and autonomic changes were induced by systemic injections of L-5-hydroxytryptophan (5-HTP) or the serotonin agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in rats previously lesioned with intracranial 5,7-dihydroxytryptamine (5,7-DHT) after desmethylimipramine. Movements were recorded sensitively and continuously by an electronic activity monitor. Spontaneous locomotor activity was strongly reduced after 5-HTP in both intact and lesioned rats, so that electronically recorded activity correlated very closely with disordered jerking movements scored by a behavioral rating scale. This myoclonus was dependent on the doses of 5-HTP and of 5,7-DHT and was strongly inhibited by serotonin antagonists. In lesioned rats, myoclonus occurred with unaltered activity of monoamine oxidase (MAO) and after only small increases in serotonin levels after 5-HTP, but even large increases in availability of serotonin in intact rats, or strong inhibition of serotonin uptake failed to induce myoclonus unless MAO was first inhibited. The response to 5-HTP in lesioned rats was attenuated by repeated injections of 5-HTP or 5-MeO-DMT. This decreased response was in turn blocked by repeated doses of a serotonin antagonist, but appeared not to be due to altered metabolism of 5-HTP or of serotonin; repeated pretreatment with cyproheptadine potentiated the myoclonic response to 5-HTP after DHT. Changes in postsynaptic receptors may be important in the behavioral supersentivity following 5,7-DHT, and restitution of serotonin or stimulation of its receptors after presynaptic denervation may suppress an evolving supersensitivity at receptive postsynaptic membranes.

Key words

Denervation Dihydroxytryptamines Muscle spasms Myoclonus Serotonin Super-sensitivity 


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  1. Alpert, M., Friedhoff, A. J.: Receptor sensitivity modification in the treatment of tardive dyskinesia. Clin. Pharmacol. Ther. 19, 103–104 (1976)Google Scholar
  2. Baumgarten, H. G., Björkland, A.: Neurotoxins for indoleamine and monoamine neurons. Annu. Rev. Pharmacol. 16, 101–111 (1976)Google Scholar
  3. Baumgarten, H. G., Lachenmayer, L.: 5,7-Dihydroxytryptamine: improvement in chemical lesioning of indoleamine neurons in the mammalian brain. Z. Zellforsch. Mikrosk. Anat. 135, 399–414 (1972)Google Scholar
  4. Christensen, A. V., Fjalland, B., Møller-Nielsen, I.: On the supersensitivity of dopamine receptors, induced by neuroleptics. Psychopharmacology 48, 1–6 (1976)Google Scholar
  5. Costentin, J., Marcais, H., Protais, P., Baudry, M., Delabaume, S., Martres, M. P., Schwartz J. C.: Rapid development of hypersensivity of striatal dopamine receptors induced by alpha-methylparatyrosine and its prevention by protein synthesis inhibitors. Life Sci. 21, 307–314 (1977)Google Scholar
  6. Deguchi, T., Axelrod, J.: Supersensitivity and subsensitivity of the beta-adrenergic receptor in pineal gland regulated by catecholamine transmitter. Proc. Natl. Acad. Sci. U.S.A. 70, 2411–2414 (1973)Google Scholar
  7. Fleming, W., McPhillips, J. J., Westfall, D. P.: Postjunctional supersensitivity and subsensitivity of excitable tissues to drugs. Ergeb. Physiol. Biol. Chem. Exp. Pharmakol. 68, 55–119 (1973)Google Scholar
  8. Friedhoff, A. J., Bonnet, K., Rosengarten, H.: Reversal of two manifestations of dopamine receptor supersensitivity by administration of L-dopa. Res. Commun. Chem. Pathol. Pharmacol. 16, 411–423 (1977)Google Scholar
  9. Friedman, E., Buchweitz, E., Lambert, G.: Sensitivity changes in the central cardiovascular actions of serotonin. Proc. Soc. Neurosci. 3, 249 (1977)Google Scholar
  10. Friedman, M. J., Jaffe, J. H., Sharpless, S. K.: Central nervous system supersensitivity to pilocarpine after withdrawal of chronically administered scopolamine. J. Pharmacol. Exp. Ther. 167, 45–55 (1969)Google Scholar
  11. Gerson, S., Baldessarini, R. J.: Selective destruction of serotonin terminals in rat forebrain by high doses of 5,7-dihydroxytryptamine. Brain Res. 85, 140–145 (1975)Google Scholar
  12. Gerson, S., Baldessarini, R. J., Wheeler, S. C.: Biochemical effects of dihydroxylated tryptamines on central indoleamine neurons. Neuropharmacology 13, 987–1004 (1974)Google Scholar
  13. Jonsson, G., Pollare, T., Hallman, H., Sachs, C.: Developmental plasticity of central serotonin neurons following 5,7-dihydroxytryptamine treatment. In: Serotonin neurotoxins, J. H. Jacoby, L. D. Lytle (eds.). Ann. N. Y. Acad. Sci. 305, 328–345 (1978)Google Scholar
  14. Klawans, H. L., Margolin, D. I., Dana, N., Crosset, P.: Supersensitivity to d-amphetamine- and apomorphine-induced stereotyped behavior induced by chronic d-amphetamine administration. J. Neurol. Sci. 25, 283–289 (1975)Google Scholar
  15. Klawans, H. L., D'Amico, D. J., Nausieda, P. A., Weiner, W. J.: The specificity of neuroleptic- and methysergide-induced behavioral supersensitivity. Psychopharmacology 55, 49–52 (1977)Google Scholar
  16. Maickel, R. P., Miller, F. P.: Fluorescent products formed by reaction of indole derivatives and o-phthaldialdehyde. Analyt. Chem. 38, 1937–1938 (1966)Google Scholar
  17. Marsden, C. D., Tarsy, D., Baldessarini, R. J.: Spontaneous and drug-induced movement disorders in psychotic patients. In: Psychiatric aspects of neurologic disease, D. F. Benson, D. Blumer (eds.), pp. 219–265 New York: Grune and Stratton 1975Google Scholar
  18. Martres, M. P., Costentin, J., Baudry, M., Marcais, H., Protais, P., Schwartz J. C.: Long-term changes in the sensitivity of pre- and postsynaptic dopamine receptors in mouse striatum evidenced by behavioral and biochemical studies. Brain Res. 136, 319–337 (1977)Google Scholar
  19. Otsuka, S., Kobayashi, Y.: A radioisotopic assay for monoamine oxidase determination in human plasma. Biochem. Pharmacol. 13, 995–1006 (1964)Google Scholar
  20. Pelz, K., Jirkovsky, I., Adierova, E., Metysova, J., Protiva, M.: Neurotrope und psychotrope Substanzen. XXV. Über die in 8-Stellung durch die methyl-, ter-butylmethoxy-methylthio und methansulfonylgruppe substituierten 10-(4-methylpiperazine) 10,11-dihydrobenzo b,f thiepin-derivate. Collect. Czech. Chem. Commun. 33, 1894–1910 (1968)Google Scholar
  21. Sperk, G., Stewart, R. M., Campbell, A., Baldessarini, R. J.: Inhibition of the development of supersensitivity to serotonin after lesioning with 5,7-dihydroxytryptamine by treatment of mice with cycloheximide. Brain Res. 159, 183–194 (1978)Google Scholar
  22. Stewart, R. M., Growdon, J. H., Cancian, D., Baldessarini, R. J.: 5-Hydroxytryptophan induced myoclonus: increased sensitivity to serotonin after intracranial 5,7-dihydroxytryptamine in the adult rat. Neuropharmacology 15, 449–455 (1976)Google Scholar
  23. Tang, L. C., Cotzias, G. C.: L-3,4-Dihydroxyphenylalanine induced hypersensitivity simulating features of denervation. Proc. Natl. Acad. Sci. U.S.A. 74, 2126–2129 (1977)Google Scholar
  24. Tarsy, D., Baldessarini, R. J.: Behavioural supersensitivity to apomorphine following chronic treatment with drugs which interfere with the synaptic function of catecholamines. Neuropharmacology 13, 927–940 (1974)Google Scholar
  25. Tarsy, D., Baldessarini, R. J.: The tardive dyskinesia syndrome. In: Clinical neuropharmacology, Vol. I, H. Klawans (ed.), pp. 29–61. New York: Raven 1976Google Scholar
  26. Trulson, M. E., Eubanks, E. E., Jacobs, B. L.: Behavioral evidence for supersensitivity following destruction of central serotonergic nerve terminals by 5,7-dihydroxytryptamine. J. Pharmacol. Exp. Ther. 198, 23–32 (1976)Google Scholar
  27. Warbritton, J. D., Stewart, R. M., Baldessarini, R. J.: Decreased locomotor activity and attenuation of amphetamine hyperactivity with intraventricular infusion of serotonin in the rat. Brain Res. 143, 373–382 (1978)Google Scholar

Copyright information

© Springer-Verlag 1979

Authors and Affiliations

  • R. Malcolm Stewart
    • 1
  • Alexander Campbell
    • 1
  • Günther Sperk
    • 1
  • Ross J. Baldessarini
    • 1
  1. 1.Mailman Laboratories for Psychiatric Research, McLean Division of Massachusetts General Hospital, and Departments of Psychiatry and NeurologyHarvard Medical SchoolBostonUSA

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