, Volume 48, Issue 3, pp 295–301 | Cite as

Mepiprazole, a new psychotropic drug: Effects on uptake and retention of monoamines in rat brain synaptosomes

  • P. Placheta
  • E. Singer
  • W. Kriwanek
  • G. Hertting
Laboratory Studies


The influence of mepiprazole (EMD 16,923), a new pyrazol-ylalkyl-piperazine derivative, on the uptake of 3H-norepinephrine (NE), 3H-dopamine (DA), and 3H-serotonin (5-HT) into rat brain synaptosomes from cerebral cortex, corpus striatum, and hypothalamus was investigated in comparison with several psychotropic drugs, including oxypertine, d-amphetamine, imipramine, desipramine, chlorimipramine, amitriptyline, and chlorpromazine in vitro. Mepiprazole was a relatively weak inhibitor of monoamine uptake and exhibited its strongest action on the hypothalamic 5-HT uptake, being almost equipotent with desipramine (IC50=0.9 μM). Furthermore, the influence of the drugs on the retention of 3H-amines previously taken up by whole rat brain synaptosomes was studied. Unlike the tricyclic antidepressants, mepiprazole as well as oxypertine and d-amphetamine markedly increased the efflux of radioactivity during a 20-min incubation at 37°C at low concentrations (10−6 to 10−5 M), whereas at 10−4M all drugs greatly enhanced the efflux. The ability of mepiprazole to increase 5-HT concentration at the receptor level by a combination of neuronal uptake inhibition and release is discussed in relationship to the central actions of the drug.

Key words

Synaptosomes Monoamine uptake Monoamine release Mepiprazole Oxypertine d-Amphetamine Imipramine Desipramine Chlorimipramine Amitriptyline Chlorpromazine 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Azzaro, A. J., Ziance, R. J., Rutledge, C. O.: The importance of neuronal uptake of amines for amphetamine-induced release of 3H-norepinephrine from isolated brain tissue. J. Pharmacol. exp. Ther. 189, 110–118 (1974)Google Scholar
  2. Carlsson, A., Corrodi, H., Fuxe, K., Hökfelt, T.: Effect of anti-depressant drugs on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by 4-methyl-α-ethyl-metatyramine. Europ. J. Pharmacol. 5, 357–366 (1969)Google Scholar
  3. Carlsson, A., Fuxe, K., Hamberger, B., Lindquist, M.: Biochemical and histochemical studies on the effects of imipramine-like drugs and (+)-amphetamine on central and peripheral catechol-amine neurons. Acta physiol. scand. 67, 481–497 (1966)Google Scholar
  4. Cheng, Y., Prusoff, W. H.: Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50% inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 22, 3099–3108 (1973)Google Scholar
  5. Corrodi, H., Fuxe, K.: The effect of imipramine on central monoamine neurons. J. Pharm. Pharmacol. 20, 230–231 (1968)Google Scholar
  6. Cuasnicú, A.: Comparación doble-ciego del nuevo tranquilizante Mepiprazol con diazepan. Therapia (Revista Mensual de Terapeutica) 49, 34–40 (1974)Google Scholar
  7. Dotevall, G., Groll, E.: Controlled clinical trial of mepiprazole in irritable bowel syndrome. Brit. med. J. 1974 IV, 16–18Google Scholar
  8. Foguet, G.: Evaluación terapéutica de un nuevo tranquilizante menor. El Dia Medico 46, 698–704 (1974)Google Scholar
  9. Glowinski, J., Axelrod, J., Iversen, L. L.: Regional studies of catecholamines in the rat brain. IV. Effects of drugs on the disposition and metabolism of 3H-norepinephrine and 3H-dopamine. J. Pharmacol. exp. Ther. 153, 30–41 (1966)Google Scholar
  10. Glowinski, J., Iversen L. L.: Regional studies of catecholamines in the rat brain. I. The disposition of 3H-norepinephrine, 3H-dopamine and 3H-dopa in various regions of the brain. J. Neurochem. 13, 655–669 (1966)Google Scholar
  11. Goncalves, N.: Das klinische Wirkungsbild des Tranquilizers Mepiprazol bei hospitalisierten Schizophrenen. Psychopharmacologia (Berl.) 25, 281–290 (1972)Google Scholar
  12. Goncalves, N., Fieguth, G.: Veränderung der Aufmerksamkeits-und Konzentrationsleistung chronisch Schizophrener unter zusätzlicher Behandlung mit Mepiprazol und ihre Bedeutung für die Resozialisierung. Pharmakopsychiat. 6, 167–177 (1973)Google Scholar
  13. Harris, J. E., Baldessarini, R. J.: Uptake of 3H-catecholamines by homogenates of rat corpus striatum and cerebral cortex: Effects of amphetamine analogues. Neuropharmacology 12, 669–679 (1973)Google Scholar
  14. Hassler, R., Bak, I. J., Kim, J. S.: Unterschiedliche Entleerung der Speicherorte für Noradrenalin, Dopamin und Serotonin als Wirkungsprinzip des Oxypertins. Nervenarzt 41, 105–118 (1970)Google Scholar
  15. Heikkila, R. E., Orlansky, H., Cohen, G.: Studies on the distinction between uptake inhibition and release of 3H-dopamine in rat brain tissue slices. Biochem. Pharmacol. 24, 847–852 (1975)Google Scholar
  16. Hamberger, B.: Reserpine-resistant uptake of catecholamines in isolated tissues of the rat. Acta physiol scand. 71, Suppl. 295, 1–56 (1967)Google Scholar
  17. Henkel, D., Bastine, R.: Vergleichende Untersuchungen zur systematischen Desensibilisierung in Gruppen mit verbal-muskulärer und pharmakologischer Entspannungsinduktion. Z. klin. Psychol. 1, 150–163 (1972)Google Scholar
  18. Horn, A. S., Coyle, J. D., Snyder, S. H.: Catecholamine uptake by synaptosomes from rat brain. Structure-activity relationships of drugs with differential effects on dopamine and norepinephrine neurons. Molec. Pharmacol. 7, 66–80 (1971)Google Scholar
  19. Kebabian, J. W., Petzold, G. L., Greengard, P.: Dopamine sensitive adenylate cyclase in the caudate nucleus of the rat brain and its similarity to the “dopamine receptor”. Proc. nat. Acad. Sci. (Wash.) 69, 2145–2149 (1972)Google Scholar
  20. Leitz, F. H., Stefano, F. J. E.: Desipramine-induced release of norepinephrine from heart. Biochem. Pharmacol. 19, 1797–1801 (1970)Google Scholar
  21. Lineweaver, H., Burk, D.: The determination of enzyme dissociation constants. J. Amer. chem. Soc. 56, 658–666 (1934)Google Scholar
  22. Lowry, O., Rosebrough, N., Farr, A., Randall, R.: Protein measurements with the Folin phenol reagent. J. biol. Chem. 193, 265–275 (1951)Google Scholar
  23. Müller-Calgan, H.: Psychopharmacological characteristics of certain new tranquilizing piperazine derivatives in rats and rhesus monkeys. In: Proceedings of 5th World Congress on Psychiatry, Mexico City (1971)Google Scholar
  24. Müller-Calgan, H.: A pharmacological model with rhesus monkeys for the prediction of selective depression of psychic functions. Activ. nerv. sup. (Praha) 16, 1–3 (1974)Google Scholar
  25. Ng, K. Y., Chase, T. N., Kopin, I. J.: Drug-induced release of 3H-norepinephrine and 3H-serotonin from brain slices. Nature (Lond.) 228, 468–469 (1970)Google Scholar
  26. Placheta, P., Singer, E., Kriwanek, W., Hertting, G.: The effect of mepiprazole on the uptake of norepinephrine, dopamine, and serotonin into rat brain synaptosomes. Naunyn-Schmiede-berg's Arch Pharmacol., Suppl. 287, R4 (1975)Google Scholar
  27. Pöldinger, W.: Clinical trial of 3-methyl-5-(β-N′-[N-m-chlorophenylpiperazino]ethyl)-pyrazole dihydrochloride (mepiprazole) in the therapy of psychovegetative disorders. Int. Pharmacopsychiat. 10, 1–8 (1975)Google Scholar
  28. Ross, S. B., Renyi, A. L.: Inhibition of the uptake of tritiated catecholamines by antidepressant and related agents. Europ. J. Pharmacol. 2, 181–186 (1967)Google Scholar
  29. Ross, S. B., Renyi, A. L.: Tricyclic antidepressant agents. I. Comparison of the inhibition of the uptake of 3H-noradrenaline and 14C-5-hydroxytryptamine in slices and crude synaptosome preparations of the midbrain-hypothalamus region of the rat brain. Acta pharmacol. (Kbh.) 36, 382–394 (1975)Google Scholar
  30. Shaskan, E. G., Snyder, S. H.: Kinetics of serotonin accumulation into slices from rat brain: Relationship to catecholamine uptake. J. Pharmacol. exp. Ther. 175, 404–418 (1970)Google Scholar
  31. Snyder, S. H., Coyle, J. T.: Regional differences in 3H-norepinephrine and 3H-dopamine uptake into rat brain homogenates. J. Pharmacol. exp. Ther. 165, 78–86 (1969)Google Scholar
  32. Van Rossum, J. M.: The significance of dopamine-receptor block-ade for the mechanism of action of neuroleptic drugs. Arch. int. Pharmacodyn. 160, 492–494 (1966)Google Scholar
  33. Whittaker, V. P.: The synaptosome. In: Handbook of neurochemistry, Vol. 2, A. A. Lajtha, ed., pp. 327–364. New York: Plenum Press 1969Google Scholar
  34. Wong, D. T., Horng, J., Fuller, R. W.: Kinetics of serotonin accumulation into synaptosomes of rat brain-Effects of amphetamine and chloroamphetamines. Biochem. Pharmacol. 22, 311–322 (1973)Google Scholar

Copyright information

© Springer-Verlag 1976

Authors and Affiliations

  • P. Placheta
    • 1
    • 2
  • E. Singer
    • 1
    • 2
  • W. Kriwanek
    • 1
    • 2
  • G. Hertting
    • 1
    • 2
  1. 1.Institute of PharmacologyUniversity of ViennaViennaAustria
  2. 2.Institute of PharmacologyFreiburg i. Br.Germany

Personalised recommendations