Psychopharmacology

, Volume 63, Issue 1, pp 67–73 | Cite as

A possible intraneuronal site of action of thymoleptics

  • Toshikazu Okada
  • Yuhko Seki
  • Isami Kuruma
Original Investigations
Received:
Accepted:

Abstract

The uptake of catecholamines (CAs) into crude mitochondria preparations (P2 fractions) and vesicle preparations from rat hypothalamus and striatum were compared in terms of the inhibition by thymoleptics and other drugs.

Thymoleptics preferentially inhibited the uptake of CAs into hypothalamic P2 fractions, while ATPase inhibitors preferentially inhibited the uptake of dopamine into striatal P2 fractions. When the preparation obtained from rats pretreated with reserpine was used, the preferential inhibition of hypothalamic uptake by thymoleptics was entirely abolished. When P2 fractions from both regions were incubated with 10-6M 14C-imipramine, the intrasynaptosomal distribution of labeled imipramine revealed its affinity not only to the synaptosomal membrane, but also to the synaptic vesicles. Accumulated 3H-norepinephrine (NE) could be released by a hypoosomotic shock from striatal P2 fractions, but not from hypothalamic P2 fractions. The ATP-Mg2+-dependent uptake of 3H-NE into the synaptic vesicles from rat brain stem was inhibited by desipramine.

These results indicate that the inhibition of CA uptake by thymoleptics in the hypothalamus is predominantly due to the inhibition at the synaptic vesicle, while in the striatum the uptake at the synaptosomal membrane is predominantly inhibited.

Key words

Thymoleptics Catecholamines uptake Catecholamines retention Rat hypothalamus and striatum Metabolic inhibitors Neuroleptics 
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References

  1. Carlsson, A., Waldeck, B.: Mechanism of amine transport in the cell membranes of the adrenergic nerves. Acta Pharmacol. Toxicol. 22, 293 (1965)Google Scholar
  2. Carlsson, A., Fuxe, K., Hamberger, B., Lindqvist, M.: Biochemical and histochemical studies on the effect of imipramine-like drugs and (+)-amphetamine on central and peripheral catecholamine neurons. Acta Physiol. Scand. 67, 481 (1966)Google Scholar
  3. Coyle, J. H., Snyder, S. H.: Catecholamine uptake by synaptosomes in homogenates of rat brain; stereospecificity in different areas. J. Pharmacol. Exp. Ther. 170, 221 (1969)Google Scholar
  4. 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 as 3H-dopamine. J. Pharmacol. Exp. Ther. 153, 30 (1966)Google Scholar
  5. Horn, A. S., Coyle, J. T., Snyder, S. H.: Catecholamine uptake by synaptosomes from rat brain; structure-activity relationships of drugs with differential effects on dopamine and norepinephrine. Mol. Pharmacol. 7, 66 (1971)Google Scholar
  6. Lowry, O. H., Rosebrough, N. J., Farr, A. L., Randall, R. J.: Protein measurement with the folin phenol reagent. J. Biol. Chem. 193, 265 (1951)Google Scholar
  7. Philippu, A., Becke, H., Burger, A.: Effect of drugs on the uptake of noradrenaline by isolated hypothalamic vesicles. Eur. J. Pharmacol. 6, 96 (1969)Google Scholar
  8. Reid, W. D., Stefano, F. J. E., Kurzepa, S., Brodie, B. B.: Tricyclic antidepressants; evidence for an intraneuronal site of action. Science 164, 437 (1969)Google Scholar
  9. Ross, C. B., Renyi, A. L.: Inhibition of the uptake of tritiated catecholamine by antidepressant and related agents. Eur. J. Pharmacol. 2, 181 (1967)Google Scholar
  10. Roth, J. A., Gillis, C. N.: Inhibition of lung, liver and brain monoamine oxidase by imipramine and desipramine. Biochem. Pharmacol. 23, 1138 (1974)Google Scholar
  11. Schildkraut, J. J., Winokur, A., Draskoczy, P. R., Hensle, J. H.: Changes in norepinephrine turnover in rat brain during chronic administration of imipramine and protriptyline; a possible explanation for the delay in onset of clinical antidepressant effects. Am. J. Psychiatry 128, 1032 (1971)Google Scholar
  12. 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 (1969)Google Scholar
  13. Steinberg, M. I., Smith, C. B.: Effects of desmethylimipramine and cocaine on the uptake, retention and metabolism of 3H-tyramine in rat brain slices. J. Pharmacol. Exp. Ther. 173, 176 (1970)Google Scholar
  14. Wagner, L. A., Stitzel, R. E.: The relation between the subcellular distribution of [3H]reserpine and its proposed site of action. J. Pharm. Pharmacol. 24, 396 (1972)Google Scholar
  15. White, T. D., Archibald, J. T.: Rapid binding of newly accumulated noradrenaline within synaptosomes. Brain Res. 82, 360 (1974)Google Scholar
  16. Whittaker, V. P., Michaelson, I. A., Kirkland, R. J. A.: The separation of synaptic vesicles from nerve ending particles (‘synaptosomes’). Biochem. J. 90, 293 (1964)Google Scholar

Copyright information

© Springer-Verlag 1979

Authors and Affiliations

  • Toshikazu Okada
    • 1
  • Yuhko Seki
    • 1
  • Isami Kuruma
    • 1
  1. 1.Department of BiochemistryNippon Roche Research CenterKamakura, KanagawaJapan

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