Advertisement

Psychopharmacology

, Volume 100, Issue 4, pp 470–476 | Cite as

[3H] sertraline binding to rat brain membranes

  • B. K. Koe
  • L. A. Lebel
  • W. M. Welch
Original Investigations

Abstract

Tritiated sertraline, a radiolabeled form of a potent and selective inhibitor of serotonin uptake, was found to bind with high affinity to rat whole brain membranes. Characterization studies showed that [3H] sertraline binding occurred at a single site with the following parameters:K d 0.57 nM,Bmax 821 fmol/mg protein,n h 1.06. This binding was reversible; the dissociation constant calculated from kinetic measurements (K d 0.81 nM) agreed with that determined by saturation binding experiments. [3H] Sertraline binding in the presence of serotonin, paroxetine, fluoxetine or imipramine suggested competitive inhibition of binding (large increase inK d with little change inBmax). The rank order of potency of inhibition of [3H] sertraline binding was similar to that of inhibition of serotonin uptake for known uptake inhibitors and the 1-amino-4-phenyltetralin uptake blockers. A marked decrease in ex vivo [3H] sertraline binding in the brain of rats 7 days after treatment withp-chloroamphetamine was consistent with the loss of serotonin uptake sites induced by this agent. The results of our study indicated that [3H] sertraline labels serotonin uptake sites in rat brain.

Key words

[3H] Sertraline binding Serotonin uptake Uptake blockers 1-Amino-4-phenyltetralins 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Benavides J, Savaki HE, Malgouris C, Laplace C, Margelidon C, Daniel M, Courteix J, Uzan A, Gueremy C and Le Fur G (1985) Quantitative autoradiography of [3H] indalpine binding sites in the rat brain: I. Pharmacological characterization. J Neurochem 45:514–520Google Scholar
  2. Bennett Jr JP, Yamamura HI (1985) Neurotransmitter, hormone or drug receptor binding. In: Yamamura HI, Enna SJ, Kuhar MJ (ed) Neurotransmitter receptor binding. Raven Press, New York, pp 61–89Google Scholar
  3. Blier P, de Montigny C (1983) Electrophysiological investigations on the effect of repeated zimelidine administration on serotonergic neurotransmission in the rat. J Neurosci 3:1270–1278Google Scholar
  4. Blier P, de Montigny C, Tardif D (1984) Effects of the two antide-pressant drugs mianserin and indalpine on the serotonergic system: single-cell studies in the rat. Psychopharmacology 84:242–249Google Scholar
  5. Blier P, Chaput Y, de Montigny C (1988) Long-term 5-HT reuptake blockade, but not monoamine oxidase inhibition, decrease the function of terminal 5-HT autoreceptors: an electrophysiological study in the rat brain. Naunyn-Schmiedeberg's Arch Pharmacol 337:246–254Google Scholar
  6. Byerley WF, McConnell EJ, McCabe RT, Dawson TM, Grosser BI Wamsley JK (1987) Chronic administration of sertraline, a selective serotonin uptake inhibitor, decreased the density ofβ-adrenergic receptors in rat frontoparietal cortex. Brain Res 421:377–381Google Scholar
  7. Byerley WF, McConnell EJ, McCabe RT, Dawson TM, Grosser BI, Wamsley JK (1988) Decreased beta-adrenergic receptors in rat brain after chronic administration of the selective serotonin uptake inhibitor fluoxetine. Psychopharmacology 94:141–143Google Scholar
  8. Chaput Y, de Montigny C, Blier P (1986) Effects of a selective 5-HT reuptake blocker, citalopram, on the sensitivity of 5-HT autoreceptors: electrophysiological studies in the rat brain. Naunyn-Schmiedeberg's Arch Pharmacol 333:342–348Google Scholar
  9. D'Amato RJ, Largent BL, Snowman AM, Snyder SH (1987) Selective labeling of serotonin uptake sites in rat brain by [3H] citalopram contrasted to labeling of multiple sites by [3H] imipramine. J Pharmacol Exp Ther 242:364–371Google Scholar
  10. De Souza EB, Kuyatt BL (1987) Autoradiographic localization of3H-paroxetine-labeled serotonin uptake sites in rat brain. Synapses 1:488–496Google Scholar
  11. Gleiter CH, Nutt DJ (1988) Repeated electronconvulsive shock does not change [3H]-paroxetine binding to the 5-HT uptake site in rat cortical membranes. Psychopharmacology 95:68–70Google Scholar
  12. Habert E, Graham D, Tahraoul L, Claustre Y, Langer SZ (1985) Characterization of [3H] paroxetine binding to rat cortical membranes. Eur J Pharmacol 118:107–114Google Scholar
  13. Heym J, Reynolds LS (1986) Inhibition of serotonergic unit activity by sertraline, a new and highly selective inhibitor of serotonin uptake. Soc Neurosci Abstr 12:473Google Scholar
  14. Hrdina PD (1988) Inhibition of sodium-dependent [3H] imipramine binding in rat brain by serotonin and serotonin uptake inhibitors. Eur J Pharmacol 148:279–282Google Scholar
  15. Hyttel J (1984) Experimental pharmacology of selective 5-HT reuptake inhibitors: differences and similarities. Clin Neuropharmacol [Suppl 1] 7:866–867Google Scholar
  16. Kinnier WJ, Chuang D-M, Gwynn G, Costa E (1981) Characteristics and regulation of high affinity [3H] imipramine binding to rat hippocampal membranes. Neuropharmacology 20:411–419Google Scholar
  17. Koe BK (1976) Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain. J Pharmacol Exp Ther 199:649–661Google Scholar
  18. Koe BK, Weissman A, Welch WM, Browne RG (1983) Sertraline, 1S, 4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine, a new uptake inhibitor with selectivity for serotonin. J Pharmacol Exp Ther 226:686–700Google Scholar
  19. Koe BK, Koch SW, Lebel LA, Minor KW, Page MG (1987) Sertraline, a selective inhibitor of serotonin uptake, induces subsensitivity ofβ-adrenoceptor system of rat brain. Eur J Pharmacol 141:187–194Google Scholar
  20. Kovachich GB, Aronson CE, Brunswick DJ, Frazer A (1988) Quantitative autoradiography of serotonin uptake sites in rat brain using [3H] cyanoimipramine. Brain Res 454:78–88Google Scholar
  21. Langer SZ (1984) [3H] imipramine and [3H] desipramine binding: non-specific displaceable sites or physiologically relevant sites associated with the uptake of serotonin and noradrenaline? TIPS 5:51–53Google Scholar
  22. Langer SZ, Moret C, Raisman R, Dubocovich ML, Briley M (1980) High affinity binding3H-imipramine binding in rat hypothalamus: association with uptake of serotonin but not of norepinephrine. Science 210:1133–1135Google Scholar
  23. Marcusson JO, Bergstrom M, Eriksson K, Ross SB (1988) Characterization of [3H] paroxetine binding in rat brain. J Neurochem 50:1783–1790Google Scholar
  24. Mellerup ET, Plenge P (1986) High affinity binding of3H-paroxetine and3H-imipramine to rat neuronal membranes. Psychopharmacology 89:436–439Google Scholar
  25. Mishra R, Janowsky A, Sulser F (1980) Action of mianserine and zimelidine on the norepinephrine receptor coupled adenylate cyclase system in brain: subsensitivity without reduction inβ-adrenergic receptor binding. Neuropharmacology 19:983–987Google Scholar
  26. Reimherr FW, Byerley WF, Ward MF, Lebegue BJ, Wender PH (1988) Sertraline, a selective serotonin uptake blocker, for the treatment of outpatients with major depressive disorder. Psychopharmacol Bull 24:200–203Google Scholar
  27. Rosenthal HE (1967) Graphic method for the determination and presentation of binding parameters in a complex system. Anal Biochem 20:525–532Google Scholar
  28. Sanders-Bush E, Breeding M, Knoth K, Tsutsumi M (1989) Sertraline-induced desensitization of the serotonin 5-HT-2 receptor transmembrane signaling system. Psychopharmacology 99:64–69Google Scholar
  29. Sarges R (1975) Synthesis of phenyl-substituted 1-aminotetralines. J Org Chem 40:1216–1224Google Scholar
  30. Savaki H, Malgouris C, Benavides J, Laplace C, Uzan A, Gueremy C, Le Fur G (1985) Quantitative autoradiography of [3H] indalpine binding sites in the rat brain: II. Regional distribution. J Neurochem 45:521–526Google Scholar
  31. Shank RP, Vaught JL, Pelley KA, Setler PE, McComsey DF, Maryanoff BE (1988) McN-5652: a highly potent inhibitor of serotonin uptake. J Pharmacol Exp Ther 247:1032–1038Google Scholar
  32. Welch WM, Kraska AR, Sarges R, Koe BK (1984) Nontricyclic antidepressant agents derived from cis- and trans-1-amino-4-aryltetralins. J Med Chem 27:1508–1515Google Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • B. K. Koe
    • 1
  • L. A. Lebel
    • 1
  • W. M. Welch
    • 1
  1. 1.Central Research Division, Pfizer Inc.GrotonUSA

Personalised recommendations