Neurochemical Research

, Volume 21, Issue 5, pp 557–562 | Cite as

Enhancement of fluoxetine-dependent increase of extracellular serotonin (5-HT) levels by (−)-pindolol, an antagonist at 5-HT1A receptors

  • Laura J. Dreshfield
  • David T. Wong
  • Kenneth W. Perry
  • Eric A. Engleman
Original Articles


The somatodendritic 5-HT1A autoreceptor is known to regulate activity of 5-HT neurons and consequently 5-HT release. Administration of a selective 5-HT uptake inhibitor, fluoxetine (10 mg/kg, i.p.) increased extracellular 5-HT levels in rat hypothalamus up to 260 percent of basal levels. (−)-Pindolol, an antagonist at the somatodendritic 5-HT1A autoreceptor, dose-dependently (1, 3 and 5 mg/kg, s.c.) potentiated the fluoxetine dependent increase up to 458 percent of basal 5-HT levels for approximately 1.5 hours. Continuous infusion of (±)-pindolol at 30 mg/kg/h s.c. enhanced the fluoxetine dependent elevation of extracellular 5-HT concentrations in hypothalamus up to 464 percent of basal levels and lasted for 3 hours. Thus, the combination of 5-HT uptake inhibition with antagonism at the somatodendritic 5-HT1A autoreceptor can enhance 5-HT release to levels beyond those achieved with uptake inhibition alone. The present findings are consistent with the hypothesis that blockade of somatodendritic 5-HT1A autoreceptors removes the inhibitory effect exerted by the elevated 5-HT levels resulting from uptake inhibition.

Key Words

Serotonin hypothalamus fluoxetine pindolol microdialysis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hjorth, S. 1993. Serotonin 5-HT1A autoreceptor blockade potentiates the ability of the 5-HT reuptake inhibitor citalopram to increase nerve terminal output of 5-HT in vivo: a microdialysis study. J. Neurochem. 60:776–779.PubMedCrossRefGoogle Scholar
  2. 2.
    Invernizzi, R., Belli, S., and Samanin, R. 1992. Citalopram’s ability to increase extracellular concentrations of serotonin in the dorsal raphe prevents the drug’s effect in the frontal cortex. Brain Res. 584:322–324.PubMedCrossRefGoogle Scholar
  3. 3.
    Gartside, S. E., Umbers, V., Hajós, M., and Sharp, T. 1995. Interaction between a selective 5-HT1A receptor antagonist and an SSRI in vivo: effects on 5-HT cell firing and extracellular 5-HT. Bri. J. Pharmacol. 115:1064–1070.Google Scholar
  4. 4.
    Hoyer, D., Engle, G., and Kalkman, H. O. 1985. Molecular pharmacology of 5-HT1 and 5-HT2 recognition sites in rat and pig brain membranes: radioligand binding studies with [3H]5-HT, [3H]8-OH-DPAT, (−)[125I]iodocyanopindolol,[3H]mesulergine and [3H]ketanserin. Eur. J. Pharmacol. 118:13–23.PubMedCrossRefGoogle Scholar
  5. 5.
    Artigas, F., Perez, V., and Alvarez, E. 1994. Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors. Arch. Gen. Psychiatry 51:248–251.PubMedGoogle Scholar
  6. 6.
    Blier, P., and Bergeron, R. 1995. Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression. J. Clin. Psychopharm. 15:217–222.CrossRefGoogle Scholar
  7. 7.
    Wong, D. T., Dreshfield, L. J., Perry, K. W., and Engleman, E. A. 1994. Augmentation of fluoxetine-induced elevation of extracellular 5-HT levels by pindolol, an antagonist at 5-HT1A receptor. Am. Coll. Neuropsychopharm. 33rd Annual Meeting Abst. P102.Google Scholar
  8. 8.
    Artigas, F., Romero, L., Celada, P., and Bel, N. 1994. 5-HT1A antagonists and terminal 5-HT release effects of the combined treatment with 5-HT uptake inhibitors. Ann. Meeting of Soc. for Neurosci. Abstr. 20:1541.Google Scholar
  9. 9.
    Perry, K. W., and Fuller, R. W. 1992. Effect of fluoxetine on serotonin and dopamine concentration in microdialysis fluid from rat striatum. Life Sci. 50:1683–1690.PubMedCrossRefGoogle Scholar
  10. 10.
    Paxinos, G., and Watson, C. 1986. The rat brain in stereotaxic coordinates. Academic Press, London.Google Scholar
  11. 11.
    Perry, K. W., and Fuller, R. W. 1993. Extracellular 5-hydroxytryptamine concentration in rat hypothalamus after administration of fluoxetine plus L-5-hydroxytryptophan. J. Pharm. Pharmacol. 45:759–761.PubMedGoogle Scholar
  12. 12.
    Jacobs, B. L., Fornal, C. A., and Wilkinson, L. O. 1990. Neurophysiological and neurochemical studies of brain serotonergic neurons in behaving animals. Annals of New York Acad. Sci. 600: 260–271.Google Scholar
  13. 13.
    Fornal, C. A., Metzler, C. W., and Jacobs, B. L. 1994. Role of somatodendritic 5-HT1A autoreceptors in the regulation of brain 5-HT neuronal activity in behaving cats. IUPHAR satellite meeting on serotonin. Abst. p. 46.Google Scholar
  14. 14.
    Engleman, E. A., Robertson, D. W., Thompson, D., Perry, K. W., and Wong, D. T. 1996. Antagonism of 5-HT1A receptors potentiates the increase in extracellular monoamines induced by duloxetine in rat hypothalamus. J. Neurochem. 66:599–603.PubMedCrossRefGoogle Scholar
  15. 15.
    Bel, N., and Artigas, F. 1992. Fluvoxamine preferentially increases extracellular 5-hydroxytryptamine in the raphe nuclei: anin vivo microdialysis study [published erratum appears in Eur. J. Pharmacol. 1993, Mar. 2:232(2–3):326]. Eur. J. Pharmacol. 229: 101–103.PubMedCrossRefGoogle Scholar
  16. 16.
    Wozniak, K., Pert, A., and Linnoila, M. 1992. Alterations in raphe and frontal cortex serotonin over-flow following focal and systemic administration of fluoxetine. Soc. Neurosci. Abst. 18:1525.Google Scholar
  17. 17.
    Guan, X.-M., and McBride, W. J. 1988. Fluoxetine increases the extracellular levels of serotonin in the nucleus accumbens. Brain Res. Bull. 21:43–46.PubMedCrossRefGoogle Scholar
  18. 18.
    Kalen, P., Strecker, R. E., Rosengren, E., and Bjorklund, A. 1988. Endogenous release of neuronal serotonin and 5-hydroxyindoleacetic acid in the caudate-putamen of the rat as revealed by intracerebral dialysis coupled to high pressure liquid chromatography with fluorimetric detection. J. Neurochem. 51:1422–1435.PubMedCrossRefGoogle Scholar
  19. 19.
    Kreiss, D. S., and Lucki, I. 1995. Effects of acute and repeated administration of antidepressant drugs on extracellular levels of 5-hydroxytryptamine measured in vivo. J. Pharmacol. Exp. Ther. 274:866–876.PubMedGoogle Scholar
  20. 20.
    Bel, N., and Artigas, F. 1992. Fluvoxamine preferentially increases extracellular 5-hydroxytryptamine in the raphe nuclei: an in vivo microdialysis study. Eur. J. Pharmacol. 229:101–103.PubMedCrossRefGoogle Scholar
  21. 21.
    Tanda, G., Carboni, E., Frau, R., and Di Chiara, G. 1994. Increase of extracellular dopamine in the prefrontal cortex: a trait of drugs with antidepressant potential. Psychopharmacol. 115:285–288.CrossRefGoogle Scholar
  22. 22.
    Rutter, J. J., and Auerbach, S. B. 1993. Acute uptake inhibition increases extracellular serotonin in the rat forebrain. J. Pharmacol. Exp. Ther. 265:1319–1324.PubMedGoogle Scholar
  23. 23.
    Rutter, J. J., Gundlah, C., and Auerbach, S. B. 1995. Systemic uptake inhibition decreases serotonin release via somatodendritic autoreceptor activation. Synapse 20:225–233.PubMedCrossRefGoogle Scholar
  24. 24.
    Hjorth, S., and Auerbach, S. B. 1994. Further evidence for the importance of 5-HT1A autoreceptors in the action of selective serotonin uptake inhibitors. Eur. J. Pharmacol. 260:251–255.PubMedCrossRefGoogle Scholar
  25. 25.
    Hjorth, S., and Carlsson, A. 1986. Is pindolol a mixed agonist-antagonist at central serotonin (5-HT) receptors? Eur. J. Pharmacol. 129:131–138.PubMedCrossRefGoogle Scholar
  26. 26.
    Hjorth, S., and Sharp, T. 1993.In vivo microdialysis evidence for central serotonin 1A and 1B autoreceptor blocking properties of the beta adrenoceptor antagonist (−)penbutolol. J. Pharmacol. Exp. Ther. 265:707–712.PubMedGoogle Scholar
  27. 27.
    Bosker, F. J., Donker, M. G., Klompmakers, A. A., Kurata, K., and Westenberg, H. G. M. 1994. 5-hydroxytryptamine release in dorsal hippocampus of freely moving rats: modulation by pindolol. Prog. Neuropsychopharmacol. & Biol. Psychiat. 18:765–778.CrossRefGoogle Scholar
  28. 28.
    Hrdina, P. D., Foy, B., Hepner, A., and Summers, R. J. 1990. Antidepressant binding sites in brain: autoradiographic comparison of [3H]paroxetine and [3H]imipramine localization and relationship to serotonin transporter. J. Pharmacol. Exp. Ther. 252: 410–418.PubMedGoogle Scholar
  29. 29.
    Moret, C. 1985. Pharmacology of the serotonin autoreceptor. Pages 21–49,in Green, A. R. (ed.) Neuropharmacology of Serotonin. Oxford University Press, Oxford.Google Scholar
  30. 30.
    Clemens, J. A., Sawyer, B. D., and Cerimele, B. 1977. Further evidence that serotonin is a neurotransmitter involved in the control of prolactin secretion. Endocrinology 100:692–698.PubMedCrossRefGoogle Scholar
  31. 31.
    Blier, P., and de Montigny, C. 1987. Modification of 5-HT neuron properties by sustained administration of the 5-HT1A agonist gepirone: electrophysiological studies in the rat brain. Synapse 1: 470–480.PubMedCrossRefGoogle Scholar
  32. 32.
    Blier, P., Chaput, Y., and de Montigny, C. 1988. Long-term 5-HT reuptake blockade but not monoamine oxidase inhibition, decreases the function of terminal 5-HT autoreceptors: an electrophysiological study in the rat brain. Naunyn-Schmieleberg’s Arch. Pharmacol. 337:246–254.Google Scholar
  33. 33.
    Bel, N., and Artigas, F. 1993. Chronic treatment with fluvoxamine increases extracellular serotonin in frontal cortex but not in raphe nuclei. Synapse 15:243–245.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • Laura J. Dreshfield
    • 1
  • David T. Wong
    • 1
  • Kenneth W. Perry
    • 1
  • Eric A. Engleman
    • 1
  1. 1.Lilly Research Laboratories, Eli Lilly and CompanyLilly Corporate CenterIndianapolis

Personalised recommendations