, Volume 117, Issue 3, pp 358–363 | Cite as

Chronic treatment with fluvoxamine by osmotic minipumps fails to induce persistent functional changes in central 5-HT1A and 5-HT1B receptors, as measured by in vivo microdialysis in dorsal hippocampus of conscious rats

  • F. J. Bosker
  • K. E. van Esseveldt
  • A. A. Klompmakers
  • H. G. M. Westenberg
Original Investigation


This study investigated the alterations of the 5-HT1A and 5-HT1B autoreceptor function following chronic treatment with fluvoxamine using osmotic minipumps. The 5-HT1A and 5-HT1B autoreceptor function were studied using microdialysis in the dorsal hippocampus. The effect of the 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, SC) and the 5-HT1B receptor agonist RU-24969 (100 nM through the dialysis probe for 30 min) on 5-HT release was compared with rats chronically treated with saline. 8-OH-DPAT decreased 5-HT release to 55% and 60% of baseline, while RU-24969 decreased 5-HT release to 66% and 70% of baseline value in the saline and fluvoxamine group, respectively. In both cases, differences between the saline and fluvoxamine groups were not statistically significant. Plasma levels of fluvoxamine after 21 days of treatment ranged from 3 to 5 ng/ml. Fluvoxamine concentration in rat brain during treatment was estimated between 100 and 200 nM, which approximates to the IC50 value of fluvoxamine on the 5-HT transporter in synaptosomes and is 50 times higher than the Kd value for the 5-HT reuptake site. In conclusion, no evidence was found for changes in 5-HT1A,B receptor function using 8-OH-DPAT and RU-24969 as probes after continuous treatment with fluvoxamine by means of osmotic minipumps.

Key words

Microdialysis Dorsal hippocampus 5-HT1A and 5-HT1B receptors Chronic treatment Fluvoxamine Rat 


  1. Bel N, Artigas F (1993) Chronic treatment with fluvoxamine increases extracellular serotonin in frontal cortex but not in raphe nuclei. Synapse 15:243–245CrossRefPubMedGoogle Scholar
  2. Blier P, 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: 470–480CrossRefPubMedGoogle Scholar
  3. Bonvento G, Scatton B, Claustre Y, Rouquier L, (1992) Effect of local injection of 8-OH-DPAT into the dorsal or median raphe nuclei on extracellular levels of serotonin in serotonergic projection areas in the rat brain. Neurosci Lett 137:101–104CrossRefPubMedGoogle Scholar
  4. Bosker FJ, Donker MG, Klompmakers AA, Kurata K, Westenberg HGM (1994) 5-Hydroxytryptamine release in dorsal hippocampus of freely moving rats: modulation by pindolol. Prog Neuro psychopharmacol Biol Psychiatry 18:765–778Google Scholar
  5. Chaput Y, de Montigny C, Blier P (1986) Effects of a selective 5-HT reuptake blocker, citalopram, on the sensitivity of the 5-HT autoreceptors: electrophysiological studies in the rat. Naunyn-Schmiedebergs Arch Pharmacol 333:342–345CrossRefPubMedGoogle Scholar
  6. Chaput Y, Blier P, de Montigny C (1988) Acute and long-term effects of antidepressant serotonin (5-HT) reuptake blockers on the efficacy of 5-HT neurotransmission: electrophysiological studies in the rat central nervous system. Adv Biol Psychiatry 17:1–17Google Scholar
  7. Chaput Y, de Montigny C, Blier P (1991) Presynaptic and postsynaptic modifications of the serotonergic system by long-term administration of antidepressant treatments. Neuropsychopharmacology 5:219–229PubMedGoogle Scholar
  8. Griebel G, Moreau JL, Jenck F, Misslin R, Martin JR (1994) Acute and chronic treatment with 5-HT reuptake inhibitors differentially modulate emotional responses in anxiety models in rodents. Psychopharmacology 113:463–470PubMedGoogle Scholar
  9. Leonard BE (1992) Pharmacological differences of serotonin reuptake inhibitors and possible clinical relevance. Drugs 43:3–10PubMedGoogle Scholar
  10. Lesch KP, Aulakh CS, Wolozin BL, Tolliver TJ, Hill JL, Murphy DL (1993) Regional brain expression of serotonin transporter mRNA and its regulation by reuptake inhibiting antidepressants. Mol Brain Res 17:31–35CrossRefPubMedGoogle Scholar
  11. Malagie I, Jacquot C, Gardier AM (1992) In vivo release of scrotonin at fontocortical nerve terminals evoked by electrical stimulation of the dorsal raphe nucleus: effect of repeated administration of fluoxetine. Abstract 2nd International Symposium on Serotonin, Houston, p 47Google Scholar
  12. Montero D, de Felipe MC, del Rio J (1991) Acute or chronic antidepressants do not modify125I-cyanopindolol binding to 5-HT1B receptors in rat brain. Eur J Pharmacol 196: 327–329CrossRefPubMedGoogle Scholar
  13. Moret C, Briley M (1990) Serotonin autoreceptor subsensitivity and antidepressant activity. Eur J Pharmacol 180: 351–356CrossRefPubMedGoogle Scholar
  14. Pandey SC, Isaac L, Davis JM, Pandey GN (1991) Similar effects of treatment with desipramine and electroconvulsive shock on 5-hydroxytryptamine1A receptors in rat brain. Eur J Pharmacol 202:221–225CrossRefPubMedGoogle Scholar
  15. Paxinos S, Watson C (1982) The rat brain in stereotoxic coordinates, Academic Press, New YorkGoogle Scholar
  16. Santiago M, Westérink BHC (1990) Characterization of the in-vivo release of dopamine as recorded by different types of intracerebral microdialysis probes. Naunyn-Schmiedeberg's Arch Pharmacol 342:407–414CrossRefGoogle Scholar
  17. Schechter LE, Bolanos FJ, Gozlan H, Lanfumay L, Haj-Dahmane S, Laporte AM, Fattaccinic, Hamon M (1990) Alterations of central serotonergic and dopaminergic transmission in rats chronically treated with ipsapirone: biochemical and electrophysiological studies. J Pharmacol Exp Ther 255:1335–1347PubMedGoogle Scholar
  18. Sharp T, Bramwell SR, Grahame-Smith DG (1989a) 5-HT1 agonists reduce 5-hydroxytryptamine release in rat hippocampus in vivo as determined by brain microdialysis. Br J Pharmacol 96:283–290PubMedGoogle Scholar
  19. Sharp T, Bramwell SR, Hjorth S, Grahame-Smith DG (1989b) Pharmacological characterization of 8-OH-DPAT-induced inhibition of rat hippocampal 5-HT release in vivo as measured by microdialysis. Br J Pharmacol 98:989–997Google Scholar
  20. Sharp T, Bramwell SR, Clark D, Grahame-Smith DG (1989c) In vivo measurements of extracellular 5-hydroxytryptamine in hippocampus of the anaesthetized rat using microdialysis: changes in relation to 5-hydroxytryptaminergic neuronal activity. J Neurochem 53:234–240PubMedGoogle Scholar
  21. Sleight AJ, Smith RJ, Marsden CA, Palfreyman MG (1989) The effects of chronic treatment with amitriptyline and MDL 72394 on the control of 5-HT release in vivo. Neuropharmacology 28:477–480CrossRefPubMedGoogle Scholar
  22. Sotelo C, Cholley B, El Mestikawy S, Gozlan H, Harmon M (1990) Direct immunohistochemical evidence of the existence of 5-HT1A autoreceptors on serotoninergic neurons in the midbrain raphe nuclei. Eur J Neurosci 12:1144–1154Google Scholar
  23. Sprouse JS, Aghajanian GK (1987) Electrophysiological responses of serotonergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists. Synapse 1:3–9CrossRefPubMedGoogle Scholar
  24. Welner SA, de Montigny C, Desorches J, Desjardins P, Suranyi-Cadotte BE (1989) Autoradiographic quantification of serotonin (5-HT1A) receptors following long-term antidepressant treatment. Synapse 4:347–352Google Scholar
  25. Westenberg HGM, den Boer JA (1993) New findings in the treatment of panic disorder. Pharmacopsychiatry 26:30–33Google Scholar
  26. Westenberg HGM, den Boer JA (1994) The neuropharmacology of anxiety: a review on the role of serotonin. In: Den Boer JA, Sitsen JM (eds) Handbook of depression and anxiety. Marcel Dekker, New York, pp 405–447Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • F. J. Bosker
    • 1
  • K. E. van Esseveldt
    • 1
  • A. A. Klompmakers
    • 1
  • H. G. M. Westenberg
    • 1
  1. 1.Laboratory of Biological PsychiatryAcademic Hospital UtrechtUtrechtThe Netherlands

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