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Journal of Neural Transmission

, Volume 104, Issue 8–9, pp 953–966 | Cite as

Fluoxetine increases norepinephrine release in rat hypothalamus as measured by tissue levels of MHPG-SO4 and microdialysis in conscious rats

  • K. W. Perry
  • R. W. Fuller
Biological Psychiatry

Summary

The selective serotonin uptake inhibitor fluoxetine (10mg/kg i.p.) increased tissue levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MHPG-SO4) in rat hypothalamus, indicating an increased release of norepinephrine. Microdialysis studies in conscious rats showed that fluoxetine (10 mg/kg i.p.) increased extracellular concentrations of norepinephrine as well as serotonin in the hypothalamus. In contrast, desipramine (10mg/kg i.p.) increased extracellular concentration of norepinephrine but not serotonin in the hypothalamus. Consistent with its mechanism of being a selective serotonin uptake inhibitor, local perfusion of fluoxetine (10μM) caused a 7-fold increase in hypothalamic extracellular serotonin and a small non-significant increase in extracellular norepinephrine. The subsequent systemic injection of fluoxetine (10mg/kg s.c.) after local perfusion caused a 3-fold increase in extracellular norepinephrine, indicating that fluoxetine's action leading to an increase in extracellular norepinephrine was not occurring in the terminal areas of the hypothalamus but elsewhere in the brain, possibly cell bodies in the locus coeruleus.

Keywords

Fluoxetine rat hypothalamus norepinephrine microdialysis brain MHPG desipramine DMI HPLC-EC 

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References

  1. Bareggi SR, Markey K, Genovese E (1978) Effects of single and multiple doses of desipramine on endogenous levels of 3-methyoxy-4-hydroxyphenylglycol-sulfate (MOPEG-SO4) in rat brain. Eur J Pharmacol 50: 301–306PubMedGoogle Scholar
  2. Blandina P, Goldfarb J, Walcott J, Green JP (1991) Serotonergic modulation of the release of endogenous norepinephrine from rat hypothalamic slices. J Pharmacol Exp Ther 256: 341–347PubMedGoogle Scholar
  3. Calderini G, Morselli PL, Garattini S (1975) Effect of amphetamine and fenfluramine on brain noradrenaline and MOPEG-SO4. Eur J Pharmacol 34: 345–350PubMedGoogle Scholar
  4. Cedarbaum JM, Aghajanian GK (1978) Afferent projections to the rat locus coeruleus as determined by a retrograde tracing technique. J Comp Neurol 178: 1–16PubMedGoogle Scholar
  5. Chen NH, Reith MEA (1995) Monoamine interactions measured by microdialysis in the ventral tegmental area of rats treated systemically with (±)-8-hydroxy-2-(di-n-proplyamino)tetralin. J Neurochem 64: 1585–1597PubMedGoogle Scholar
  6. Clement HW, Gemsa D, Wesmann W (1992) Serotonin-norepinephrine interactions: a voltammetric study on the effect of serotonin receptor stimulation followed in the N raphe dorsalis and the locus coeruleus of the rat. J Neural Transm [GenSect] 88: 11–23Google Scholar
  7. Crawley JN, Mass JW, Roth RH (1980) Biochemical evidence for simultaneous activation of multiple locus coeruleus efferents. Life Sci 26: 1373–1378PubMedGoogle Scholar
  8. Done CJ, Sharp T (1994) Biochemical evidence for the regulation of central noradrenergic activity by 5-HT1A and 5-HT2 receptors: microdialysis studies in the awake and anaesthetized rat. Neuropharmacology 33: 411–421PubMedGoogle Scholar
  9. Feuerstein TJ, Hertting G (1986) Serotonin (5-HT) enhances hippocampal noradrenaline (NA) release: evidence for facilitatory 5-HT receptors within the CNS. Naunyn Schmiedebergs Arch Pharmacol 333: 191–197PubMedGoogle Scholar
  10. Fuller RW (1994) Uptake inhibitors increase extracellular serotonin concentration measured by brain microdialysis. Life Sci 55: 163–167PubMedGoogle Scholar
  11. Fuller RW, Perry KW (1989) Effects of buspirone and its metabolite, 1-(2-pyrimidinyl)piperazine, on brain monoamines and their metabolites in rats. J Pharmacol Exp Ther 248: 50–56PubMedGoogle Scholar
  12. Gariepy KC, Bailey B, Yu J, Maher T, Ackworth IN (1994) Simultaneous determination of norepinephrine, dopamine, and serotonin in hippocampal microdialysis samples using normal bore high performance liquid chromatography: effects of dopamine receptor agonist stimulation and euthanasia. J Liquid Chromatogr 17: 1541–1556Google Scholar
  13. Goldfarb J, Walcott J, Blandina P (1993) Serotonergic modulation of L-glutamic acidevoked release of endogenous norepinephrine from rat hypothalamus. J Pharmacol Exp Ther 267: 45–50PubMedGoogle Scholar
  14. Hemrick-Luecke SK, Snoddy HD, Fuller RW (1994) Evaluation of nefazodone as a serotonin uptake inhibitor and serotonin antagonist in vivo. Life Sci 55: 479–483PubMedGoogle Scholar
  15. Herve D, Pickel VM, Joh TH, Beaudet A (1987) Serotonin axon terminals in the ventral tegmental area of the rat: fine structure and synaptic input to dopaminergic neurons. Brain Res 435: 71–83PubMedGoogle Scholar
  16. Hjorth S, Carlsson A (1986) Is pindolol a mixed agonist-antagonist at central serotonin(5-HT) receptors? Eur J Pharmacol 129: 131PubMedGoogle Scholar
  17. Jordan S, Kramer GL, Zukas PK, Moeller M, Petty F (1994) In vivo biogenic amine efflux in medial prefrontal cortex with imipramine, fluoxetine, and fluvoxamine. Synapse 18: 294–297PubMedGoogle Scholar
  18. Leger L, Descarries L (1978) Serotonin nerve terminals in the locus coeruleus of adult rat: a radioautographic study. Brain Res 145: 1–13PubMedGoogle Scholar
  19. Mayle DA, Robertson DW, Wong DT (1991) Elevation of catecholaminergic metabolite levels in the rat hypothalamus by an agonist of serotonin 1C/2 receptors, MK212 (6-chloro-2-(l-piperazinyl) pyrazine). Neurosci Abstr 17: 407Google Scholar
  20. McRae-Degueurce A, Dennis T, Leger L, Scatton B (1985) Regulation of noradrenergic neuronal activity in the rat locus coeruleus by serotonergic afferents. Physiol Psychol 13: 188–196Google Scholar
  21. Mongeau R, De Montigny C, Blier P (1994) Activation of 5-HT3 receptors enhances the electrically evoked release of [3H]noradrenaline in rat brain limbic structures. Eur J Pharmacol 256: 269–279PubMedGoogle Scholar
  22. Paez X, Leibowitz S (1993) Changes in extracellular PVN monoamines and macronutrient intake after idazoxan or fluoxetine injection. Pharm Biochem Behav 46: 933–941Google Scholar
  23. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, San Diego CAGoogle Scholar
  24. Perry KW, Fuller RW (1991) Serotonergic drugs increase MHPG-SO4 in rat hypothalamus. Neurosci Abstr 17: 1178Google Scholar
  25. Perry KW, Fuller RW (1992) Effect of fluoxetine on serotonin and dopamine concentration in microdialysis fluid from rat striatum. Life Sci 50: 1683–1690PubMedGoogle Scholar
  26. Pickel VM, Joh TH, Chan J, Beaudet A (1984) Serotonergic terminals: ultrastuctural and synaptic interaction with catecholamine-containing neurons in the medial nuclei of the solitary tracts. J Comp Neurol 225: 291–301PubMedGoogle Scholar
  27. Pozzi L, Invernizzi R, Cervi L, Vallebuona F, Samanin R (1994) Evidence that extracellular concentrations of dopamine are regulated by noradrenergic neurons in the frontal cortex of rats. J Neurochem 63: 195–200PubMedGoogle Scholar
  28. Rutter JJ, Auerbach SB (1993) Acute uptake inhibition increases extracellular serotonin in the rat forebrain. J Pharmacol Exp Ther 265: 1319–1324PubMedGoogle Scholar
  29. Sabol SE, Richards JB, Sciden LS (1992) Fenfluramine-induced increases in extracellular hippocampal serotonin are progressively attenuated in vivo during a four-day fenfluramine regimen in rats. Brain Res 571: 64–72PubMedGoogle Scholar
  30. Scatton B, Claustre Y, Graham D, Dennis T, Serrano A, Arbilla S, Pimoule C, Schoemaker H, Bigg D, Langer SZ (1988) SL 81 0385: a novel selective and potent serotonin uptake inhibitor. Drug Dev Res 12: 29–40Google Scholar
  31. Smythe GA, Gleeson RM, Stead BM (1988) Mechanisms of 5-hydroxy-L-tryptophaninduced adrenocorticotropin release: a major role for central noradrenergic drive. Neuroendocrinology 47: 389–397PubMedGoogle Scholar
  32. Suzuki M, Matsuda T, Asano S, Somboonthum P, Takuma K, Baba A (1995) Increase of noradrenaline release in the hypothalamus of freely moving rat by postsynaptic 5-hydroxytryptamine(la) receptor activation. Br J Pharmacol 115: 703–711PubMedGoogle Scholar
  33. Tanda G, Carboni E, Frau R, Di Chiara G (1994) Increase in extracellular dopamine in the prefrontal cortex: a trait of drugs with antidepressant potential? Psychopharmacology 115: 285–288PubMedGoogle Scholar
  34. Tian Y, Eaton MJ, Goudreau JL, Lookingland KJ, Moore KE (1993) Neurochemical evidence that 5-hydroxytryptaminergic neurons tonically inhibit noradrenergic neurons terminating in the hypothalamus. Brain Res 607: 215–221PubMedGoogle Scholar
  35. Weissmann-Nanopoulos D, Mach E, Magre J, Demassey Y, Pujo J (1985) Evidence for the localization of 5HT1A binding sites on serotonin containing neurons in the raphe dorsalis and raphe centralis nuclei of the rat brain. Neurochem Int 7: 1061–1072Google Scholar
  36. Wong DT, Bymaster FP, Reid LR, Threlkeld PG (1983) Fluoxetine and two other serotonin uptake inhibitors without affinity for neuronal receptors. Biochem Pharmacol 32: 1287–1293PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1997

Authors and Affiliations

  • K. W. Perry
    • 1
  • R. W. Fuller
    • 1
  1. 1.Central Nervous System Research, Lilly Research LaboratoriesEli Lilly and Company, Lilly Corporate CenterIndianapolisUSA

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