Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 367, Issue 3, pp 297–305 | Cite as

Effects of selective serotonin and serotonin/noradrenaline reuptake inhibitors on extracellular serotonin in rat diencephalon and frontal cortex

  • Tracy M. Felton
  • Tommy B. Kang
  • Stephan Hjorth
  • Sidney B. Auerbach
Original Article


Some clinical reports suggest that tricyclic antidepressants which block both noradrenaline and serotonin (5-HT) reuptake (SNRIs) are more effective than selective 5-HT reuptake inhibitors (SSRIs) in treating severe depression. Moreover, one neurochemical study reported larger increases in extracellular 5-HT in rat frontal cortex in response to the tricyclic antidepressant imipramine compared to the SSRI fluoxetine. However, imipramine, which blocks both 5-HT and noradrenaline reuptake, also binds with relatively high affinity to receptors for noradrenaline, histamine and acetylcholine. Thus, to test the hypothesis that compounds that inhibit both 5-HT and noradrenaline reuptake produce larger increases in 5-HT efflux, we compared the effects of acute systemic administration of several SNRIs and SSRIs. Extracellular 5-HT was measured using microdialysis probes implanted in the diencephalon and frontal cortex of unanesthetized rats. We tested the SSRIs paroxetine (0.3–10 mg/kg), citalopram (10–20 mg/kg) and fluoxetine (10 mg/kg), the nonselective tricyclic antidepressant imipramine (20 mg/kg) and the more selective SNRIs duloxetine (3–30 mg/kg) and venlafaxine (30–50 mg/kg). During the lights-off period, paroxetine and duloxetine increased 5-HT in the diencephalon ~300 and ~200%, respectively. During the lights-on period, paroxetine and duloxetine each increased 5-HT ~400% in the diencephalon. In the frontal cortex, both paroxetine and duloxetine increased 5-HT ~200%. Citalopram and venlafaxine each increased 5-HT in the diencephalon ~300%. Fluoxetine and imipramine increased 5-HT in the diencephalon by ~125 and ~80%, respectively. Thus, these results do not support the hypothesis that compared to SSRIs, compounds which inhibit both 5-HT and noradrenaline reuptake have a larger acute effect on extracellular 5-HT.


Serotonin (5-hydroxytryptamine, 5-HT) Selective serotonin reuptake inhibitor (SSRI) Mixed serotonin/noradrenaline reuptake inhibitor (SNRI) Microdialysis Noradrenaline (norepinephrine) Depression 



This work was supported by U.S. Public Health Service Grant MH51080 to S.B. Auerbach, and by Goljes Stiftelse, the Sw. Medical Society and Sw. MRC (#07486) to S. Hjorth.


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Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Tracy M. Felton
    • 1
  • Tommy B. Kang
    • 1
  • Stephan Hjorth
    • 2
  • Sidney B. Auerbach
    • 1
  1. 1.Department of Cell Biology and NeuroscienceNelson Biological Laboratories, Rutgers UniversityPiscatawayUSA
  2. 2.Integrative PharmacologyAstraZeneca R&DMölndalSweden

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