, Volume 217, Issue 3, pp 377–386 | Cite as

Fluvoxamine enhances prefrontal dopaminergic neurotransmission in adrenalectomized/castrated mice via both 5-HT reuptake inhibition and σ1 receptor activation

  • Yukio Ago
  • Koji Yano
  • Naoki Hiramatsu
  • Kazuhiro Takuma
  • Toshio Matsuda
Original Investigation



Fluvoxamine, a selective serotonin (5-HT) reuptake inhibitor (SSRI) and an agonist for the σ1 receptors, increases extracellular monoamines in the prefrontal cortex, but it is not known whether the σ1 receptor is involved in the neurochemical effect of fluvoxamine.


In view of the fact that circulating steroids exert a tonic modulatory effect on σ1 receptor-mediated effects, the present study examines the effects of fluvoxamine on prefrontal extracellular monoamine levels in adrenalectomized/castrated mice lacking the peripheral sources of steroids.


Fluvoxamine-induced increases in the extracellular levels of dopamine (DA), but not of 5-HT and noradrenaline, were significantly higher in adrenalectomized/castrated than in sham-operated mice, and this effect was blocked by BD1047, a selective σ1 receptor antagonist. In contrast, the effects of paroxetine, an SSRI without affinity for the σ1 receptors, and (+)-SKF-10,047, a selective σ1 receptor agonist, on the extracellular monoamine levels did not differ between adrenalectomized/castrated and sham-operated mice, while the increase in extracellular DA levels induced by co-administration of these drugs was higher in adrenalectomized/castrated than in the control mice. Moreover, fluvoxamine increased c-Fos expression, a marker of neuronal activity, in the prefrontal cortex of adrenalectomized/castrated mice, and this effect was blocked by BD1047. The similar increase in c-Fos expression was observed by co-administration of paroxetine and (+)-SKF-10,047.


These findings suggest that fluvoxamine enhances prefrontal dopaminergic neurotransmission via both 5-HT reuptake inhibition and σ1 receptor activation under the circulating neuroactive steroid-deficient conditions.


Fluvoxamine σ1 receptor c-Fos Adrenalectomy/castration Dopamine (DA) Prefrontal cortex 



This study was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (from the Ministry of Education, Culture, Sports, Science and Technology of Japan).

Conflicts of interest

The authors state no conflicts of interest.

Supplementary material

213_2011_2293_Fig8_ESM.jpg (68 kb)

Supplementary figure legend Effect of the co-administration of fluvoxamine and (+)-SKF-10,047 on the extracellular levels of 5-HT, NA, and DA in the prefrontal cortex of adrenalectomized/castrated mice. Fluvoxamine (30 mg/kg, i.p.; Flv) alone and in combination with (+)-SKF-10,047 (5 mg/kg, s.c.; SKF) were injected at 0 min (arrow). Data are expressed as the mean ± SEM of four mice. (JPEG 68 kb)

Supplementary figure results

(+)-SKF-10,047 did not affect fluvoxamine (30 mg/kg)-induced increase in DA levels in adrenalectomized/castrated mice. Statistical analysis revealed the main significant effect of time (F 8,48 = 37.523, p < 0.0001 for 5-HT; F 8,48 = 21.797, p < 0.0001 for NA; F 8,48 = 20.744, p < 0.0001 for DA), but not of treatment (F 1,6 = 0.264, n.s. for 5-HT; F 1,6 = 0.017, n.s. for NA; F 1,6 = 0.485, n.s. for DA). There was no significant interaction between the time and treatment (F 8,48 = 0.169, n.s. for 5-HT; F 8,48 = 0.153, n.s. for NA; F 8,48 = 0.408, n.s. for DA).

213_2011_2293_MOESM1_ESM.tiff (8 kb)
High resolution image file (TIFF 7 kb)


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Yukio Ago
    • 1
  • Koji Yano
    • 1
  • Naoki Hiramatsu
    • 1
  • Kazuhiro Takuma
    • 1
  • Toshio Matsuda
    • 1
    • 2
    • 3
  1. 1.Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical SciencesOsaka UniversitySuitaJapan
  2. 2.Department of Experimental Disease Model, The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Graduate School of MedicineOsaka UniversitySuitaJapan
  3. 3.United Graduate School of Child Development, Osaka University, Kanazawa University and Hamamatsu University School of MedicineOsaka UniversitySuitaJapan

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