, Volume 217, Issue 3, pp 377-386

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

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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.