title: Fluvoxamine enhances prefrontal dopaminergic neurotransmission in adrenalectomized/castrated mice via both 5-HT reuptake inhibition and σ(1) receptor activation.
abstract: BACKGROUND
  Fluvoxamine, a selective serotonin (5-HT) reuptake inhibitor (SSRI) and an agonist for the σ(1) receptors, increases extracellular monoamines in the prefrontal cortex, but it is not known whether the σ(1) receptor is involved in the neurochemical effect of fluvoxamine.
  
  
  OBJECTIVE
  In view of the fact that circulating steroids exert a tonic modulatory effect on σ(1) 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.
  
  
  RESULTS
  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 σ(1) receptor antagonist. In contrast, the effects of paroxetine, an SSRI without affinity for the σ(1) receptors, and (+)-SKF-10,047, a selective σ(1) 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.
  
  
  CONCLUSIONS
  These findings suggest that fluvoxamine enhances prefrontal dopaminergic neurotransmission via both 5-HT reuptake inhibition and σ(1) receptor activation under the circulating neuroactive steroid-deficient conditions.
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ago
authors.forename: Koji
authors.initials: K
authors.lastname: Yano
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takuma
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D000315:Adrenalectomy; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D005029:Ethylenediamines / Q000494:pharmacology; D016666:Fluvoxamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009638:Norepinephrine / Q000378:metabolism; D009919:Orchiectomy; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*; D000097605:Sigma-1 Receptor
chemical_list: D004298:Dopamine; D005029:Ethylenediamines; D016666:Fluvoxamine; D009638:Norepinephrine; D010620:Phenazocine; D011985:Receptors, Serotonin; D017480:Receptors, sigma; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D000097605:Sigma-1 Receptor; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; C012134:SK&F 10047