title: Anti-anhedonic effect of selective serotonin reuptake inhibitors with affinity for sigma-1 receptors in picrotoxin-treated mice.
abstract: Prefrontal dopamine release by the combined activation of 5-HT1Aand sigma-1 (σ1) receptors is enhanced by the GABAAreceptor antagonist picrotoxin in mice. Here, we examined whether this neurochemical event was accompanied by behavioural changes.
  
  
  
  Male mice were treated with picrotoxin to decrease GABAAreceptor function. Their anhedonic behaviour was measured using the female encounter test. The expression of c-Fos was determined immunohistochemically.
  
  
  
  Picrotoxin caused an anxiogenic effect on three behavioural tests, but it did not affect the immobility time in the forced swim test. Picrotoxin decreased female preference in the female encounter test and attenuated the female encounter-induced increase in c-Fos expression in the nucleus accumbens. Picrotoxin-induced anhedonia was ameliorated by fluvoxamine and S-(+)-fluoxetine, selective serotonin reuptake inhibitors with high affinity for the σ1receptor. The effect of fluvoxamine was blocked by a 5-HT1Aor a σ1receptor antagonist, and co-administration of the σ1receptor agonist (+)-SKF-10047 and the 5-HT1Areceptor agonist osemozotan mimicked the effect of fluvoxamine. By contrast, desipramine, duloxetine and paroxetine, which have little affinity for the σ1receptor, did not affect picrotoxin-induced anhedonia. The effect of fluvoxamine was blocked by a dopamine D2/3receptor antagonist. Methylphenidate, an activator of the prefrontal dopamine system, ameliorated picrotoxin-induced anhedonia.
  
  
  
  Picrotoxin-treated mice show anhedonic behaviour that is ameliorated by simultaneous activation of 5-HT1Aand σ1receptors. These findings suggest that the increased prefrontal dopamine release is associated with the anti-anhedonic effect observed in picrotoxin-treated mice.
authors.affiliation: Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hasebe
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ago
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Watabe
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Oka
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Hiramatsu
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Umehara
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.|United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Osaka, Japan.|Division of Bioscience, Institute for Datability Science, Osaka University, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka, Japan.|United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Osaka, Japan.
authors.forename: K
authors.identifier: 0000-0001-6484-1122
authors.initials: K
authors.lastname: Takuma
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D059445:Anhedonia / Q000187:drug effects*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D010852:Picrotoxin / Q000737:chemistry / Q000494:pharmacology*; D017480:Receptors, sigma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
chemical_list: D010852:Picrotoxin; D017480:Receptors, sigma; D017367:Selective Serotonin Reuptake Inhibitors; D000097605:Sigma-1 Receptor