title: Involvement of GABAA receptors in 5-HT1A and σ1 receptor synergism on prefrontal dopaminergic transmission under circulating neurosteroid deficiency.
abstract: We previously reported that the fluvoxamine-induced increase in prefrontal dopamine levels is enhanced by adrenalectomy/castration (which results in circulating neurosteroid deficiency), via combined activation of serotonin1A (5-HT1A) and σ1 receptors. However, the mechanistic details of the interaction between 5-HT1A and σ1 receptors are unknown.
  
  
  
  Because most neurosteroids have affinity for γ-aminobutyric acid (GABA)A receptors, in the present study, we examined the involvement of GABAA receptors in this process.
  
  
  
  Adrenalectomy/castration decreased pentobarbital-induced sleeping time in mice, suggesting that it reduced GABAA receptor function. The GABAA receptor antagonist picrotoxin (1 mg/kg) enhanced the fluvoxamine-induced increase in prefrontal dopamine, but not noradrenaline or serotonin, levels in mice, suggesting that picrotoxin mimicked the effect of adrenalectomy/castration. Picrotoxin also potentiated the increase in prefrontal dopamine levels mediated by co-administration of the 5-HT1A receptor agonist osemozotan and the σ1 receptor agonist (+)-SKF-10,047, while it did not affect the co-administration-induced changes in noradrenaline and serotonin levels. Conversely, the GABAA receptor agonist diazepam (1 mg/kg) blocked the effect of adrenalectomy/castration on the fluvoxamine-induced increase in prefrontal dopamine levels. Co-administration of osemozotan and (+)-SKF-10,047 did not affect the expression of the neuronal activity marker c-Fos in the prefrontal cortex, ventral tegmental area, and nucleus accumbens in control mice, while it increased the c-Fos expression only in the prefrontal cortex and ventral tegmental area in picrotoxin-treated mice.
  
  
  
  These results suggest that the GABAA receptor plays a key role in mediating the synergistic effects of 5-HT1A and σ1 receptor activation on prefrontal dopamine neurotransmission.
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.|Laboratory of Molecular Neuropharmacology, 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.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.|Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hasebe
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Mori
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Watabe
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Onaka
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.|United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamada-oka, Suita, Osaka, 565-0871, Japan.|United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takuma
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan. matsuda@phs.osaka-u.ac.jp.
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D000315:Adrenalectomy; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002369:Castration; D003975:Diazepam / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D016666:Fluvoxamine / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D009919:Orchiectomy; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D018079:Receptors, GABA / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D014150:Antipsychotic Agents; D003975:Diazepam; D004146:Dioxanes; D004149:Dioxoles; D004298:Dopamine; D016666:Fluvoxamine; D018756:GABA Antagonists; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D009638:Norepinephrine; D010620:Phenazocine; D010852:Picrotoxin; D016760:Proto-Oncogene Proteins c-fos; D044282:Receptor, Serotonin, 5-HT1A; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D017480:Receptors, sigma; D012701:Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D005680:gamma-Aminobutyric Acid; D000097605:Sigma-1 Receptor; C012134:SK&F 10047; C096294:osemozotan
keywords: 5-HT1A receptor; GABAA receptor; Picrotoxin; Prefrontal dopamine release; σ1 receptor