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Mood Disorders and Addiction

開催日 2014/9/12
時間 10:00 - 11:00
会場 Room I(311+312)
Chairperson(s) 尾崎 紀夫 / Norio Ozaki (名古屋大学大学院医学系研究科 / Department of Psychiatry, Nagoya University Graduate School of Medecine, Japan)
尾上 浩隆 / Hirotaka Onoe (独立行政法人理化学研究所ライフサイエンス技術基盤研究センター / RIKEN Center for Life Science Technologies, Japan)

ケタミンの抗うつ薬作用のメカニズム ―側坐核と腹側淡蒼球のセロトニン1Bレセプターの関与―
Ketamine Acts As an Antidepressant : Involvement of Nucleus Accumbens and Ventral Pallidum 5-HT1B Receptors

  • O2-I-2-2
  • 山中 創 / Hajime Yamanaka:1 横山 ちひろ / Chihiro Yokoyama:1 土居 久志 / Hisashi Doi:2 Halldin Christer / Christer Halldin:3 尾上 浩隆 / Hirotaka Onoe:1 
  • 1:理研・CLST・生体機能評価 / Bio-Func Imaging, RIKEN CLST, Hyogo, Japan 2:理研・CLST・標識化学 / Labelling Chemistry, RIKEN CLST, Hyogo, Japan 3:Karolinska Institute, Stockholm, Sweden / Karolinska Institute, Stockholm, Sweden 

Ketamine is a unique anesthetic reagent known to produce various psychotic symptoms. Interestingly, ketamine has been reported to elicit fast-acting and long-lasting antidepressant effect in patients with major depression. Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism has not been fully elucidated. To understand the involvement of the brain serotonergic system in the actions of ketamine, we performed a positron emission tomography (PET) study on non-human primates. Four rhesus monkeys underwent PET studies with two serotonin (5-HT)-related PET radioligands, [11C]AZ10419369 and [11C]DASB, which are highly selective for the 5-HT1B receptor and serotonin transporter (SERT), respectively. With the standardized brain MRI, voxel-based analysis revealed that ketamine administration significantly increased 5-HT1B receptor binding in two brain regions: the nucleus accumbens and ventral pallidum, both of which are key neural substrates in motivation and reward system. In contrast, ketamine significantly reduced SERT binding in these brain regions. Furthermore, pretreatment with NBQX, a potent antagonist of the glutamate AMPA receptor, blocked the action of ketamine on 5-HT1B receptor but not SERT binding. This indicates the involvement of AMPA receptor activation in ketamine-induced alterations of 5-HT1B receptor binding. Because NBQX is known to block the antidepressant effect of ketamine in rodents, alterations in the serotonergic neurotransmission, particularly upregulation of postsynaptic 5-HT1B receptors in the nucleus accumbens and ventral pallidum may be critically involved in the antidepressant action of ketamine. A recent PET study has also shown that 5-HT1B receptor binding within the identical brain regions is significantly low in patients with major depressive disorder compared with that in healthy subjects. Therefore, PET imaging studies for 5-HT1B receptor binding might be useful for a diagnosis of major depression as well as for the development of novel antidepressants (Yamanaka et al., Transl Psychiatry 2014).

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