Feb 13, 2015
The brain stores memories by changing the sensitivity of the connections made by one brain cell onto another. Here's a bit of the history and how synapses remodel their functional connections. Full size comic here.
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The brain stores memories by changing the sensitivity of the connections made by one brain cell onto another. Here's a bit of the history and how synapses remodel their functional connections. Full size comic here.
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Ketamineの臨床評価
Ketamineはグルタミン酸受容体サブタイプのNMDA受容体拮抗薬であり、治療抵抗性の大うつ病患者及び双極性障害のうつ病相に対する即効性の抗うつ作用のメカニズム及び有効性が注目されている。
慢性軽度ストレスモデルによる前頭前皮質と海馬の萎縮に対してKetamineはシナプス形成と棘形成を促進する。 言い換えれば治療抵抗性の大うつ病患者は前頭前皮質や海馬の機能が非効率になっているともいえる。
また、その詳細な生化学的機序も解明されていようとしている。
Ketamineは同じグルタミン酸サブタイプのAMPA受容体を活性化 ↓ BDNF/TrkBシグナル伝達活性化／BDNF産生 ↓ mTORシグナル伝達活性化／elongation factor-2キナーゼ抑制 ↓ シナプスタンパク生成
それに加えてGSK-3β阻害作用も効果発現に関与されるとの報告もあるが、慢性軽度ストレスモデルにおける選択的GSK-3β阻害薬が坑うつ作用を示さなかったことを報告している。
また、Ketamineはσ1受容体のアゴニストであり、PCPほど高頻度に精神病誘発することはないのはσ1受容体を介したNMDA受容体のアロステックな作用も関係しているかもしれない。
引用文献
1. 橋本謙二 : NMDA受容体拮抗薬ketamineの即効性の抗うつ作用. 臨床精神薬理 17 : 1495-1500, 2014. 2. 茶木茂之 : NMDA受容体機能に着目した創薬研究 臨床精神薬理 17 : 1485-1494, 2014. 3. Ma, X.C., et al. : Long-lasting antidepressant action of ketamine, but not glycogen synthase kinase-3 inhibitor SB216763, in the chronic mild stress model of mice. PLoS One, 8 : e56053 2013. 4. Ronald S. Duman et al. : A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Phil Trans. R. Soc. B, 367 : 2475-2484, 2012.
Role of NMDA Receptors in Tolerance and Dependence
Despite the many centuries of effective treatment with opiate drugs, it has never been possible to separate effectiveness from the development of tolerance and dependence.The goal with opiate.iherapeutics has always been to keep the dose as low as possible to provide needed relief from pain and... Role of NMDA Receptors in Tolerance and Dependence
Great Study: Stimulation of brain activity increases anaerobic glucose consumption and lactate levels. In this study, both natural olfactory stimulation of the limbic system and induced limbic seizures increased lactic acid in the hippocampus. Interestingly, " . . . . other natural stimuli (i.e. tail pinch) produced a similar increase in extracellular lactate . . . " "Increases in lactic acid following natural olfactory stimulation were . . . . significantly attenuated by the local application of the N-methyl-D-aspartate antagonist AP-5." ( Fornai, F. et al. 2000) (Increased glutamate in pain-processing centers of the brain could play a role in FM. NMDA is a glutamate receptor, so an NMDA antagonist blocks glutamate signals.)