Abstract:
Noribogaine (noribo) is the primary metabolite from ibogaine, an atypical psychedelic alkaloid isolated from the root bark of the African shrub Tabernanthe iboga. The main objective of this study was to test the hypothesis that molecular, electrophysiological, and behavioral responses of noribo are mediated by the 5-HT2A receptor (5-HT2AR) in mice. In that regard, we used male and female, 5-HT2AR knockout (KO) and wild type (WT) mice injected with a single noribo dose (10 or 40 mg/kg; i.p.). After 30 min., locomotor activity was recorded followed by mRNA measurements by qPCR (immediate early genes; IEG, glutamate receptors, and 5-HT2AR levels) and electrophysiology recordings of layer V pyramidal neurons from the medial prefrontal cortex. Noribo 40 decreased locomotion in male, but not female WT. Sex and genotype differences were observed for IEG and glutamate receptor expression. Expression of 5-HT2AR mRNA increased in the mPFC of WT mice following Noribo 10 (males) or Noribo 40 (females). Patch-clamp recordings showed that Noribo 40 reduced the NMDA-mediated postsynaptic current density in mPFC pyramidal neurons only in male WT mice, but no effects were found for either KO males or females. Our results highlight that noribo produces sexually dimorphic effects while the genetic removal of 5HT2AR blunted noribo-mediated responses to NMDA synaptic transmission.
摘要:
诺里波加因(Noribogaine)是伊波加因的主要代谢产物,一种非典型的迷幻生物碱,从非洲灌木Tabernantheiboga的根皮中分离出来。这项研究的主要目的是检验以下假设:分子,电生理学,小鼠的行为反应由5-HT2A受体(5-HT2AR)介导。在这方面,我们用男性和女性,5-HT2AR敲除(KO)和野生型(WT)小鼠注射单一降液剂量(10或40mg/kg;i.p.)。30分钟后。,记录运动活性,然后通过qPCR进行mRNA测量(立即早期基因;IEG,谷氨酸受体,和5-HT2AR水平)和内侧前额叶皮层V层锥体神经元的电生理记录。Noribo40降低了男性的运动能力,但不是女性WT。观察到IEG和谷氨酸受体表达的性别和基因型差异。在Noribo10(雄性)或Noribo40(雌性)之后,WT小鼠的mPFC中5-HT2ARmRNA的表达增加。膜片钳记录显示,Noribo40仅在雄性WT小鼠中降低mPFC锥体神经元中NMDA介导的突触后电流密度,但是KO男性或女性都没有发现任何影响。我们的结果强调,Noribo产生性二态效应,而5HT2AR的遗传去除减弱了Noribo介导的对NMDA突触传递的反应。