Nature: 新进展!科学家揭示快速抗抑郁药物氯胺酮低成瘾性的机制

2022-08-03 周科 “神经周K”公众号

氯胺酮主要通过拮抗离子型谷氨酸能N‑甲基‑D‑天冬氨酸受体(NMDAR)发挥作用。啮齿类动物实验表明氯胺酮可促进NAc多巴胺释放的增加。

尽管目前氯胺酮很少用作麻醉剂,但随着氯胺酮作为一种快速抗抑郁药物的应用越来越广泛,关于氯胺酮是否会引起药物成瘾的争论再次出现。

可卡因等成瘾性药物会增加伏隔核(NAc)中的多巴胺水平。这促进了中脑边缘系统的突触可塑性,从而引起行为适应,并最终驱动向强迫性行为过渡。近来认为可能具有快速抗抑郁作用,见:FDA:氯胺酮或是真正有效的抑郁症新治疗药物?2020 CANMAT建议:外消旋氯胺酮在成人抑郁症中的应用BMJ:氯胺酮用于自杀意念患者的紧急治疗

氯胺酮主要通过拮抗离子型谷氨酸能N-甲基-D-天冬氨酸受体(NMDAR)发挥作用。啮齿类动物实验表明氯胺酮可促进NAc多巴胺释放的增加。

2022年7月27日日内瓦大学Christian Lüscher研究团队发现氯胺酮可引起伏隔核多巴胺浓度瞬变,通过去抑制腹侧被盖区(VTA)多巴胺神经元增强奖赏效应,但它不会诱导出成瘾性药物相关的突触可塑性。

1 氯胺酮通过促进多巴胺释放维持奖赏功能

腹腔注射30mg/kg氯胺酮产生类似于可卡因的作用:可明显促进小鼠在旷场实验中的运动,表现出奖赏效应。通过多巴胺荧光探针发现氯胺酮可引起NAc多巴胺短暂的增加。

光纤钙成像技术发现在单剂量注射氯胺酮可增加VTA多巴胺能神经元的活性,抑制性神经元活性降低,而可卡因却降低多巴胺能神经元的活性。多巴胺2型受体拮抗剂可进一步增强氯胺酮引起的多巴胺能神经元的活性增加,降低可卡因对多巴胺神经元的抑制作用。

进一步通过CRISPR–SaCas9 技术特异性敲除VTA抑制性神经元NMDARs亚基NR1 后氯胺酮并不能降低VTA抑制性神经元活性。光遗传技术抑制VTA抑制性神经元后多巴胺释放增加,但在注射氯胺酮后可减弱这种多巴胺释放增加。

图1:氯胺酮的奖赏效应

2 氯胺酮不产生成瘾药物相关的突触可塑性,具有低成瘾性

突触可塑性是药物成瘾的关键机制:可卡因通过钙离子通透性α-氨基-3-羟基-5-甲基-4-异恶唑丙酸(AMPA)受体增强VTA多巴胺神经元上的谷氨酸能突触。

可卡因可促进AMPAR的表达,但氯氨酮并不存在这种突触可塑性变化。光激活15分钟VTA多巴胺神经元并不促进AMPARs表达,但连续激活1小时可促进AMPAR表达。有意思的是,即便经过多次重复给予氯氨酮进行持续激活VTA多巴胺神经元也并不能引起上述突触可塑性的变化。

已有研究表明NMDAR的激活参与增强VTA多巴胺神经元和多巴胺1型受体中等多棘神经元(D1R MSN)兴奋性突触。而氯氨酮是NMDAR的拮抗剂,抑制NMDAR活性,可能是氯氨酮无法引起药物适应性突触可塑性的原因。

NAc D1-MSN中FOS表达增加是药物诱发可塑性的早期指标。可卡因可诱发NAc D1-MSN中FOS表达增加,但氯胺酮并不发挥这种增加作用。

在暴露药物,戒断,再暴露药物训练过程中,氯氨酮和可卡因均可引起短暂的行为敏化。在2周戒断后可卡因引起的行为敏化持续存在,诱发药物适应性的突触可塑性变化,但戒断后氯氨酮引起的行为敏化不存在,也不引起上述药物相关的突触可塑性变化。

图2:氯胺酮不产生成瘾药物适应性的突触可塑性

总结

本文发现氯氨酮通过抑制VTA区域抑制性神经元上NMDAR活性促进VTA多巴胺能神经元活性,发挥奖赏效应。与成瘾药物可卡因不同的是:氯胺酮不会引起药物适应性突触可塑性、长期行为敏化。多巴胺2型受体介导的快速关闭动力学和NMDAR拮抗作用阻止了VTA和NAc中兴奋性突触的增强,限制了氯胺酮的成瘾性。

原始出处:

Simmler, L.D., Li, Y., Hadjas, L.C. et al. Dual action of ketamine confines addiction liability. Nature (2022). https://doi.org/10.1038/s41586-022-04993-7.

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    2022-10-02 liye789132251
  2. [GetPortalCommentsPageByObjectIdResponse(id=1885907, encodeId=49aa188590e19, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=39, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Sun Oct 02 13:55:34 CST 2022, time=2022-10-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1722546, encodeId=3bc01e22546e3, content=<a href='/topic/show?id=7ff5549865a' target=_blank style='color:#2F92EE;'>#抑郁药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54986, encryptionId=7ff5549865a, topicName=抑郁药)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=78fa33270286, createdName=wetgdt, createdTime=Wed Aug 10 22:55:34 CST 2022, time=2022-08-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1242937, encodeId=12e0124293e23, content=不要被这样文章给骗了,绝对的有成瘾性, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=da6b8306175, createdName=ms2000002125233860, createdTime=Sat Sep 03 11:14:04 CST 2022, time=2022-09-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1273690, encodeId=111412e3690c9, content=<a href='/topic/show?id=35136411609' target=_blank style='color:#2F92EE;'>#氯胺酮#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=64116, encryptionId=35136411609, topicName=氯胺酮)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=04d6114, createdName=jml2009, createdTime=Thu Aug 04 12:55:34 CST 2022, time=2022-08-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1446711, encodeId=90c01446e11a6, content=<a href='/topic/show?id=38bf553405a' target=_blank style='color:#2F92EE;'>#抗抑郁药物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=55340, encryptionId=38bf553405a, topicName=抗抑郁药物)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f4bd5278649, createdName=huhuaidong389, createdTime=Thu Aug 04 12:55:34 CST 2022, time=2022-08-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1492290, encodeId=d22d1492290fd, content=<a href='/topic/show?id=7999553333c' target=_blank style='color:#2F92EE;'>#抗抑郁#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=55333, encryptionId=7999553333c, topicName=抗抑郁)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a59b8920619, createdName=wushaoling, createdTime=Thu Aug 04 12:55:34 CST 2022, time=2022-08-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1236260, encodeId=30771236260ff, content=<a href='/topic/show?id=25dd1045665a' target=_blank style='color:#2F92EE;'>#***#</a><a href='/topic/show?id=0a0b5496306' target=_blank style='color:#2F92EE;'>#抑郁#</a>是比较有希望的药物了, beContent=null, objectType=article, channel=null, level=null, likeNumber=60, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=104566, encryptionId=25dd1045665a, topicName=***), TopicDto(id=54963, encryptionId=0a0b5496306, topicName=抑郁)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/Random/55971dc507c93968175ce7cc1e177b372a83869f.jpg, createdBy=f63e4754896, createdName=小小医者, createdTime=Wed Aug 03 06:57:51 CST 2022, time=2022-08-03, status=1, ipAttribution=)]
    2022-08-10 wetgdt
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    2022-09-03 ms2000002125233860

    不要被这样文章给骗了,绝对的有成瘾性

    0

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    2022-08-04 jml2009
  5. [GetPortalCommentsPageByObjectIdResponse(id=1885907, encodeId=49aa188590e19, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=39, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Sun Oct 02 13:55:34 CST 2022, time=2022-10-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1722546, encodeId=3bc01e22546e3, content=<a href='/topic/show?id=7ff5549865a' target=_blank style='color:#2F92EE;'>#抑郁药#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54986, encryptionId=7ff5549865a, topicName=抑郁药)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=78fa33270286, createdName=wetgdt, createdTime=Wed Aug 10 22:55:34 CST 2022, time=2022-08-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1242937, encodeId=12e0124293e23, content=不要被这样文章给骗了,绝对的有成瘾性, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=da6b8306175, createdName=ms2000002125233860, createdTime=Sat Sep 03 11:14:04 CST 2022, time=2022-09-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1273690, encodeId=111412e3690c9, content=<a href='/topic/show?id=35136411609' target=_blank style='color:#2F92EE;'>#氯胺酮#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=64116, encryptionId=35136411609, topicName=氯胺酮)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=04d6114, createdName=jml2009, createdTime=Thu Aug 04 12:55:34 CST 2022, time=2022-08-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1446711, encodeId=90c01446e11a6, content=<a href='/topic/show?id=38bf553405a' target=_blank style='color:#2F92EE;'>#抗抑郁药物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=55340, encryptionId=38bf553405a, topicName=抗抑郁药物)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f4bd5278649, createdName=huhuaidong389, createdTime=Thu Aug 04 12:55:34 CST 2022, time=2022-08-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1492290, encodeId=d22d1492290fd, content=<a href='/topic/show?id=7999553333c' target=_blank style='color:#2F92EE;'>#抗抑郁#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=55333, encryptionId=7999553333c, topicName=抗抑郁)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a59b8920619, createdName=wushaoling, createdTime=Thu Aug 04 12:55:34 CST 2022, time=2022-08-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1236260, encodeId=30771236260ff, content=<a href='/topic/show?id=25dd1045665a' target=_blank style='color:#2F92EE;'>#***#</a><a href='/topic/show?id=0a0b5496306' target=_blank style='color:#2F92EE;'>#抑郁#</a>是比较有希望的药物了, beContent=null, objectType=article, channel=null, level=null, likeNumber=60, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=104566, encryptionId=25dd1045665a, topicName=***), TopicDto(id=54963, encryptionId=0a0b5496306, topicName=抑郁)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/Random/55971dc507c93968175ce7cc1e177b372a83869f.jpg, createdBy=f63e4754896, createdName=小小医者, createdTime=Wed Aug 03 06:57:51 CST 2022, time=2022-08-03, status=1, ipAttribution=)]
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    2022-08-03 小小医者

    #***##抑郁#是比较有希望的药物了

    0

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