The SERT Met172 Mouse: An Engineered Model To Elucidate the Contributions of Serotonin Signaling to Cocaine Action
The SERT Met172 Mouse: An Engineered Model To Elucidate the Contributions of Serotonin Signaling to Cocaine Action
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DOI：
10.1021/acschemneuro.9b00005
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发表时间：
2019-07-01
影响因子：
5
通讯作者：
Blakely, Randy D.
中科院分区：
文献类型：
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作者：
Simmler, Linda D.;Blakely, Randy D.
可卡因滥用和成瘾仍然非常普遍，不幸的是，治疗不善。众所周知，可卡因成瘾行为的基本方面涉及药物阻断突触前多巴胺（DA）转运体（DAT）的能力，从而提高大脑回路中负责奖励、强化和习惯的细胞外DA水平。我们和其他人都认为，可卡因的多重独立于da的作用是解开可卡因成瘾、治疗和复发之谜的关键。特别是，大量的研究表明改变的5-羟色胺（5-HT）信号就是这样一个成分，这并不奇怪，因为相对于DAT，可卡因阻断5-羟色胺转运体（SERT）的作用与阻断DAT的作用一样有效，因此，当奖赏诱发的DA升高时，整个大脑的细胞外5-羟色胺水平升高。为了阐明SERT拮抗剂对可卡因作用的贡献，我们设计了一个小鼠模型，该模型在不破坏体内SERT的表达或功能的情况下显著降低了SERT的可卡因效力。在这个简短的展望中，我们回顾了SERT Met172模型发展的基本原理，记录Ile172Met在体外和体内替代的药理学影响的研究，以及我们在模型中证明血清素能对可卡因的遗传，生理和行为作用的研究结果。
Cocaine abuse and addiction remain highly prevalent and, unfortunately, poorly treated. It is well-known that essential aspects of cocaine's addictive actions involve the drug's ability to block the presynaptic dopamine (DA) transporter (DAT), thereby elevating extracellular levels of DA in brain circuits that subserve reward, reinforcement, and habit. Less well appreciated are the multiple DA-independent actions of cocaine, activities that we and others believe contribute key pieces to the puzzle of cocaine addiction, treatment, and relapse. In particular, a significant body of work points to altered serotonin (5-HT) signaling as one such component, not surprising given that, relative to DAT, cocaine acts as potently to block the 5-HT transporter (SERT) as to block DAT, and thereby elevates extracellular 5-HT levels throughout the brain when reward-eliciting DA elevations occur. To elucidate the contribution of SERT antagonism to the actions of cocaine, we engineered a mouse model that significantly reduces cocaine potency at SERT without disrupting the expression or function of SERT in vivo. In this short Perspective, we review the rationale for development of the SERT Met172 model, the studies that document the pharmacological impact of the Ile172Met substitution in vitro and in vivo, and our findings with the model that demonstrate serotonergic contributions to the genetic, physiological, and behavioral actions of cocaine.