瑞士日内瓦大学
研究人员使用携带不与可卡因结合转运体的SERT172基因敲除（SertKI）小鼠来废除了药物自我给药期间的细胞外血清素（5-HT）瞬态。SertKI小鼠显示出向强迫性过渡的增强。相反，通过药理学方法提高5-HT可以扭转光遗传多巴胺自我刺激的强迫过渡的固有高速率。对行为的双向影响是由5-HT通过5-HT1B受体诱导的眶额皮层到背侧纹状体突触的突触前抑制所实现的。因此，在投射特异性5-HT1B受体敲除的小鼠中，强迫性地自我施用可卡因的个体比例升高了。
据介绍，尽管有不良后果，但强迫性地使用毒品被定义为成瘾。虽然间叶多巴胺信号足以驱动强迫症，但可卡因等精神刺激剂也通过抑制再摄取来提高5-HT。
附：英文原文
Title: Synaptic mechanism underlying serotonin modulation of transition to cocaine addiction
Author: Yue Li, Linda D. Simmler, Ruud Van Zessen, Jérme Flakowski, Jin-Xia Wan, Fei Deng, Yu-Long Li, Katherine M. Nautiyal, Vincent Pascoli, Christian Lüscher
Issue&Volume: 2021-09-10
Abstract: Compulsive drug use despite adverse consequences defines addiction. While mesolimbic dopamine signaling is sufficient to drive compulsion, psychostimulants such as cocaine also boost extracellular serotonin (5-HT) by inhibiting reuptake. We used SERT Met172 knockin (SertKI) mice carrying a transporter that no longer binds cocaine to abolish 5-HT transients during drug self-administration. SertKI mice showed an enhanced transition to compulsion. Conversely, pharmacologically elevating 5-HT reversed the inherently high rate of compulsion transition with optogenetic dopamine self-stimulation. The bidirectional effect on behavior is explained by presynaptic depression of orbitofrontal cortex–to–dorsal striatum synapses induced by 5-HT via 5-HT1B receptors. Consequently, in projection-specific 5-HT1B receptor knockout mice, the fraction of individuals compulsively self-administering cocaine was elevated.
DOI: abi9086
Source: https://www.science.org/doi/10.1126/science.abi9086