Increased cocaine self-administration in rats lacking the serotonin transporter: a role for glutamatergic signaling in the habenula
Increased cocaine self-administration in rats lacking the serotonin transporter: a role for glutamatergic signaling in the habenula
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DOI：
10.1111/adb.12673
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发表时间：
2019-11-01
影响因子：
3.4
通讯作者：
Fumagalli, Fabio
中科院分区：
文献类型：
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作者：
Caffino, Lucia;Verheij, Michel M. M.;Fumagalli, Fabio
5-羟色胺（5-HT）和缰（Hb）有助于动机和情绪状态，如抑郁症和药物滥用。5-HT神经元起源的中缝背核和Hb在解剖学上和解剖学上相互连接。有证据表明，5-HT影响血红蛋白受体的传递。使用5-羟色胺转运体敲除（SERT-/-）大鼠，表现出抑郁样行为和可卡因摄入量增加，我们研究了在基线条件下以及短期或长期摄入可卡因（分别为ShA和LgA）摄入后，SERT减少对谷氨酸神经传递相关基因表达的影响。在可卡因-幼稚动物中，SERT去除导致谷氨酸传输的关键决定因素的基线Hb mRNA水平降低，如SLC 1A 2，主要的谷氨酸转运蛋白和N-甲基-D-天冬氨酸（Grin 1，Grin 2A和Grin 2B）以及α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（Gria 1和Gria 2）受体亚基，支架蛋白Dlg 4没有变化。响应于ShA和LgA可卡因摄入，SLC 1A 2和Grin 1 mRNA水平在SERT+/+大鼠中降低至与SERT-/-大鼠相等的水平。我们的数据显示，细胞外5-HT水平的增加调节谷氨酸神经传递的Hb，作为关键的神经生物学基板的脆弱性可卡因成瘾。
Serotonin (5-HT) and the habenula (Hb) contribute to motivational and emotional states such as depression and drug abuse. The dorsal raphe nucleus, where 5-HT neurons originate, and the Hb are anatomically and reciprocally interconnected. Evidence exists that 5-HT influences Hb glutamatergic transmission. Using serotonin transporter knockout (SERT-/-) rats, which show depression-like behavior and increased cocaine intake, we investigated the effect of SERT reduction on expression of genes involved in glutamate neurotransmission under both baseline conditions as well as after short-access or long-access cocaine (ShA and LgA, respectively) intake. In cocaine-naive animals, SERT removal led to reduced baseline Hb mRNA levels of critical determinants of glutamate transmission, such as SLC1A2, the main glutamate transporter and N-methyl-D-aspartate (Grin1, Grin2A and Grin2B) as well as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (Gria1 and Gria2) receptor subunits, with no changes in the scaffolding protein Dlg4. In response to ShA and LgA cocaine intake, SLC1A2 and Grin1 mRNA levels decreased in SERT+/+ rats to levels equal of those of SERT-/- rats. Our data reveal that increased extracellular levels of 5-HT modulate glutamate neurotransmission in the Hb, serving as critical neurobiological substrate for vulnerability to cocaine addiction.