Upregulation of GLT1 attenuates cue-induced reinstatement of cocaine-seeking behavior in rats.
Upregulation of GLT1 attenuates cue-induced reinstatement of cocaine-seeking behavior in rats.
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DOI：
10.1523/jneurosci.1746-09.2009
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发表时间：
2009-07-22
期刊：
影响因子：
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通讯作者：
Rebec GV
中科院分区：
文献类型：
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作者：
Sari Y;Smith KD;Ali PK;Rebec GV
可卡因寻求行为的复发依赖于中皮质边缘运动回路关键区域谷氨酸传递的增加，包括前额皮质（PFC）和伏隔核（NAcc）。由于GLT1负责摄取≥90%的细胞外谷氨酸，我们验证了GLT1表达增加可减轻可卡因复发的假设。大鼠被训练在一个杠杆按压任务中自我注射可卡因（每次静脉注射0.125毫克），每天两小时，持续10-14天，然后是5天的灭绝训练。每次灭绝后，大鼠立即接受头孢曲松（ip），一种β-内酰胺类抗生素，被认为可以增加GLT1表达，或给药。在第二天，先前与可卡因自我给药相关的提示（光和音调）在给药的大鼠中恢复了杠杆按压，而100或200 mg/kg头孢曲松阻断了这种反应，而不是50 mg/kg头孢曲松阻断了这种反应。免疫印迹证实，头孢曲松诱导的可卡因复发阻断与PFC和NAcc中GLT1表达的增加有关。在不同的大鼠组中，200 mg/kg的头孢曲松未能阻止线索诱导的食物寻找，这与头孢曲松诱导的灭绝训练或杠杆按压所特有的效果相反。我们的研究结果表明，谷氨酸在线索诱导的可卡因寻求行为复发中起着关键作用，这意味着GLT1是可卡因成瘾的潜在治疗靶点。
Relapse to cocaine-seeking behavior depends on increased glutamate transmission in key regions of the mesocorticolimbic motive circuit, including prefrontal cortex (PFC) and nucleus accumbens (NAcc). Because GLT1 is responsible for the uptake of ≥90% of extracellular glutamate, we tested the hypothesis that increased GLT1 expression attenuates cocaine relapse. Rats were trained to self-administer cocaine (0.125 mg per iv infusion) in a lever-pressing task in a daily two-hour session for 10–14 days followed by five days of extinction training. Immediately after each extinction session, rats received ceftriaxone (ip), a β-lactam antibiotic believed to increase GLT1 expression, or vehicle. On the following day, presentation of the cue (light and tone) previously associated with cocaine self-administration reinstated lever-pressing in rats treated with vehicle, whereas 100 or 200, but not 50 mg/kg ceftriaxone blocked this response. Immunoblotting confirmed that the ceftriaxone-induced blockade of cocaine relapse was associated with an increase in GLT1 expression in both PFC and NAcc. In separate groups of rats, 200 mg/kg ceftriaxone failed to block cue-induced food seeking, arguing against a ceftriaxone-induced effect unique to extinction training or lever pressing. Our results suggest that glutamate plays a key role in cue-induced relapse to cocaine-seeking behavior, implicating GLT1 as a potential therapeutic target for cocaine addiction.