Role of the major glutamate transporter GLT1 in nucleus accumbens core versus shell in cue-induced cocaine-seeking behavior.
Role of the major glutamate transporter GLT1 in nucleus accumbens core versus shell in cue-induced cocaine-seeking behavior.
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DOI：
10.1523/jneurosci.3278-12.2013
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发表时间：
2013-05-29
期刊：
影响因子：
--
通讯作者：
Rebec GV
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文献类型：
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作者：
Fischer KD;Houston AC;Rebec GV
可卡因寻求行为的复发需要增加脑桥核（NAc）核心谷氨酸传输。谷氨酸I型转运体（GLT 1）的表达减少，其负责>90%的谷氨酸清除，发生在从可卡因自我给药中戒断的大鼠的核心中，而头孢曲松（一种先前显示在啮齿动物中增加GLT 1表达和功能的β-内酰胺抗生素）治疗上调GLT 1并减弱线索诱导的可卡因复吸。在这里，我们测试了增加GLT 1表达对大鼠暴露于有限（2小时/天）或延长（6小时/天）可卡因访问，然后短（2天）或长（45天）戒断期的线索诱导的可卡因寻求的影响。头孢曲松（200 mg/kg，ip）治疗，上调核心GLT 1表达和衰减线索诱导的可卡因寻求行为，只有在大鼠暴露于长时间的戒断期，在延长访问条件下的效果更大。Pearson相关性分析显示，GLT 1在核心中的表达与线索诱导的可卡因寻求行为呈负相关。为了定位NAc内GLT 1上调的作用，我们检验了以下假设：在NAc核心而不是外壳中阻断GLT 1将逆转头孢曲松介导的作用。停止可卡因自我给药的大鼠接受相同剂量的头孢曲松治疗，然后在芯内或壳内输注两种GLT 1阻断剂之一，二氢红藻氨酸（500 μM）或DL-苏型-β-苄氧基天冬氨酸（250 μM）或生理盐水。我们的研究结果表明，头孢曲松介导的线索诱导的可卡因复吸的衰减被逆转的GLT 1封锁的核心，但不壳，并进一步牵连核心GLT 1作为可卡因复吸的潜在治疗靶点。
Relapse to cocaine-seeking behavior requires an increase in nucleus accumbens (NAc) core glutamate transmission. Decreased expression of glutamate type I transporter (GLT1), which is responsible for >90% of glutamate clearance, occurs in the core of rats withdrawn from cocaine self-administration, while treatment with ceftriaxone, a beta-lactam antibiotic previously shown to increase GLT1 expression and function in rodents, up-regulates GLT1 and attenuates cue-induced cocaine reinstatement. Here, we tested the effects of increasing GLT1 expression on cue-induced cocaine seeking in rats exposed to either limited (2 h/d) or extended (6 h/d) cocaine access followed by short (2 d) or long (45 d) withdrawal periods. Treatment with ceftriaxone (200 mg/kg, ip), up-regulated core GLT1 expression and attenuated cue-induced cocaine-seeking behavior only in rats exposed to long withdrawal periods, with a greater effect in the extended access condition. Pearson's correlation revealed GLT1 expression in core to be inversely correlated with cue-induced cocaine-seeking behavior. To localize the effects of GLT1 up-regulation within NAc, we tested the hypothesis that blockade of GLT1 in NAc core, but not shell, would reverse the ceftriaxone-mediated effect. Rats withdrawn from cocaine self-administration were treated with the same dose of ceftriaxone followed by intra-core or intra-shell infusions of one of two GLT1 blockers, dihydrokainic acid (500 μM) or DL-threo-beta-benzyloxyaspartate (250 μM), or saline. Our results reveal that the ceftriaxone-mediated attenuation of cue-induced cocaine reinstatement is reversed by GLT1 blockade in core, but not shell, and further implicate core GLT1 as a potential therapeutic target for cocaine relapse.