Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking.
Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking.
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DOI：
10.1016/j.biopsych.2009.07.018
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发表时间：
2010-01-01
影响因子：
10.6
通讯作者：
Kalivas PW
中科院分区：
文献类型：
--
作者：
Knackstedt LA;Melendez RI;Kalivas PW
胱氨酸-谷氨酸交换器在慢性可卡因后下调，导致细胞外核谷氨酸水平降低。可卡因引起的谷氨酸稳态丧失的重要性通过N-乙酰半胱氨酸恢复胱氨酸-谷氨酸交换和减弱可卡因寻求的恢复来揭示。细胞外谷氨酸的另一种调节剂是神经胶质谷氨酸转运蛋白GLT-1。我们假设可卡因自我给药减少GLT-1，而GLT-1上调抑制可卡因寻求。我们测量了可卡因自我给药和3周的消退训练后GLT-1和xCT（胱氨酸-谷氨酸交换器的催化亚基）的[3 H]谷氨酸摄取和蛋白表达。我们还检查了头孢曲松（先前显示增加GLT-1）和N-乙酰半胱氨酸治疗对GLT-1和xCT表达的影响。还测试了头孢曲松抑制线索和可卡因诱导的复发的能力。自身给予皮质醇降低谷氨酸摄取以及GLT-1和xCT的表达。头孢曲松恢复GLT-1和xCT水平，并防止线索和可卡因诱导的药物寻求恢复。NAC还恢复了GLT-1和xCT水平。这些结果表明，谷氨酸转运和胱氨酸-谷氨酸交换可能是共同调节的，并提供了进一步的证据，靶向谷氨酸稳态是治疗可卡因复发的潜在方法。
The cystine-glutamate exchanger is down-regulated after chronic cocaine, resulting in reduced extracellular levels of nucleus accumbens glutamate. The importance of cocaine-induced loss of glutamate homeostasis is revealed by N-acetylcysteine restoring cystine-glutamate exchange and attenuating reinstatement to cocaine-seeking. Another regulator of extracellular glutamate is the glial glutamate transporter GLT-1. We hypothesized that cocaine self-administration reduces GLT-1, and that GLT-1 up-regulation inhibits cocaine-seeking. We measured [3H] glutamate uptake and protein expression of GLT-1 and xCT, the catalytic subunit of the cystine-glutamate exchanger, following cocaine self-administration and 3 weeks of extinction training. We also examined the affect of ceftriaxone (previously shown to increase GLT-1) and N-acetylcysteine treatment on the expression of GLT-1 and xCT. Ceftriaxone was also tested for the capacity to inhibit cue- and cocaine-induced relapse. Cocaine self-administration reduced glutamate uptake and the expression of both GLT-1 and xCT. Ceftriaxone restored GLT-1 and xCT levels and prevented cue- and cocaine-induced reinstatement of drug-seeking. NAC also restored GLT-1 and xCT levels. These results indicate that glutamate transport and cystine-glutamate exchange may be co-regulated, and provide further evidence that targeting glutamate homeostasis is a potential method for treating cocaine relapse.
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影响因子：
25
作者：
Moussawi, Khaled;Pacchioni, Alejandra;Moran, Megan;Olive, M. Foster;Gass, Justin T.;Lavin, Antonieta;Kalivas, Peter W.
通讯作者：
Kalivas, Peter W.
影响因子：
4.8
作者：
Lee, Seok-Geun;Su, Zhao-Zhong;Fisher, Paul B.
通讯作者：
Fisher, Paul B.
影响因子：
16.2
作者：
MURPHY, TH;MIYAMOTO, M;COYLE, JT
通讯作者：
COYLE, JT
影响因子：
4.8
作者：
Haugeto, O;Ullensvang, K;Danbolt, NC
通讯作者：
Danbolt, NC
影响因子：
25
作者：
Baker, DA;McFarland, K;Kalivas, PW
通讯作者：
Kalivas, PW