Baclofen attenuates conditioned locomotion to cues associated with cocaine 123 administration and stabilizes extracellular glutamate levels in rat nucleus accumbens
Baclofen attenuates conditioned locomotion to cues associated with cocaine 123 administration and stabilizes extracellular glutamate levels in rat nucleus accumbens
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DOI：
10.1016/s0306-4522(02)00951-x
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发表时间：
2003-01-01
期刊：
影响因子：
3.3
通讯作者：
Wolf, ME
中科院分区：
文献类型：
--
作者：
Hotsenpiller, G;Wolf, ME
我们使用大鼠可卡因条件运动作为可卡因条件反应的动物模型，这些反应有助于人类成瘾者的药物渴望和复发。本研究的目的是检查GABA（B）激动剂巴氯芬减弱这种联想反应的能力。首先，进行实验以确定不妨碍探索性或自发行为的巴氯芬剂量范围。该剂量范围用于测试特定于闪光灯和节拍器的条件运动，其先前与可卡因（配对组）或盐水（未配对组）给药相关。在2.0 mg/kg时，巴氯芬将配对受试者的条件运动减弱至接受盐水或2.0 mg/kg巴氯芬的非配对受试者的水平。考虑到谷氨酸传输的重要性，在联想反应的奖励相关的刺激，巴氯芬对细胞外谷氨酸水平的NAc的影响进行了测试与微透析。巴氯芬（2.0 mg/kg）未改变基础谷氨酸水平。然而，巴氯芬预处理防止了捕食性气味，2，5-二氢-2，4，5-三甲基噻唑啉，从增加谷氨酸水平。这是巴氯芬调节NAc细胞外谷氨酸水平的首次报道。巴氯芬可能被证明具有抑制刺激诱发的NAc谷氨酸水平增加的一般效用。这可以解释它阻止可卡因条件反应的能力。总之，我们的研究结果表明，增强GABAB传输抑制可卡因条件反应，可能是通过抑制谷氨酸在NAc的传输。更好地了解GABA和谷氨酸传输之间的相互作用，在NAC可能会导致药物治疗可卡因的渴望。(C)2003年IBRO。由Elsevier Science Ltd.出版，版权所有。
We have used cocaine-conditioned locomotion in rats as an animal model for cocaine-conditioned responses that contribute to drug craving and relapse in human addicts. The purpose of the present study was to examine the ability of the GABA(B) agonist, baclofen, to attenuate such associative responses. First, experiments were conducted to identify a dose range of baclofen that did not impede exploratory or spontaneous behavior. This dose range was used during testing for conditioned locomotion specific to a flashing light and metronome, which were previously associated with administration of cocaine (PAIRED group) or saline (UNPAIRED group). At 2.0 mg/kg, baclofen attenuated conditioned locomotion in PAIRED subjects to the level of UNPAIRED subjects receiving saline or 2.0 mg/kg baclofen. Considering the importance of glutamate transmission in the nucleus accumbens (NAc) during associative responses to reward-related stimuli, the effect of baclofen on extracellular levels of glutamate in the NAc was tested with microdialysis. Baclofen (2.0 mg/kg) did not alter basal glutamate levels. However, baclofen pretreatment prevented the predatory odor, 2,5-dihydro-2,4,5-trimethylthiazoline, from increasing glutamate levels. This is the first report of baclofen modulating extracellular levels of glutamate in the NAc. Baclofen may prove to have general utility for suppressing stimulus-evoked increases in NAc glutamate levels. This could explain its ability to prevent cocaine-conditioned responses. In summary, our results suggest that enhancing GABAB transmission inhibits cocaine-conditioned responses, possibly by suppressing glutamate transmission in the NAc. A better understanding of interactions between GABA and glutamate transmission in the NAc may lead to the development of pharmacotherapies for cocaine craving. (C) 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.