Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence:: Reversal by D1 antagonists
Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence:: Reversal by D1 antagonists
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DOI：
10.1073/pnas.98.4.1976
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发表时间：
2001-02-13
影响因子：
11.1
通讯作者：
Weiss, F
中科院分区：
文献类型：
--
作者：
Ciccocioppo, R;Sanna, PP;Weiss, F
环境刺激对可卡因主观行为的制约可能是与可卡因成瘾相关的长期复发风险的关键因素。为了研究学习因素在持续成瘾行为中的重要性以及这一现象的神经生物学基础，我们训练大鼠将区别性刺激（SD）与静脉注射可卡因和无奖励生理盐水的可用性联系起来，然后将其置于停止静脉注射和S(D)溶液的灭绝条件下。再暴露于SD对先前可卡因配对水平反应恢复的影响以及对两组Fos蛋白表达的影响。一组在灭绝后立即进行测试，而第二组在测试前将大鼠关在笼子里4个月。在两组中，可卡因SD（而非非奖励SD）引起了反应的强烈恢复，并增加了杏仁核基底外侧和内侧前额叶皮层（Cg1/Cg3区域）的Fos免疫反应性。选择性多巴胺D-1受体拮抗剂可逆转可卡因SD诱导的反应恢复和Fos表达。在4个月的戒断后，可卡因SD诱导药物寻求行为的效果没有减弱，这与人类条件线索反应和线索诱导的可卡因渴望的持久性相似，并证实了学习因素在可卡因持久成瘾潜力中的重要作用。此外，研究结果表明，可卡因预测环境刺激引发的可卡因寻求行为中，内侧前额叶皮层和基底外侧杏仁核内的d -1依赖神经机制是基础。
The conditioning of cocaine's subjective actions with environmental stimuli may be a critical factor in long-lasting relapse risk associated with cocaine addiction. To study the significance of learning factors in persistent addictive behavior as well as the neurobiological basis of this phenomenon, rats were trained to associate discriminative stimuli (SD) with the availability of i.v. cocaine vs. nonrewarding saline solution, and then placed on extinction conditions during which the i.v. solutions and S(D)s were withheld. The effects of reexposure to the SD on the recovery of responding at the previously cocaine-paired lever and on Fos protein expression then were determined in two groups. One group was tested immediately after extinction, whereas rats in the second group were confined to their home cages for an additional 4 months before testing, In both groups, the cocaine SD, but not the non-reward SD, elicited strong recovery of responding and increased Fos immunoreactivity in the basolateral amygdala and medial prefrontal cortex (areas Cg1/Cg3). The response reinstatement and Fos expression induced by the cocaine SD were both reversed by selective dopamine D-1 receptor antagonists. The undiminished efficacy of the cocaine SD to elicit drug-seeking behavior after 4 months of abstinence parallels the long-lasting nature of conditioned cue reactivity and cue-induced cocaine craving in humans, and confirms a significant role of learning factors in the long-lasting addictive potential of cocaine. Moreover, the results implicate D-1-dependent neural mechanisms within the medial prefrontal cortex and basolateral amygdala as substrates for cocaine-seeking behavior elicited by cocaine-predictive environmental stimuli.