Department of Psychology, Boston University, Boston, MA, USA.
Behav Brain Res. 2012 Sep 1;234(1):100-6. doi: 10.1016/j.bbr.2012.06.010. Epub 2012 Jun 18.
Extinguishing abnormally strengthened learned responses to cues associated with drugs of abuse remains a key tactic for alleviating addiction. To assist in developing pharmacotherapies to augment exposure therapy for relapse prevention, investigation into neurobiological underpinnings of drug-cue extinction learning is needed. We used regional analyses of c-Fos and GluR2 protein expression to delineate neural activity and plasticity that may be associated with cocaine-cue extinction learning. Rats were trained to self-administer cocaine paired with a light cue, and later underwent a single 2h extinction session for which cocaine was withheld but response-contingent cues were presented (cocaine-cue extinction). Control groups consisted of rats yoked to animals self-administering cocaine and receiving saline non-contingently followed by an extinction session, or rats trained to self-administer cocaine followed by a no-extinction session for which levers were retracted, and cocaine and cues were withheld. Among 11 brain sites examined, extinction training increased c-Fos expression in basolateral amygdala and prelimbic prefrontal cortex of cocaine-cue extinguished rats relative to both control conditions. In dorsal subiculum and infralimbic prefrontal cortex, extinction training increased c-Fos expression in both cocaine-cue and saline-cue extinguished rats relative to the no-extinction control condition. GluR2 protein expression was not altered in any site examined after extinction or control training. Findings suggest that basolateral amygdala and prelimbic prefrontal cortex neurons are activated during acquisition of cocaine-cue extinction learning, a process that is independent of changes in GluR2 abundance. Other sites are implicated in processing the significance of cues that are present early in extinction training.
消除与滥用药物相关线索的异常强化学习反应仍然是缓解成瘾的关键策略。为了协助开发增强暴露疗法预防复发的药物治疗方法，需要研究药物线索消除学习的神经生物学基础。我们使用 c-Fos 和 GluR2 蛋白表达的区域分析来描绘可能与可卡因线索消除学习相关的神经活动和可塑性。大鼠接受训练，使其自行注射可卡因，并与光线索配对，然后进行单次 2 小时的消退训练，在此期间不给予可卡因，但呈现与反应相关的线索（可卡因线索消退）。对照组包括与自行注射可卡因并接受盐水非条件刺激的动物配对的大鼠，然后进行消退训练，或接受训练自行注射可卡因，然后进行无消退训练，在此期间撤回杠杆，同时不给予可卡因和线索。在 11 个检查的脑区中，与对照条件相比，消退训练增加了可卡因线索消退大鼠的外侧杏仁核和前额叶皮层的 c-Fos 表达。在背侧海马旁回和下边缘前额皮层，与无消退对照条件相比，可卡因线索和盐水线索消退大鼠的 c-Fos 表达均增加。在任何检查的部位，消退或对照训练后 GluR2 蛋白表达均未改变。研究结果表明，在可卡因线索消退学习的获得过程中，外侧杏仁核和前额叶皮层神经元被激活，该过程与 GluR2 丰度的变化无关。其他部位则涉及处理在消退训练早期存在的线索的意义。
