Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA.
Neuropharmacology. 2014 Jan;76 Pt B(0 0):287-300. doi: 10.1016/j.neuropharm.2013.04.061. Epub 2013 May 30.
Cue-induced cocaine craving in rodents intensifies or "incubates" during the first months of withdrawal from long access cocaine self-administration. This incubation phenomenon is relevant to human users who achieve abstinence but exhibit persistent vulnerability to cue-induced relapse. It is well established that incubation of cocaine craving involves complex neuronal circuits. Here we will focus on neuroadaptations in the nucleus accumbens (NAc), a region of convergence for pathways that control cocaine seeking. A key adaptation is a delayed (~3-4 weeks) accumulation of Ca(2+)-permeable AMPAR receptors (CP-AMPARs) in synapses on medium spiny neurons (MSN) of the NAc. These CP-AMPARs mediate the expression of incubation after prolonged withdrawal, although different mechanisms must be responsible during the first weeks of withdrawal, prior to CP-AMPAR accumulation. The cascade of events leading to CP-AMPAR accumulation is still unclear. However, several candidate mechanisms have been identified. First, mGluR1 has been shown to negatively regulate CP-AMPAR levels in NAc synapses, and it is possible that a withdrawal-dependent decrease in this effect may help explain CP-AMPAR accumulation during incubation. Second, an increase in phosphorylation of GluA1 subunits (at the protein kinase A site) within extrasynaptic homomeric GluA1 receptors (CP-AMPARs) may promote their synaptic insertion and oppose their removal. Finally, elevation of brain-derived neurotrophic factor (BDNF) levels in the NAc may contribute to maintenance of incubation after months of withdrawal, although incubation-related increases in BDNF accumulation do not account for CP-AMPAR accumulation. Receptors and pathways that negatively regulate incubation, such as mGluR1, are promising targets for the development of therapeutic strategies to help recovering addicts maintain abstinence. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
在长期接触可卡因自我给药后戒断的头几个月，线索诱发的可卡因渴望会加剧或“孵化”。这种孵化现象与人类使用者有关，他们已经戒除毒瘾，但仍然容易因线索诱发而复吸。众所周知，可卡因渴望的孵化涉及复杂的神经元回路。在这里，我们将重点关注伏隔核（NAc）中的神经适应性变化，这是控制可卡因寻求的途径的汇聚区域。一个关键的适应性变化是，在 NAc 中的中脑多巴胺神经元（MSN）突触上，Ca(2+)-通透性 AMPAR 受体（CP-AMPAR）的延迟（~3-4 周）积累。这些 CP-AMPAR 介导了长时间戒断后的孵化表达，尽管在 CP-AMPAR 积累之前，在戒断的头几周内，必须有不同的机制负责。导致 CP-AMPAR 积累的事件链仍不清楚。然而，已经确定了几个候选机制。首先，mGluR1 已被证明可负向调节 NAc 突触中的 CP-AMPAR 水平，并且这种作用的戒断依赖性降低可能有助于解释孵化期间 CP-AMPAR 的积累。其次，在 extrasynaptic homomeric GluA1 受体（CP-AMPARs）内 GluA1 亚基的磷酸化（在蛋白激酶 A 位点）的增加可能促进它们的突触插入并反对它们的去除。最后，脑源性神经营养因子（BDNF）水平在 NAc 中的升高可能有助于维持戒断数月后的孵化，尽管孵化相关的 BDNF 积累并不能解释 CP-AMPAR 的积累。负向调节孵化的受体和途径，如 mGluR1，是开发治疗策略以帮助康复的瘾君子保持戒断的有希望的靶点。本文是题为“NIDA 40 周年特刊”的特刊的一部分。
