Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago IL, USA.
Front Mol Neurosci. 2012 Jun 27;5:72. doi: 10.3389/fnmol.2012.00072. eCollection 2012.
In animal models of drug addiction, cocaine exposure has been shown to increase levels of calcium-permeable AMPA receptors (CP-AMPARs) in two brain regions that are critical for motivation and reward-the ventral tegmental area (VTA) and the nucleus accumbens (NAc). This review compares CP-AMPAR plasticity in the two brain regions and addresses its functional significance. In VTA dopamine neurons, cocaine exposure results in synaptic insertion of high conductance CP-AMPARs in exchange for lower conductance calcium-impermeable AMPARs (CI-AMPARs). This plasticity is rapid in onset (hours), GluA2-dependent, and can be observed with a single cocaine injection. Whereas it is short-lived after experimenter-administered cocaine, it persists for months after cocaine self-administration. In addition to strengthening synapses and altering Ca(2+) signaling, CP-AMPAR insertion alters subsequent induction of plasticity at VTA synapses. However, CP-AMPAR insertion is unlikely to mediate the increased DA cell activity that occurs during early withdrawal from cocaine exposure. Metabotropic glutamate receptor 1 (mGluR1) exerts a negative influence on CP-AMPAR accumulation in the VTA. Acutely, mGluR1 stimulation elicits a form of LTD resulting from CP-AMPAR removal and CI-AMPAR insertion. In medium spiny neurons (MSNs) of the NAc, extended access cocaine self-administration is required to increase CP-AMPAR levels. This is first detected after approximately a month of withdrawal and then persists. Once present in NAc synapses, CP-AMPARs mediate the expression of incubation of cue-induced cocaine craving. The mechanism of their accumulation may be GluA1-dependent, which differs from that observed in the VTA. However, similar to VTA, mGluR1 stimulation removes CP-AMPARs from MSN synapses. Loss of mGluR1 tone during cocaine withdrawal may contribute to CP-AMPAR accumulation in the NAc. Thus, results in both brain regions point to the possibility of using positive modulators of mGluR1 as treatments for cocaine addiction.
在药物成瘾的动物模型中，可卡因暴露已被证明会增加两个对动机和奖励至关重要的大脑区域中的钙通透性 AMPA 受体 (CP-AMPAR) 水平——腹侧被盖区 (VTA) 和伏隔核 (NAc)。 本篇综述比较了这两个脑区中的 CP-AMPAR 可塑性，并探讨了其功能意义。 在 VTA 多巴胺神经元中，可卡因暴露导致高电导 CP-AMPAR 的突触插入，以换取低电导非钙通透性 AMPAR (CI-AMPAR)。 这种可塑性在发作时很快 (数小时)，依赖于 GluA2，并且可以通过单次可卡因注射观察到。 虽然在实验者给予可卡因后短暂存在，但在可卡因自我给药后持续数月。 除了增强突触和改变 Ca(2+)信号外，CP-AMPAR 的插入还改变了 VTA 突触随后的可塑性诱导。 然而，CP-AMPAR 的插入不太可能介导可卡因暴露后早期戒断期间 DA 细胞活动的增加。 代谢型谷氨酸受体 1 (mGluR1) 对 VTA 中 CP-AMPAR 的积累产生负向影响。 急性刺激 mGluR1 会引发 CP-AMPAR 去除和 CI-AMPAR 插入导致的 LTD 形式。 在 NAc 的中间神经元 (MSNs) 中，需要延长可卡因自我给药才能增加 CP-AMPAR 水平。 这在戒断约一个月后首次检测到，然后持续存在。 一旦存在于 NAc 突触中，CP-AMPAR 介导线索诱导的可卡因渴望的潜伏期表达。 它们积累的机制可能依赖于 GluA1，这与 VTA 中观察到的不同。 然而，与 VTA 相似，mGluR1 刺激会从 MSN 突触中去除 CP-AMPAR。 可卡因戒断期间 mGluR1 张力的丧失可能导致 NAc 中 CP-AMPAR 的积累。 因此，两个脑区的结果都表明，使用 mGluR1 的正调节剂作为可卡因成瘾的治疗方法是可能的。
