Wolf Marina E, Sun Xiu, Mangiavacchi Simona, Chao Steven Z
Department of Neuroscience, The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064-3095, USA.
Neuropharmacology. 2004;47 Suppl 1:61-79. doi: 10.1016/j.neuropharm.2004.07.006.
Considerable evidence suggests that neuroadaptations leading to addiction involve the same glutamate-dependent cellular mechanisms that enable learning and memory. Long-term potentiation (LTP) and long-term depression (LTD) have therefore become an important focus of addiction research. This article reviews: (1) basic mechanisms underlying LTP and LTD, (2) the properties of LTP and LTD in ventral tegmental area, nucleus accumbens, dorsal striatum and prefrontal cortex, (3) studies demonstrating that psychomotor stimulants influence LTP or LTD in these brain regions. In addition, we discuss our recent work on cellular mechanisms by which dopamine may influence LTP and LTD. Based on evidence that AMPA receptors are inserted into synapses during LTP and removed during LTD, we investigated the effects of D1 receptor stimulation on AMPA receptor trafficking using primary cultures prepared from nucleus accumbens and prefrontal cortex. Our results suggest that activation of the D1 receptor-protein kinase A signaling pathway leads to externalization of AMPA receptors and promotes LTP. This provides a mechanism to explain facilitation of reward-related learning by dopamine. When this mechanism is activated in an unregulated manner by psychostimulants, maladaptive forms of neuroplasticity may occur that contribute to the transition from casual to compulsive drug use.
大量证据表明，导致成瘾的神经适应性变化涉及与学习和记忆相同的谷氨酸依赖细胞机制。因此，长时程增强（LTP）和长时程抑制（LTD）已成为成瘾研究的重要焦点。本文综述：（1）LTP和LTD的基本机制；（2）腹侧被盖区、伏隔核、背侧纹状体和前额叶皮质中LTP和LTD的特性；（3）证明精神运动兴奋剂影响这些脑区LTP或LTD的研究。此外，我们还讨论了我们最近关于多巴胺可能影响LTP和LTD的细胞机制的研究工作。基于AMPA受体在LTP期间插入突触并在LTD期间移除的证据，我们使用从伏隔核和前额叶皮质制备的原代培养物研究了D1受体刺激对AMPA受体转运的影响。我们的结果表明，D1受体 - 蛋白激酶A信号通路的激活导致AMPA受体外化并促进LTP。这提供了一种机制来解释多巴胺对奖赏相关学习的促进作用。当这种机制被精神兴奋剂以不受调节的方式激活时，可能会出现适应不良的神经可塑性形式，这有助于从偶尔吸毒转变为强迫性吸毒。
