Self David W, Choi Kwang-Ho, Simmons Diana, Walker John R, Smagula Cynthia S
Department of Psychiatry, The Seay Center for Basic and Applied Research in Psychiatric Illness, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070 USA.
Learn Mem. 2004 Sep-Oct;11(5):648-57. doi: 10.1101/lm.81404.
Cocaine produces multiple neuroadaptations with chronic repeated use. Many of these neuroadaptations can be reversed or normalized by extinction training during withdrawal from chronic cocaine self-administration in rats. This article reviews our past and present studies on extinction-induced modulation of the neuroadaptive response to chronic cocaine in the mesolimbic dopamine system, and the role of this modulation in addictive behavior in rats. Extinction training normalizes tyrosine hydroxylase levels in the nucleus accumbens (NAc) shell, an effect that could help ameliorate dysphoria and depression associated with withdrawal from chronic cocaine use. Extinction training also increases levels of GluR1 and GluR2/3 AMPA receptor subunits, while normalizing deficits in NR1 NMDA receptor subunits, in a manner consistent with long-term potentiation of excitatory synapses in the NAc shell. Our results suggest that extinction-induced increases in AMPA and NMDA receptors may restore deficits in cortico-accumbal neurotransmission in the NAc shell and facilitate inhibitory control over cocaine-seeking behavior. Other changes identified by gene expression profiling, including up-regulation in the AMPA receptor aggregating protein Narp, suggest that extinction training induces extensive synaptic reorganization. These studies highlight potential benefits for extinction training procedures in the treatment of drug addiction.
长期反复使用可卡因会产生多种神经适应性变化。在大鼠从长期可卡因自我给药中戒断期间，通过消退训练，其中许多神经适应性变化可以被逆转或恢复正常。本文回顾了我们过去和现在关于消退诱导对中脑边缘多巴胺系统中慢性可卡因神经适应性反应的调节作用，以及这种调节在大鼠成瘾行为中的作用的研究。消退训练可使伏隔核（NAc）壳中的酪氨酸羟化酶水平恢复正常，这一效应可能有助于改善与长期使用可卡因戒断相关的烦躁不安和抑郁情绪。消退训练还会增加GluR1和GluR2/3 AMPA受体亚基的水平，同时使NR1 NMDA受体亚基的缺陷恢复正常，其方式与NAc壳中兴奋性突触的长期增强作用一致。我们的结果表明，消退诱导的AMPA和NMDA受体增加可能会恢复NAc壳中皮质-伏隔核神经传递的缺陷，并促进对觅药行为的抑制控制。基因表达谱分析确定的其他变化，包括AMPA受体聚集蛋白Narp的上调，表明消退训练会诱导广泛的突触重组。这些研究突出了消退训练程序在治疗药物成瘾方面的潜在益处。
