Liang Jing, Lindemeyer A Kerstin, Suryanarayanan Asha, Meyer Edward M, Marty Vincent N, Ahmad S Omar, Shao Xuesi Max, Olsen Richard W, Spigelman Igor
Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, California; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California;
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California;
J Neurophysiol. 2014 Jul 1;112(1):39-50. doi: 10.1152/jn.00565.2013. Epub 2014 Apr 2.
Chronic alcohol exposure-induced changes in reinforcement mechanisms and motivational state are thought to contribute to the development of cravings and relapse during protracted withdrawal. The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system and plays an important role in mediating alcohol-seeking behaviors. Here we describe the long-lasting alterations of γ-aminobutyric acid type A receptors (GABA(A)Rs) of medium spiny neurons (MSNs) in the NAcc after chronic intermittent ethanol (CIE) treatment, a rat model of alcohol dependence. CIE treatment and withdrawal (>40 days) produced decreases in the ethanol and Ro15-4513 potentiation of extrasynaptic GABA(A)Rs, which mediate the picrotoxin-sensitive tonic current (I(tonic)), while potentiation of synaptic receptors, which give rise to miniature inhibitory postsynaptic currents (mIPSCs), was increased. Diazepam sensitivity of both I(tonic) and mIPSCs was decreased by CIE treatment. The average magnitude of I(tonic) was unchanged, but mIPSC amplitude and frequency decreased and mIPSC rise time increased after CIE treatment. Rise-time histograms revealed decreased frequency of fast-rising mIPSCs after CIE treatment, consistent with possible decreases in somatic GABAergic synapses in MSNs from CIE rats. However, unbiased stereological analysis of NeuN-stained NAcc neurons did not detect any decreases in NAcc volume, neuronal numbers, or neuronal cell body volume. Western blot analysis of surface subunit levels revealed selective decreases in α1 and δ and increases in α4, α5, and γ2 GABA(A)R subunits after CIE treatment and withdrawal. Similar, but reversible, alterations occurred after a single ethanol dose (5 g/kg). These data reveal CIE-induced long-lasting neuroadaptations in the NAcc GABAergic neurotransmission.
长期酒精暴露引起的强化机制和动机状态变化被认为是导致长期戒断期间渴望和复发的原因。伏隔核（NAcc）是中脑边缘多巴胺能奖赏系统的关键结构，在介导觅酒行为中起重要作用。在此，我们描述了慢性间歇性乙醇（CIE）处理（一种酒精依赖大鼠模型）后，NAcc中中等棘状神经元（MSNs）的γ-氨基丁酸A型受体（GABA(A)Rs）的长期改变。CIE处理和戒断（>40天）导致乙醇和Ro15-4513对突触外GABA(A)Rs的增强作用降低，突触外GABA(A)Rs介导对印防己毒素敏感的强直电流（I(tonic)），而产生微小抑制性突触后电流（mIPSCs）的突触受体的增强作用增加。CIE处理降低了I(tonic)和mIPSCs的地西泮敏感性。I(tonic)的平均幅度未改变，但CIE处理后mIPSC幅度和频率降低，mIPSC上升时间增加。上升时间直方图显示CIE处理后快速上升的mIPSCs频率降低，这与CIE大鼠MSNs中躯体GABA能突触可能减少一致。然而，对NeuN染色的NAcc神经元进行的无偏立体分析未检测到NAcc体积、神经元数量或神经元细胞体体积有任何减少。表面亚基水平的蛋白质印迹分析显示，CIE处理和戒断后，α1和δ亚基选择性减少，α4、α5和γ2 GABA(A)R亚基增加。单次乙醇剂量（5 g/kg）后也出现了类似但可逆的改变。这些数据揭示了CIE诱导的NAcc GABA能神经传递的长期神经适应性变化。
