Marty Vincent N, Spigelman Igor
Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, CA, USA.
Front Neurosci. 2012 Jun 8;6:86. doi: 10.3389/fnins.2012.00086. eCollection 2012.
Chronic alcohol exposure causes marked changes in reinforcement mechanisms and motivational state that 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. Although the NAcc plays an important role in mediating alcohol-seeking behaviors, little is known about the molecular mechanisms underlying alcohol-induced neuroadaptive changes in NAcc function. The aim of this study was to investigate the effects of chronic intermittent ethanol (CIE) treatment, a rat model of alcohol withdrawal and dependence, on intrinsic electrical membrane properties and glutamatergic synaptic transmission of medium spiny neurons (MSNs) in the NAcc core during protracted withdrawal. We show that CIE treatment followed by prolonged withdrawal increased the inward rectification of MSNs observed at hyperpolarized potentials. In addition, MSNs from CIE-treated animals displayed a lower input resistance, faster action potentials (APs), and larger fast afterhyperpolarizations (fAHPs) than MSNs from vehicle-treated animals, all suggestive of increases in K(+)-channel conductances. Significant increases in the Cs(+)-sensitive inwardly rectifying K(+)-current accounted for the increased input resistance, while increases in the A-type K(+)-current accounted for the faster APs and increased fAHPs in MSNs from CIE rats. We also show that the amplitude and the conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated mEPSCs were enhanced in CIE-treated animals due to an increase in a small fraction of functional postsynaptic GluA2-lacking AMPARs. These long-lasting modifications of excitability and excitatory synaptic receptor function of MSNs in the NAcc core could play a critical role in the neuroadaptive changes underlying alcohol withdrawal and dependence.
长期饮酒会导致强化机制和动机状态发生显著变化，这些变化被认为会导致在长期戒断期间出现渴望和复吸。伏隔核（NAcc）是中脑边缘多巴胺能奖赏系统的关键结构。尽管NAcc在介导觅酒行为中起重要作用，但关于酒精诱导的NAcc功能神经适应性变化的分子机制却知之甚少。本研究的目的是调查慢性间歇性乙醇（CIE）处理（一种酒精戒断和依赖的大鼠模型）对长期戒断期间NAcc核心中中等棘状神经元（MSNs）的内在电膜特性和谷氨酸能突触传递的影响。我们发现，CIE处理后长期戒断会增加在超极化电位下观察到的MSNs的内向整流。此外，与接受载体处理的动物的MSNs相比，接受CIE处理的动物的MSNs表现出更低的输入电阻、更快的动作电位（APs）和更大的快速超极化后电位（fAHPs），所有这些都表明钾离子通道电导增加。Cs（+）敏感的内向整流钾电流的显著增加导致了输入电阻的增加，而A型钾电流的增加导致了CIE大鼠的MSNs中更快的APs和增加的fAHPs。我们还发现，由于一小部分缺乏功能性突触后GluA2的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）增加，CIE处理动物中AMPAR介导的微小兴奋性突触后电流（mEPSCs）的幅度和电导增强。NAcc核心中MSNs的兴奋性和兴奋性突触受体功能的这些长期改变可能在酒精戒断和依赖的神经适应性变化中起关键作用。
