Ernest Gallo Research Center and Department of Neurology, University of California at San Francisco, Emeryville, California 94608, USA.
J Neurosci. 2012 Oct 24;32(43):15124-32. doi: 10.1523/JNEUROSCI.2783-12.2012.
We found previously that acute ex vivo as well as repeated cycles of in vivo ethanol exposure and withdrawal, including excessive voluntary consumption of ethanol, produces a long-lasting increase in the activity of NR2B-containing NMDA receptors (NR2B-NMDARs) in the dorsomedial striatum (DMS) of rats (Wang et al., 2010a). Activation of NMDARs is required for the induction of long-term potentiation (LTP) of AMPA receptor (AMPAR)-mediated synaptic response. We therefore examined whether the ethanol-mediated upregulation of NMDAR activity alters the induction of LTP in the DMS. We found that ex vivo acute exposure of striatal slices to, and withdrawal from, ethanol facilitates the induction of LTP in DMS neurons, which is abolished by the inhibition of NR2B-NMDARs. We also report that repeated systemic administration of ethanol causes an NR2B-NMDAR-dependent facilitation of LTP in the DMS. LTP is mediated by the insertion of AMPAR subunits into the synaptic membrane, and we found that repeated systemic administration of ethanol, as well as cycles of excessive ethanol consumption and withdrawal, produced a long-lasting increase in synaptic localization of the GluR1 and GluR2 subunits of AMPARs in the DMS. Importantly, we report that inhibition of AMPARs in the DMS attenuates operant self-administration of ethanol, but not of sucrose. Together, our data suggest that aberrant synaptic plasticity in the DMS induced by repeated cycles of ethanol exposure and withdrawal contributes to the molecular mechanisms underlying the development and/or maintenance of excessive ethanol consumption.
我们之前发现，急性离体以及反复的体内乙醇暴露和戒断循环，包括过量的自愿饮酒，会导致大鼠背内侧纹状体（DMS）中含有 NR2B 的 NMDA 受体（NR2B-NMDAR）的活性长期增加（Wang 等人，2010a）。NMDAR 的激活是诱导 AMPA 受体（AMPAR）介导的突触反应长时程增强（LTP）所必需的。因此，我们检查了乙醇介导的 NMDAR 活性上调是否会改变 DMS 中的 LTP 诱导。我们发现，纹状体切片离体急性暴露于乙醇并从乙醇中戒断会促进 DMS 神经元中 LTP 的诱导，而 NR2B-NMDAR 的抑制则会消除这种诱导。我们还报告说，重复的系统给予乙醇会导致 DMS 中 NR2B-NMDAR 依赖性的 LTP 易化。LTP 是由 AMPAR 亚基插入突触膜介导的，我们发现，重复的系统给予乙醇以及过量饮酒和戒断循环会导致 DMS 中 AMPAR 的 GluR1 和 GluR2 亚基的突触定位长期增加。重要的是，我们报告说，DMS 中 AMPAR 的抑制会减弱乙醇的操作性自我给药，但不会减弱蔗糖的自我给药。总之，我们的数据表明，反复的乙醇暴露和戒断循环引起的 DMS 中异常的突触可塑性可能是导致过度饮酒发展和/或维持的分子机制之一。
