Nona Christina N, Li Rui, Nobrega José N
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Behavioural Neurobiology Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Behavioural Neurobiology Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Behav Brain Res. 2014 Mar 1;260:58-66. doi: 10.1016/j.bbr.2013.11.037. Epub 2013 Dec 4.
Repeated administration of ethanol (EtOH) in mice leads to behavioural sensitization, a progressive increase in locomotor activity. Since not all mice sensitize equally to EtOH, the objective of the present study was to determine whether variability in this response is associated with altered subunit gene expression of the N-methyl-d-aspartate receptor (NMDAR), a primary target of EtOH. We examined NR1, NR2A, and NR2B expression throughout the brain during the development phase of EtOH sensitization, as well as after a 14 day withdrawal period. Male DBA/2J mice received 5-6 injections of EtOH (2.2g/kg, i.p.) or saline (SAL) and were categorized as high- (HS) or low-sensitized (LS) on the basis of locomotor activity scores after the final injection. NMDAR subunits were analyzed by in situ hybridization in brains removed either immediately following the final EtOH injection or 14 days thereafter. At the end of development phase, LS mice showed increased NR2A expression in several brain areas compared to saline controls. LS animals also had greater NR1 expression in the nucleus accumbens core (+11%, p=0.05) and shell (+14%, p=0.04) compared to HS mice, and increased NR2B expression in hippocampal CA1 (+20%, p=0.05) relative to saline-treated animals. High-sensitized mice showed increased NR2A expression in the bed nucleus of the stria terminalis when compared to controls (+54%, p=0.02). No differences in gene expression between the treatment groups were seen 14 days after the final injection. These findings suggest that region-specific NMDAR subunits may play an important role in the variability associated with the induction of EtOH sensitization. Low-sensitized mice may be more sensitive to the NMDAR inhibitory effects of EtOH, with the NR1 and NR2A subunits potentially playing a key role in the failure to sensitize upon repeated EtOH exposure.
对小鼠反复给予乙醇（EtOH）会导致行为敏化，即运动活性逐渐增加。由于并非所有小鼠对EtOH的敏化程度相同，本研究的目的是确定这种反应的变异性是否与乙醇的主要作用靶点N-甲基-D-天冬氨酸受体（NMDAR）亚基基因表达的改变有关。我们在EtOH敏化的发育阶段以及14天的戒断期后，检测了整个大脑中NR1、NR2A和NR2B的表达。雄性DBA/2J小鼠接受5 - 6次EtOH（2.2g/kg，腹腔注射）或生理盐水（SAL）注射，并根据最后一次注射后的运动活性评分分为高敏（HS）或低敏（LS）组。在最后一次EtOH注射后立即或此后14天取出的大脑中，通过原位杂交分析NMDAR亚基。在发育阶段结束时，与生理盐水对照组相比，LS小鼠在几个脑区的NR2A表达增加。与HS小鼠相比，LS动物伏隔核核心区的NR1表达也更高（+11%，p = 0.05），壳区更高（+14%，p = 0.04），并且相对于生理盐水处理的动物，海马CA1区的NR2B表达增加（+20%，p = 0.05）。与对照组相比，高敏小鼠终纹床核中的NR2A表达增加（+54%，p = 0.02）。最后一次注射14天后，各治疗组之间未观察到基因表达差异。这些发现表明，区域特异性NMDAR亚基可能在与EtOH敏化诱导相关的变异性中起重要作用。低敏小鼠可能对EtOH的NMDAR抑制作用更敏感，NR1和NR2A亚基可能在反复接触EtOH后未能产生敏化反应中起关键作用。
