Institute of Biotechnology, HiLIFE, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland.
Neuroscience Center, HiLIFE, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland.
J Biomed Sci. 2021 Dec 20;28(1):87. doi: 10.1186/s12929-021-00782-y.
Craving for alcohol, in other words powerful desire to drink after withdrawal, is an important contributor to the development and maintenance of alcoholism. Here, we studied the role of GDNF (glial cell line-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) on alcohol-seeking behavior in group-housed female mice.
We modeled alcohol-seeking behavior in C57Bl/6J female mice. The behavioral experiments in group-housed female mice were performed in an automated IntelliCage system. We conducted RT-qPCR analysis of Gdnf, Bdnf, Manf and Cdnf expression in different areas of the female mouse brain after alcohol drinking conditioning. We injected an adeno-associated virus (AAV) vector expressing human GDNF or BDNF in mouse nucleus accumbens (NAc) after ten days of alcohol drinking conditioning and assessed alcohol-seeking behavior. Behavioral data were analyzed by two-way repeated-measures ANOVA, and statistically significant effects were followed by Bonferroni's post hoc test. The student's t-test was used to analyze qPCR data.
The RT-qPCR data showed that Gdnf mRNA level in NAc was more than four times higher (p < 0.0001) in the mice from the sweetened alcohol group compared to the water group. Our data showed a more than a two-fold decrease in Manf mRNA (p = 0.04) and Cdnf mRNA (p = 0.02) levels in the hippocampus and Manf mRNA in the VTA (p = 0.04) after alcohol consumption. Two-fold endogenous overexpression of Gdnf mRNA and lack of CDNF did not affect alcohol-seeking behavior. The AVV-GDNF overexpression in nucleus accumbens suppressed alcohol-seeking behavior while overexpression of BDNF did not.
The effect of increased endogenous Gdnf mRNA level in female mice upon alcohol drinking has remained unknown. Our data suggest that an increase in endogenous GDNF expression upon alcohol drinking occurs in response to the activation of another mesolimbic reward pathway participant.
对酒精的渴望，换句话说，即戒酒后强烈的饮酒欲望，是导致酗酒发展和维持的一个重要因素。在这里，我们研究了 GDNF（胶质细胞源性神经营养因子）和 BDNF（脑源性神经营养因子）在群居雌性小鼠酒精觅药行为中的作用。
我们在 C57Bl/6J 雌性小鼠中建立了酒精觅药行为模型。在群居雌性小鼠的行为实验中，我们在自动化 IntelliCage 系统中进行。在酒精饮用量调节后，我们对雌性小鼠大脑不同区域的 Gdnf、Bdnf、Manf 和 Cdnf 表达进行了 RT-qPCR 分析。在酒精饮用量调节 10 天后，我们在小鼠伏隔核（NAc）中注射表达人 GDNF 或 BDNF 的腺相关病毒（AAV）载体，并评估了酒精觅药行为。行为数据通过双因素重复测量方差分析进行分析，具有显著统计学意义的效应随后进行 Bonferroni 事后检验。学生 t 检验用于分析 qPCR 数据。
RT-qPCR 数据显示，与水组相比，来自加糖酒精组的小鼠 NAc 中的 Gdnf mRNA 水平高出四倍以上（p<0.0001）。我们的数据显示，酒精摄入后海马体中的 Manf mRNA（p=0.04）和 Cdnf mRNA（p=0.02）水平下降了一倍以上，VTA 中的 Manf mRNA 下降了两倍（p=0.04）。内源性 Gdnf mRNA 水平增加一倍和 CDNF 缺乏均不影响酒精觅药行为。AVV-GDNF 在伏隔核中的过表达抑制了酒精觅药行为，而 BDNF 的过表达则没有。
女性小鼠饮酒后内源性 Gdnf mRNA 水平增加的影响尚不清楚。我们的数据表明，酒精摄入后内源性 GDNF 表达的增加是对另一个参与中脑边缘奖赏通路的激活的反应。
