Förstera B, Muñoz B, Lobo M K, Chandra R, Lovinger D M, Aguayo L G
Department of Physiology, University of Concepcion, Concepcion, Chile.
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, 20 Penn Street, HSF II Rm 251, Baltimore, MD, 21201, USA.
J Physiol. 2017 Aug 1;595(15):5285-5300. doi: 10.1113/JP273767. Epub 2017 Jun 23.
The nucleus accumbens (nAc) is involved in addiction-related behaviour caused by several drugs of abuse, including alcohol. Glycine receptors (GlyRs) are potentiated by ethanol and they have been implicated in the regulation of accumbal dopamine levels. We investigated the presence of GlyR subunits in nAc and their modulation by ethanol in medium spiny neurons (MSNs) of the mouse nAc. We found that the GlyR α1 subunit is preferentially expressed in nAc and is potentiated by ethanol. Our study shows that GlyR α1 in nAc is a new target for development of novel pharmacological tools for behavioural intervention in drug abuse.
Alcohol abuse causes major social, economic and health-related problems worldwide. Alcohol, like other drugs of abuse, increases levels of dopamine in the nucleus accumbens (nAc), facilitating behavioural reinforcement and substance abuse. Previous studies suggested that glycine receptors (GlyRs) are involved in the regulation of accumbal dopamine levels. Here, we investigated the presence of GlyRs in accumbal dopamine receptor medium spiny neurons (MSNs) of C57BL/6J mice, analysing mRNA expression levels and immunoreactivity of GlyR subunits, as well as ethanol sensitivity. We found that GlyR α1 subunits are expressed at higher levels than α2, α3 and β in the mouse nAc and were located preferentially in dopamine receptor 1 (DRD1)-positive MSNs. Interestingly, the glycine-evoked currents in dissociated DRD1-positive MSNs were potentiated by ethanol. Also, the potentiation of the GlyR-mediated tonic current by ethanol suggests that they modulate the excitability of DRD1-positive MSNs in nAc. This study should contribute to understanding the role of GlyR α1 in the reward system and might help to develop novel pharmacological therapies to treat alcoholism and other addiction-related and compulsive behaviours.
伏隔核（nAc）参与由多种滥用药物（包括酒精）引起的成瘾相关行为。甘氨酸受体（GlyRs）可被乙醇增强，并且它们与伏隔核多巴胺水平的调节有关。我们研究了伏隔核中甘氨酸受体亚基的存在情况以及乙醇对小鼠伏隔核中等棘状神经元（MSNs）中甘氨酸受体亚基的调节作用。我们发现甘氨酸受体α1亚基在伏隔核中优先表达且可被乙醇增强。我们的研究表明，伏隔核中的甘氨酸受体α1是开发用于药物滥用行为干预的新型药理学工具的新靶点。
酒精滥用在全球范围内造成了重大的社会、经济和健康相关问题。与其他滥用药物一样，酒精会增加伏隔核（nAc）中的多巴胺水平，促进行为强化和物质滥用。先前的研究表明，甘氨酸受体（GlyRs）参与伏隔核多巴胺水平的调节。在此，我们研究了C57BL/6J小鼠伏隔核多巴胺受体中等棘状神经元（MSNs）中甘氨酸受体的存在情况，分析了甘氨酸受体亚基的mRNA表达水平和免疫反应性以及乙醇敏感性。我们发现，在小鼠伏隔核中，甘氨酸受体α1亚基的表达水平高于α2、α3和β亚基，并且优先位于多巴胺受体1（DRD1）阳性的MSNs中。有趣的是，乙醇可增强解离的DRD1阳性MSNs中甘氨酸诱发的电流。此外，乙醇对甘氨酸受体介导的强直电流的增强作用表明，它们可调节伏隔核中DRD1阳性MSNs的兴奋性。这项研究应有助于理解甘氨酸受体α1在奖赏系统中的作用，并可能有助于开发治疗酒精中毒及其他成瘾相关和强迫行为的新型药物疗法。
