Morud Julia, Adermark Louise, Ericson Mia, Söderpalm Bo
Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
Addict Biol. 2015 Jan;20(1):170-81. doi: 10.1111/adb.12096. Epub 2013 Sep 16.
Alcoholism is subject to extensive research, but the role of changes in metabolism caused by alcohol consumption has been poorly investigated. Zinc (Zn(2+) ) deficiency is a common metabolic aberration among alcoholics and Zn(2+) influences the function of ligand-gated ion channels, known pharmacological targets of ethanol (EtOH). Here, we investigate whether manipulation of extracellular levels of Zn(2+) modulates EtOH-induced increases of dopamine (DA) output, as measured by in vivo microdialysis in the rat, and whether voluntary EtOH consumption is altered by Zn(2+) deficiency. Our findings show that the Zn(2+) -chelating agent tricine slowly raises DA levels when perfused in the nucleus accumbens (nAc), whereas the more potent Zn(2+) chelator TPEN reduces DA levels. We also show that pre-treatment with either tricine or TPEN blocks the EtOH-induced DA elevation. Chronic Zn(2+) deficiency induced by a Zn(2+) -free diet did not affect EtOH consumption, but excitatory transmission, assessed by striatal field-potential recordings in the nAc shell, was significantly modulated both by Zn(2+) -free diet and by EtOH consumption, as compared with the EtOH naïve controls. The present study indicates that Zn(2+) influences EtOH's interaction with the brain reward system, possibly by interfering with glycine receptor and GABAA receptor function. This also implies that Zn(2+) deficiency among alcoholics may be important to correct in order to normalize important aspects of brain function.
酒精中毒已受到广泛研究，但饮酒引起的代谢变化所起的作用却鲜有研究。锌（Zn(2+)）缺乏是酗酒者中常见的代谢异常，且Zn(2+)会影响配体门控离子通道的功能，而配体门控离子通道是乙醇（EtOH）已知的药理学靶点。在此，我们研究了细胞外Zn(2+)水平的调控是否会调节EtOH诱导的多巴胺（DA）输出增加（通过大鼠体内微透析测量），以及Zn(2+)缺乏是否会改变自愿饮酒行为。我们的研究结果表明，Zn(2+)螯合剂tric ine在伏隔核（nAc）灌注时会缓慢升高DA水平，而更强效的Zn(2+)螯合剂TPEN则会降低DA水平。我们还表明，用tric ine或TPEN预处理可阻断EtOH诱导的DA升高。无锌饮食诱导的慢性Zn(2+)缺乏并未影响EtOH的摄入量，但与未接触过EtOH的对照组相比，通过nAc壳层的纹状体场电位记录评估的兴奋性传递，受到无锌饮食和EtOH摄入的显著调节。本研究表明，Zn(2+)可能通过干扰甘氨酸受体和GABAA受体功能来影响EtOH与大脑奖赏系统的相互作用。这也意味着，为了使大脑功能的重要方面恢复正常，纠正酗酒者的Zn(2+)缺乏可能很重要。
