Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen & University Hospital Rigshospitalet, Copenhagen, Denmark.
Alcohol Clin Exp Res. 2010 Mar 1;34(3):462-70. doi: 10.1111/j.1530-0277.2009.01110.x. Epub 2009 Dec 17.
Multiple episodes of ethanol intoxication and withdrawal result in progressive, irreversible intensification of the withdrawal reaction, a process termed "ethanol withdrawal kindling." Previous studies show that a single episode of chronic ethanol intoxication and withdrawal causes prominent changes in neuropeptide Y (NPY) and its receptors that have been implicated in regulating withdrawal hyperexcitability. This study for the first time examined the NPY system during ethanol withdrawal kindling.
Ethanol withdrawal kindling was studied in rats receiving 16 episodes of 2 days of chronic ethanol intoxication by intragastric intubations followed by 5 days withdrawal. The study included 6 groups: 4 multiple withdrawal episode (MW) groups [peak withdrawal plus (MW+)/minus (MW-) seizures, 3-day (MW3d), and 1-month (MW1mth) withdrawal], a single withdrawal episode group (SW), and an isocalorically fed control group. Gene expression of NPY and its receptors Y1, Y2, and Y5 was studied in the hippocampal dentate gyrus (DG) and CA3/CA1, as well as piriform cortex (PirCx), and neocortex (NeoCx).
MW+/- as well as SW groups showed decreased NPY gene expression in all hippocampal areas compared with controls, but, in the DG and CA3, decreases were significantly smaller in the MW- group compared with the SW group. In the MW+/- and SW groups, Y1, Y2, and Y5 mRNA levels were decreased in most brain areas compared with controls; however, decreases in Y1 and Y5 mRNA were augmented in the MW+/- groups compared with the SW group. The MW+ group differed from the MW- group in the PirCx, where Y2 gene expression was significantly higher.
Multiple withdrawal episodes reversibly decreased NPY and NPY receptor mRNA levels at peak withdrawal, with smaller decreases in NPY mRNA levels and augmented decreases in Y1/Y5 mRNA levels compared with a SW episode. Multiple withdrawal-induced seizures increased the Y2 mRNA levels in PirCx. These complex changes in NPY system gene expression could play a role in the ethanol withdrawal kindling process.
多次乙醇中毒和戒断会导致戒断反应逐渐增强，这是一种被称为“乙醇戒断点燃”的过程。先前的研究表明，单次慢性乙醇中毒和戒断会导致神经肽 Y（NPY）及其受体发生显著变化，这些变化与调节戒断兴奋性过高有关。本研究首次在乙醇戒断点燃过程中研究了 NPY 系统。
通过胃内插管给予大鼠 16 个 2 天的慢性乙醇中毒期，随后进行 5 天的戒断期，来研究乙醇戒断点燃。该研究包括 6 组：4 个多次戒断期（MW）组[发作性戒断高峰加（MW+）/减（MW-），3 天（MW3d）和 1 个月（MW1mth）戒断]、单次戒断期（SW）组和等热量喂养对照组。研究了 NPY 及其受体 Y1、Y2 和 Y5 在海马齿状回（DG）和 CA3/CA1 以及梨状皮层（PirCx）和新皮层（NeoCx）中的基因表达。
与对照组相比，MW+/-和 SW 组所有海马区的 NPY 基因表达均降低，但与 SW 组相比，MW-组的 DG 和 CA3 区的降低幅度明显较小。在 MW+/-和 SW 组中，与对照组相比，大多数脑区的 Y1、Y2 和 Y5 mRNA 水平降低；然而，MW+/-组的 Y1 和 Y5 mRNA 水平降低幅度增大。MW+组与 MW-组在 PirCx 中的 Y2 基因表达显著升高，与 MW-组不同。
与单次戒断发作相比，多次戒断发作可在戒断高峰时可逆性地降低 NPY 和 NPY 受体 mRNA 水平，NPY mRNA 水平降低幅度较小，Y1/Y5 mRNA 水平降低幅度增大。多次戒断诱导的发作增加了 PirCx 中的 Y2 mRNA 水平。NPY 系统基因表达的这些复杂变化可能在乙醇戒断点燃过程中发挥作用。
