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Keywords:

  • Ethanol;
  • Withdrawal;
  • Kindling;
  • Neuropeptide Y;
  • Gene Expression

Background:  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.

Methods:  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).

Results:  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.

Conclusion:  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.