Modulation of neuropeptide Y and Y-1 receptor expression in the amygdala by fluctuations in the brain content of neuroactive steroids during ethanol drinking discontinuation in Y1R/LacZ transgenic mice

Previous studies have shown that GABAergic neuroactive steroids increase Y-1 receptor (Y1R) gene expression in the amygdala of Y1R/LacZ transgenic mice, harbouring the murine Y1R gene promoter linked to a LacZ reporter gene. As ethanol is known to increase GABAergic neuroactive steroids, we investigated the relationship between fluctuations in the brain content of neuroactive steroids induced by chronic voluntary ethanol consumption or ethanol discontinuation and both the level of neuropeptide Y (NPY) immunoreactivity and Y-1 R gene expression in the amygdala of Y1R/Lac;transgenic mice. Ethanol discontinuation (48 h) after voluntary consumption of consecutive solutions of 3%, 6%, 10% and 20% (v/v) ethanol over 4 weeks produced an anxiety-like behaviour as measured by elevated plus maze. Voluntary ethanol intake increased the cerebrocortical concentration of the progesterone metabolite 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-THPROG) that returned to control level 48 h after discontinuation of ethanol intake. Ethanol discontinuation significantly decreased NPY immunoreactivity and concomitantly increased Y1R/LacZ transgene expression in the amygdala, whereas chronic ethanol intake failed to affect these parameters. The 5 alpha-reductase inhibitor finasteride prevented both the increase in the cerebrocortical concentration of 3 alpha,5 alpha-TH PROG apparent after 4 weeks of ethanol intake and the changes in NPY immunoreactivity and transgene expression induced by ethanol discontinuation. Data suggest that 3 alpha,alpha-TH PROG plays an important role in the changes in NPY-Y1R signalling in the amygdala during ethanol discontinuation