NPY is involved with neurobiological responses to ethanol. Administration of ethanol and ethanol withdrawal alter central NPY expression in rodents. Voluntary ethanol consumption and resistance to the intoxicating effects of ethanol are inversely related to NPY levels in knockout and transgenic mice. Evidence has implicated the Y1 receptor (Y1R) in the modulation of ethanol consumption since Y1R knockout mice show increased consumption of ethanol. The GABA-A receptor mediated inhibitory neurotransmission represents one of the most sensitive targets for the action of ethanol. Moreover acute administration of ethanol increases brain concentrations of the neuroactive steroids 3alpha, 5alphaTH PROG and 3alpha, 5alpha TH DOC, that act as positive allosteric modulators of GABA-A receptors. We previously demonstrated that a prolonged increase of brain concentrations of neuroactive steroids modulates Y1R gene suggesting a functional interaction between GABA and NPY in the amygdala. We now studied the effect of voluntary ethanol consumption on Y1R gene expression in the amygdala and on 3alpha, 5alpha TH PROG and 3alpha, 5alpha TH DOC cerebrocortical concentrations. Transgenic mice harbouring the LacZ reporter gene linked to the Y1R promoter were given free access to two bottles, one containing water and the other containing increasing ethanol concentrations for 4 weeks. A group of mice was withdrawn for 48 hr. Voluntary ethanol consumption increased the cerebrocortical concentrations of 3alpha, 5alpha TH PROG and 3alpha, 5alpha TH DOC, which returned to control values after 48h withdrawal. Conversely, beta-galactosidase expression in the amygdala was not affected by voluntary ethanol consumption and increased by 48h withdrawal. Administration of the 5a-reductase inhibitor finasteride prevented both the increase of neuroactive steroid concentrations as well as changes in transgene expression. These data suggest that NPY and GABA-A may interact in regulating ethanol drinking behavior.
Ethanol drinking and withdrawal modulate NPY-Y1 gene expression in the amygdala of transgenic mice: a role of neuroactive steroids
MELE, PAOLO;EVA, Carola Eugenia
2006-01-01
Abstract
NPY is involved with neurobiological responses to ethanol. Administration of ethanol and ethanol withdrawal alter central NPY expression in rodents. Voluntary ethanol consumption and resistance to the intoxicating effects of ethanol are inversely related to NPY levels in knockout and transgenic mice. Evidence has implicated the Y1 receptor (Y1R) in the modulation of ethanol consumption since Y1R knockout mice show increased consumption of ethanol. The GABA-A receptor mediated inhibitory neurotransmission represents one of the most sensitive targets for the action of ethanol. Moreover acute administration of ethanol increases brain concentrations of the neuroactive steroids 3alpha, 5alphaTH PROG and 3alpha, 5alpha TH DOC, that act as positive allosteric modulators of GABA-A receptors. We previously demonstrated that a prolonged increase of brain concentrations of neuroactive steroids modulates Y1R gene suggesting a functional interaction between GABA and NPY in the amygdala. We now studied the effect of voluntary ethanol consumption on Y1R gene expression in the amygdala and on 3alpha, 5alpha TH PROG and 3alpha, 5alpha TH DOC cerebrocortical concentrations. Transgenic mice harbouring the LacZ reporter gene linked to the Y1R promoter were given free access to two bottles, one containing water and the other containing increasing ethanol concentrations for 4 weeks. A group of mice was withdrawn for 48 hr. Voluntary ethanol consumption increased the cerebrocortical concentrations of 3alpha, 5alpha TH PROG and 3alpha, 5alpha TH DOC, which returned to control values after 48h withdrawal. Conversely, beta-galactosidase expression in the amygdala was not affected by voluntary ethanol consumption and increased by 48h withdrawal. Administration of the 5a-reductase inhibitor finasteride prevented both the increase of neuroactive steroid concentrations as well as changes in transgene expression. These data suggest that NPY and GABA-A may interact in regulating ethanol drinking behavior.
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