Acute ethanol administration increases brain and plasma levels of (3a,5a)-3-hydroxypregnan-20-one (3a,5a-THP or allopregnanolone) and its precursors progesterone and pregnenolone in rats. The increase in neurosteroid levels contributes to the anxiolytic, anticonvulsant, sedative and proaggressive actions of ethanol. In contrast, acute ethanol administration increases brain but not plasma levels of 3a,5a-THP in DBA/2J (D2) mice but not in C57BL/6J (B6) mice, suggesting that genetic background may explain the effects of ethanol on neurosteroid levels. To further explore this hypothesis, we examined ethanol-induced changes in 3a,5a-THP levels in the cerebral cortex and the olfactory bulb and tubercle of selected D2xB6 (BXD) recombinant inbred strains. Mice were injected with ethanol (2 g/kg, i.p.) or saline at 9:00 am and were sacrificed 1 hour later. 3a,5a-THP levels were measured by radioimmunoassay in the cerebral cortex and by gas chromatography/mass spectrometry in the olfactory bulb and tubercle. Basal cerebral cortical 3a,5a-THP levels across 8 BXD strains plus the parental strains range between 1.81 and 3.72 ng/g, equivalent to a 2.0-fold genetic variation [F(9,79) = 6.27, p < 0.0001] and heritability (h2) of 0.40. Basal 3a,5a-THP levels in the olfactory bulb range between 0.60 and 1.80 ng/g equivalent to a 3.0-fold genetic variation [F(9,59) = 2.46, p = 0.021] and h2 of 0.20. The ethanol-induced changes in 3a,5a-THP levels range between +4% and +63% in the cerebral cortex and between -28% and +65% in the olfactory bulb. We also examined genetic correlations with behavioral phenotypes previously determined in the BXD strains and available in GeneNetwork (www.genenetwork.org). Both basal and ethanol-induced 3a,5a-THP levels are correlated with some anxiety and ethanol phenotypes. Interestingly, the ethanol-induced changes in cerebral cortical 3a,5a-THP levels are negatively correlated with consumption of 3% ethanol in the two bottle choice paradigm (Spearman -0.82, p = 0.02, n = 7, Phillips et al., 1994) and consumption of 10% ethanol over 24 hours (Spearman -0.82, p = 0.02, n = 7, Rodriguez et al 1994). Those strains with increased 3a,5a-THP levels in response to acute ethanol consume less alcohol. This finding, albeit observed in a small number of strains, supports the hypothesis that neurosteroid responses to ethanol may be putative biomarkers of excessive alcohol consumption. Future studies are required to expand and validate these preliminary results.
Genetic differences in the effects of ethanol on brain 3alpha,5alpha-THP levels across selected BXD recombinant inbred mouse strains
Porcu P;
2011
Abstract
Acute ethanol administration increases brain and plasma levels of (3a,5a)-3-hydroxypregnan-20-one (3a,5a-THP or allopregnanolone) and its precursors progesterone and pregnenolone in rats. The increase in neurosteroid levels contributes to the anxiolytic, anticonvulsant, sedative and proaggressive actions of ethanol. In contrast, acute ethanol administration increases brain but not plasma levels of 3a,5a-THP in DBA/2J (D2) mice but not in C57BL/6J (B6) mice, suggesting that genetic background may explain the effects of ethanol on neurosteroid levels. To further explore this hypothesis, we examined ethanol-induced changes in 3a,5a-THP levels in the cerebral cortex and the olfactory bulb and tubercle of selected D2xB6 (BXD) recombinant inbred strains. Mice were injected with ethanol (2 g/kg, i.p.) or saline at 9:00 am and were sacrificed 1 hour later. 3a,5a-THP levels were measured by radioimmunoassay in the cerebral cortex and by gas chromatography/mass spectrometry in the olfactory bulb and tubercle. Basal cerebral cortical 3a,5a-THP levels across 8 BXD strains plus the parental strains range between 1.81 and 3.72 ng/g, equivalent to a 2.0-fold genetic variation [F(9,79) = 6.27, p < 0.0001] and heritability (h2) of 0.40. Basal 3a,5a-THP levels in the olfactory bulb range between 0.60 and 1.80 ng/g equivalent to a 3.0-fold genetic variation [F(9,59) = 2.46, p = 0.021] and h2 of 0.20. The ethanol-induced changes in 3a,5a-THP levels range between +4% and +63% in the cerebral cortex and between -28% and +65% in the olfactory bulb. We also examined genetic correlations with behavioral phenotypes previously determined in the BXD strains and available in GeneNetwork (www.genenetwork.org). Both basal and ethanol-induced 3a,5a-THP levels are correlated with some anxiety and ethanol phenotypes. Interestingly, the ethanol-induced changes in cerebral cortical 3a,5a-THP levels are negatively correlated with consumption of 3% ethanol in the two bottle choice paradigm (Spearman -0.82, p = 0.02, n = 7, Phillips et al., 1994) and consumption of 10% ethanol over 24 hours (Spearman -0.82, p = 0.02, n = 7, Rodriguez et al 1994). Those strains with increased 3a,5a-THP levels in response to acute ethanol consume less alcohol. This finding, albeit observed in a small number of strains, supports the hypothesis that neurosteroid responses to ethanol may be putative biomarkers of excessive alcohol consumption. Future studies are required to expand and validate these preliminary results.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
