Role of adrenal glucocorticoid signaling in prefrontal cortex gene expression and acute behavioral responses to ethanol.
Role of adrenal glucocorticoid signaling in prefrontal cortex gene expression and acute behavioral responses to ethanol.
复制标题
DOI：
10.1111/j.1530-0277.2012.01841.x
复制
发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Miles MF
中科院分区：
文献类型：
--
作者：
Costin BN;Wolen AR;Fitting S;Shelton KL;Miles MF
糖皮质激素调节对包括精神刺激剂和阿片类药物在内的滥用药物的急性和慢性行为和分子反应。越来越多的证据表明，糖皮质激素也可能调节对酒精的行为反应。急性酒精会激活HPA轴，导致肾上腺糖皮质激素的释放。我们先前的基因组研究表明，糖皮质激素在急性乙醇注射后对DBA2/J(D2)小鼠前额叶皮质(PFC)基因表达的调节中起作用。然而，很少有研究分析糖皮质激素信号在急性酒精行为反应中的作用。考虑到急性酒精反应水平对酒精中毒风险的预测价值，这项工作可能意义重大。我们研究了糖皮质激素受体(GR)拮抗剂RU-486或肾上腺切除(ADX)是否改变了雄性D2小鼠对急性(运动激活、焦虑缓解或翻正反射(LORR))或重复(敏化)乙醇处理的行为反应。全基因组微阵列分析和生物信息学方法被用来确定PFC候选基因，这些基因可能导致ADX后对乙醇的行为反应改变。ADX和RU-486均可减弱急性乙醇(2g/kg)诱导的D2小鼠的运动激活，但不影响基础运动活动。然而，ADX和RU-486都不能改变乙醇敏化(运动激活或跳跃计数)、乙醇诱导的焦虑缓解或LORR的启动。ADX小鼠在PFC中表现出微阵列基因表达的变化，这与我们之前的微阵列研究中得出的急性乙醇反应基因集显著重叠。Q-RT-PCR分析证实，ADX降低FKBP5的PFC表达，显著上调Gpr6的表达。此外，大剂量RU-486处理前可钝化乙醇诱导的FKBP5表达。我们的研究表明，乙醇对肾上腺糖皮质激素释放和随后的GR激活的激活可能部分调节了乙醇对雄性D2小鼠的急性运动激活。此外，由于肾上腺糖皮质激素基础音调节PFC基因的表达，包括一组重要的急性酒精反应基因，这表明糖皮质激素调节的PFC基因表达可能是调节酒精急性行为反应的一个重要因素。
Glucocorticoid hormones modulate acute and chronic behavioral and molecular responses to drugs of abuse including psychostimulants and opioids. There is growing evidence that glucocorticoids might also modulate behavioral responses to ethanol. Acute ethanol activates the HPA axis, causing release of adrenal glucocorticoid hormones. Our prior genomic studies suggest glucocorticoids play a role in regulating gene expression in the prefrontal cortex (PFC) of DBA2/J (D2) mice following acute ethanol administration. However, few studies have analyzed the role of glucocorticoid signaling in behavioral responses to acute ethanol. Such work could be significant, given the predictive value for level of response to acute ethanol in the risk for alcoholism. We studied whether the glucocorticoid receptor (GR) antagonist, RU-486, or adrenalectomy (ADX) altered male D2 mouse behavioral responses to acute (locomotor activation, anxiolysis or loss-of-righting reflex (LORR)) or repeated (sensitization) ethanol treatment. Whole genome microarray analysis and bioinformatics approaches were used to identify PFC candidate genes possibly responsible for altered behavioral responses to ethanol following ADX. ADX and RU-486 both impaired acute ethanol (2 g/kg) induced locomotor activation in D2 mice without affecting basal locomotor activity. However, neither ADX nor RU-486 altered initiation of ethanol sensitization (locomotor activation or jump counts), ethanol-induced anxiolysis or LORR. ADX mice showed microarray gene expression changes in PFC that significantly overlapped with acute ethanol-responsive gene sets derived by our prior microarray studies. Q-rtPCR analysis verified that ADX decreased PFC expression of Fkbp5 while significantly increasing Gpr6 expression. In addition, high dose RU-486 pre-treatment blunted ethanol-induced Fkbp5 expression. Our studies suggest that ethanol’s activation of adrenal glucocorticoid release and subsequent GR activation may partially modulate ethanol’s acute locomotor activation in male D2 mice. Furthermore, since adrenal glucocorticoid basal tone regulated PFC gene expression, including a significant set of acute ethanol-responsive genes, this suggests that glucocorticoid regulated PFC gene expression may be an important factor modulating acute behavioral responses to ethanol.
登录
查看更多内容
DOI：
10.1111/j.1530-0277.2007.00509.x
发表时间：
2007-11-01
影响因子：
3.2
作者：
Gililland, Katherine R.;Finn, Deborah A.
通讯作者：
Finn, Deborah A.
影响因子：
1.9
作者：
Palmer, AA;Miller, MN;Phillips, TJ
通讯作者：
Phillips, TJ
DOI：
10.1073/pnas.95.13.7742
发表时间：
1998-06-23
影响因子：
11.1
作者：
Marinelli, M;Aouizerate, B;Piazza, PV
通讯作者：
Piazza, PV
影响因子：
3.7
作者：
Binder, E. B.;Kuenzel, H. E.;Holsboer, F.
通讯作者：
Holsboer, F.
影响因子：
12.3
作者：
Piechota M;Korostynski M;Solecki W;Gieryk A;Slezak M;Bilecki W;Ziolkowska B;Kostrzewa E;Cymerman I;Swiech L;Jaworski J;Przewlocki R
通讯作者：
Przewlocki R