Manipulation of GABAergic steroids: Sex differences in the effects on alcohol drinking- and withdrawal-related behaviors.
Manipulation of GABAergic steroids: Sex differences in the effects on alcohol drinking- and withdrawal-related behaviors.
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DOI：
10.1016/j.yhbeh.2009.07.002
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发表时间：
2010-01
影响因子：
3.5
通讯作者：
Ford MM
中科院分区：
文献类型：
--
作者：
Finn DA;Beckley EH;Kaufman KR;Ford MM
酗酒是一种复杂的疾病，是全球健康问题的一个重要因素，很难用一个单一的临床前模型来概括。此外，酒精（乙醇）影响许多神经递质系统的功能，与γ-氨基丁酸（GABAA）受体的相互作用是乙醇增强和一些戒断相关效应的组成部分。鉴于一些类固醇衍生物作为GABAA受体的有效正调节剂发挥快速的膜作用，并表现出与乙醇相似的药理学特征，实验室研究操纵GABAA能类固醇水平，并确定对乙醇的奖励和戒断相关效应的影响。操作集中在孕酮代谢物异孕酮（ALLO）上，因为它是已知的最有效的内源性gaba能类固醇。潜在的假设是，gabaergy类固醇水平的波动（以及由此产生的gabaergy抑制性张力的变化）改变了对乙醇的敏感性，导致乙醇的积极动机或戒断相关作用的变化。这篇综述的结果强调了ALLO及其生物合成对酒精奖励和戒断相关行为的影响的性别差异，女性对ALLO对酒精饮酒行为的调节作用不太敏感，但对一些类固醇对戒断相关行为的调节作用更敏感。这些发现表明，在与酒精奖励和戒断相关的神经回路中，GABAA受体对GABAA能类固醇的敏感性存在性别差异。因此，gaba能神经类固醇调节的性别差异可能是理解和开发酒精成瘾治疗干预措施的重要考虑因素。
Alcoholism is a complex disorder that represents an important contributor to health problems worldwide and that is difficult to encompass with a single preclinical model. Additionally, alcohol (ethanol) influences the function of many neurotransmitter systems, with the interaction at γ-aminobutyric acidA (GABAA) receptors being integral for ethanol's reinforcing and several withdrawal-related effects. Given that some steroid derivatives exert rapid membrane actions as potent positive modulators of GABAA receptors and exhibit a similar pharmacological profile to that of ethanol, studies in the laboratory manipulated GABAergic steroid levels and determined the impact on ethanol's rewarding- and withdrawal-related effects. Manipulations focused on the progesterone metabolite allopregnanolone (ALLO), since it is the most potent endogenous GABAergic steroid identified. The underlying hypothesis is that fluctuations in GABAergic steroid levels (and the resultant change in GABAergic inhibitory tone) alter sensitivity to ethanol, leading to changes in the positive motivational or withdrawal-related effects of ethanol. This review describes results that emphasize sex differences in the effects of ALLO and the manipulation of its biosynthesis on alcohol reward- versus withdrawal-related behaviors, with females being less sensitive to the modulatory effects of ALLO on ethanol-drinking behaviors but more sensitive to some steroid manipulations on withdrawal-related behaviors. These findings imply the existence of sex differences in the sensitivity of GABAA receptors to GABAergic steroids within circuits relevant to alcohol reward versus withdrawal. Thus, sex differences in the modulation of GABAergic neurosteroids may be an important consideration in understanding and developing therapeutic interventions in alcoholics.
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DOI：
10.1124/jpet.106.107896
发表时间：
2007-01-01
影响因子：
3.5
作者：
Alele, P. E.;Devaud, L. L.
通讯作者：
Devaud, L. L.
影响因子：
3.4
作者：
Anton, RF;Drobes, DJ;Moak, D
通讯作者：
Moak, D
影响因子：
2.6
作者：
CRABBE, JC;KOSOBUD, A;MCSWIGAN, JD
通讯作者：
MCSWIGAN, JD
影响因子：
3.6
作者：
CRABBE, JC;YOUNG, ER;KOSOBUD, A
通讯作者：
KOSOBUD, A
DOI：
10.1621/nrs.06008
发表时间：
2008-06-27
期刊：
Nuclear receptor signaling
影响因子：
--
作者：
Claessens F;Denayer S;Van Tilborgh N;Kerkhofs S;Helsen C;Haelens A
通讯作者：
Haelens A