Social isolation stress: role of neurosteroids in the action of ethanol on GABAAR

社会隔离压力：神经类固醇在乙醇对 GABAAR 作用中的作用

• 批准号: 7563317
• 负责人: GIOVANNI BIGGIO
• 金额: $ 9万
• 依托单位: UNIVERSITY OF CAGLIARI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7563317
• 关键词: Acute; Aggressive behavior; Alcohol abuse; Alcohol consumption; Alcohols; Amygdaloid structure; Animal Model; Animals; Anxiety; Behavioral; Boutos; Brain; Breathing; Candidate Disease Gene; Cells; Characteristics; Chronic; Ethanol; Gene Expression; Goals; Head; Hippocampus (Brain); Immunohistochemistry; Laboratory Animals; Literature; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Motor Activity; Mouse Strains; Mus; Neurons; Outcome Study; Plasma; Plastics; RNase protection assay; Rattus; Receptor Gene; Research; Research Personnel; Rodent; Role; Slice; Social isolation; Steroid biosynthesis; Stimulus; Stress; Work; alcohol effect; brain tissue; depression; drinking; drinking behavior; hypothalamic-pituitary-adrenal axis; insight; neurosteroids; neurotransmission; patch clamp; receptor; receptor function; response; social stress; vapor

DESCRIPTION (provided by applicant): Recently, it has been proposed that certain effects of ethanol could be mediated by an increase in the brain levels of neuroactive steroids, such as 3a,5a-THP, which has the ability to increase at nanomolar concentrations the GABAA receptor function. Ethanol-induced increase in neuroactive steroid concentrations appear to result from stimulation of the hypothalamic-pituitary-adrenal (HPA) axis, and at least in part, from a direct stimulation of brain eurosteroidogenesis. Social isolation is a model of prolonged mild stress that has been shown to be associated to marked behavioral alterations, such as increased locomotor activity, anxiety, depression, and aggressiveness in laboratory animals. Social isolation results in a decrease in the brain and plasma concentrations of neuroactive steroids, and is accompanied by an abnormal response to acute stressful stimuli as well as by an increased neurosteroidogenic effect induced by the acute administration of ethanol. We intend to use social isolation in C57BL/6J mouse strain as a model of prolonged mild stress in which to investigate further the role of neurosteroids in the acute and chronic actions that ethanol exerts on the function of GABAA receptors in the hippocampus and amygdala and the interplay with stress. In socially isolated mice, we will measure the effects of ethanol in the following experimental condition: i) after acute administration; ii) after chronic exposure by vapor inhalation, and iii) in a free-choice drinking paradigm in order to establish if this condition can increase ethanol consuption. Neurosteroid levels in brain tissue will be assessed by RIA. GABAA receptor gene expression by RNase protection assay, and by immunohistochemistry. GABAA receptor function will be examined by conventional whole-cell patch clamp recording in brain slices. This project, if successful, by employing the social isolation stress will help to understand further the role of neurosteroids as endogenous mediators of certain pharmacological actions of ethanol as well as the molecular mechanisms underlying the neuronal plastic adaptive changes induced by stress and the interplay with ethanol consumption. Given that many stressful, as well as physiopathological, conditions such as PMS, depression and anxiety could be associated to marked fluctuations in plasma and brain concentrations of neurosteroids, the outcome of this study will provide additional insights about the vulnerability to ethanol abuse, characteristic of such conditions.

描述（由申请人提供）：最近，已经提出乙醇的某些作用可以通过神经活性类固醇（例如3 α，5 α-THP）的脑水平的增加来介导，所述神经活性类固醇具有在纳摩尔浓度下增加GABAA受体功能的能力。乙醇诱导的神经活性类固醇浓度增加似乎是由于刺激下丘脑-垂体-肾上腺（HPA）轴，至少部分是由于直接刺激脑神经类固醇生成。社会隔离是一种长期轻度压力的模型，已被证明与显著的行为改变有关，例如实验室动物的运动活动增加，焦虑，抑郁和攻击性。社会隔离的结果在大脑和血浆中的神经活性类固醇的浓度降低，并伴随着一个异常的反应，急性应激刺激，以及由乙醇的急性管理引起的神经甾体激素的作用增加。我们打算使用C57 BL/6 J小鼠品系的社会隔离作为一个模型，长期的轻度应激，其中进一步调查的作用，神经甾体的急性和慢性行动，乙醇施加在海马和杏仁核的GABAA受体的功能和相互作用与压力。在社会隔离的小鼠中，我们将在以下实验条件下测量乙醇的影响：i）急性给药后; ii）通过蒸汽吸入长期暴露后; iii）自由选择饮酒模式，以确定该条件是否会增加乙醇消耗。将通过RIA评估脑组织中的神经类固醇水平。通过RNA酶保护试验和免疫组织化学测定GABAA受体基因表达。GABAA受体功能将通过脑切片中的常规全细胞膜片钳记录来检查。本项目如果成功，将有助于进一步了解神经甾体作为乙醇某些药理作用的内源性介质的作用，以及应激诱导的神经元可塑性适应性变化的分子机制及其与乙醇消耗的相互作用。鉴于许多压力，以及生理病理学，条件，如经前综合症，抑郁症和焦虑症可能与血浆和脑神经类固醇浓度的显着波动，这项研究的结果将提供更多的见解对酒精滥用的脆弱性，这种情况的特点。

项目成果

Voluntary Ethanol Consumption Induced by Social Isolation Reverses the Increase of α(4)/δ GABA(A) Receptor Gene Expression and Function in the Hippocampus of C57BL/6J Mice.

• DOI: 10.3389/fnins.2011.00015
• 发表时间: 2011
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Sanna E;Talani G;Obili N;Mascia MP;Mostallino MC;Secci PP;Pisu MG;Biggio F;Utzeri C;Olla P;Biggio G;Follesa P
• 通讯作者: Follesa P