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Molecular Basis for Sex-Selective Effects of Ethanol

乙醇性别选择性效应的分子基础

基本信息

批准号：
7695545
负责人：
Leslie L Devaud
金额：
$ 27.39万
依托单位：
UNIVERSITY OF MAINE ORONO
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-27 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7695545
关键词：
Acoustics Acute Alcohol consumption Alcohol withdrawal syndrome Behavior Behavioral Brain Cell Fractionation Convulsants Corticosterone Dependence Development Diazepam Diestrus Environment Estradiol Ethanol Ethanol dependence Female Gender Glutamate Receptor Glutamates Goals Hippocampus (Brain)Histocytochemistry Hormonal Investigation Laboratories Link Measures Molecular N-Methyl-D-Aspartate Receptors N-Methylaspartate NR1 gene Nerve Neurobiology Ovarian Pentylenetetrazole Performance Pharmaceutical Preparations Plasma Pregnanolone Process Progesterone Rattus Recovery Regulation Risk Role Seizures Severities Sex Characteristics Site Steroids Synapses Synaptophysin System Testing Testosterone Time Withdrawal Withdrawal Symptom Woman Work alcohol effect base behavior influence density frontal lobe gamma-Aminobutyric Acid gephyrin ifenprodil improved male men neuroadaptation neurochemistry neurotransmission pregnenolone sulfate presynaptic receptor response sex spinophilin synaptogenesis trafficking transmission process young adult

项目摘要

DESCRIPTION (provided by applicant): This proposal is the second submission of a competing renewal to continue our investigations into the neurobiological basis for sex differences in ethanol dependence and withdrawal. To date, we have identified important differences between male and female rats in adaptations of GABA-A and NMDA receptors during ethanol dependence and early withdrawal across several brain sites. We recently found significant and robust behavioral sex differences in the timing for recovery from ethanol withdrawal. Whereas both males and females showed significant withdrawal signs at 24 hr, females, but not males, appeared to have recovered by 3 days. Therefore, the overall goal of this project is to elucidate the mechanistic underpinnings for behavioral expressions of ethanol withdrawal at 24 hr and 3 days. We hypothesize that differences in recovery from ethanol withdrawal involve sex-selective changes in GABAergic and glutamatergic neurotransmission that occur as a result of the differing hormonal milieu between males and females. To test this hypothesis we will compare and contrast findings in young adult male, cycling diestrus female and ovariectomized female rats. The proposed studies will allow us to delineate the importance of hormonal modulation in conferring sex differences in recovery from ethanol withdrawal. This project will test the hypothesis by these aims: 1. assessment of several ethanol withdrawal behaviors, including responses to drug treatments, at early (24 hr) and later (3 days) withdrawal, 2. identification of concomitant sex differences in brain activation with analysis of modulation of GABA-A and NMDA receptors at these same times of withdrawal, and 3. analysis of ethanol withdrawal-induced changes in GABA, glutamate and steroid levels. We expect to find that the differing hormonal milieu between males and cycling females regulates adaptations of GABAergic and glutamatergic neurotransmission that confers recovery from ethanol withdrawal. Findings resulting from these proposed studies should show that inherent, neurobiological regulation due to hormonal status is an important factor influencing actions of ethanol, with adaptations being different for recovery than development of dependence. Increasing our understanding of sex-selective mechanism underlying withdrawal should help guide us towards improving treatments for alcohol withdrawal in both women and men.

描述（由申请人提供）：本提案是第二次提交竞争性更新，以继续我们对乙醇依赖和戒断中性别差异的神经生物学基础的研究。迄今为止，我们已经确定了雄性和雌性大鼠在乙醇依赖和早期戒断过程中对GABA-A和NMDA受体的适应在几个大脑部位的重要差异。我们最近发现，在酒精戒断后恢复的时间上，行为上存在显著的性别差异。而雄性和雌性在24小时时都表现出明显的戒断迹象，雌性在3天后恢复，而雄性没有。因此，本项目的总体目标是阐明24小时和3天乙醇戒断行为表达的机制基础。我们假设乙醇戒断后恢复的差异涉及gaba能和谷氨酸能神经传递的性别选择变化，这是由于男性和女性之间不同的激素环境造成的。为了验证这一假设，我们将比较和对比年轻成年雄鼠、绝经期雌鼠和去卵巢雌鼠的研究结果。拟议的研究将使我们能够描述激素调节在乙醇戒断后恢复中赋予性别差异的重要性。本项目将通过以下几个目标来检验这一假设：评估几种乙醇戒断行为，包括对药物治疗的反应，在早期（24小时）和后期（3天）戒断，2。2 .通过分析GABA-A和NMDA受体在同一戒断时间的调节来鉴定脑激活的伴随性差异；分析乙醇戒断诱导的GABA、谷氨酸和类固醇水平的变化。我们期望发现，雄性和循环中的雌性之间不同的激素环境调节gaba能和谷氨酸能神经传递的适应性，从而从乙醇戒断中恢复过来。这些拟议的研究结果表明，激素状态引起的内在神经生物学调节是影响乙醇作用的重要因素，其适应性不同于恢复和依赖的发展。增加我们对戒酒背后的性别选择机制的理解，将有助于指导我们改进对女性和男性戒酒的治疗。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Running wheel activity protects against increased seizure susceptibility in ethanol withdrawn male rats.

DOI：
10.1016/j.pbb.2011.10.009
发表时间：
2012-01
期刊：
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
影响因子：
3.6
作者：
McCulley, Walter D., III;Walls, Shawn A.;Khurana, Ritu C.;Rosenwasser, Alan M.;Devaud, Leslie L.
通讯作者：
Devaud, Leslie L.

Ethanol-induced loss-of-righting response during ethanol withdrawal in male and female rats: associations with alterations in Arc labeling.

雄性和雌性大鼠乙醇戒断期间乙醇诱导的失正反应：与 Arc 标记变化的关联。

DOI：
10.1111/j.1530-0277.2011.01613.x
发表时间：
2012
期刊：
Alcoholism, clinical and experimental research
影响因子：
0
作者：
Walls,ShawnA;Macklin,ZacharyL;Devaud,LeslieL
通讯作者：
Devaud,LeslieL

Voluntary wheel running attenuates ethanol withdrawal-induced increases in seizure susceptibility in male and female rats.

自愿行驶的车轮会减弱乙醇提取引起的雄性和雌性大鼠的癫痫敏感性增加。

DOI：
10.1016/j.pbb.2012.07.012
发表时间：
2012-11
期刊：
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
影响因子：
3.6
作者：
Devaud, Leslie L.;Walls, Shawn A.;McCulley, Walter D., III;Rosenwasser, Alan M.
通讯作者：
Rosenwasser, Alan M.

Sex and regional differences in effects of chronic intermittent ethanol exposure on subsequent excitotoxic challenges in hippocampal slice cultures.

慢性间歇性乙醇暴露对海马切片培养物随后的兴奋性毒性挑战的影响的性别和区域差异。