Molecular Basis for Sex-Selective Effects of Ethanol

乙醇性别选择性效应的分子基础

• 批准号: 7478482
• 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
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-27 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7478482
• 关键词: Acoustics; Acute; Alcohol consumption; Alcohol withdrawal syndrome; Behavior; Behavioral; Brain; Cell Fractionation; Convulsants; Corticosterone; DLG4 gene; 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; Numbers; 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; day; density; frontal lobe; gamma-Aminobutyric Acid; gephyrin; human NR1 protein; ifenprodil; improved; male; men; neuroadaptation; neurochemistry; neurotransmission; pregnenolone sulfate; presynaptic; presynaptic density protein 95; receptor; response; sex; spinophilin; synaptogenesis; trafficking; transmission process; young adult

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，以继续研究乙醇依赖和戒断的性别差异的神经生物学基础。到目前为止，我们已经确定了重要的差异，雄性和雌性大鼠之间的适应GABA-A和NMDA受体在酒精依赖和早期戒断在几个大脑部位。我们最近发现，在从乙醇戒断中恢复的时间上，性别存在显著而强烈的行为差异。尽管雄性和雌性动物在24小时时均显示出显著的戒断体征，但雌性动物（而非雄性动物）似乎在3天前恢复。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，乙醇戒断恢复的差异涉及性别选择性的变化，GABA能和多巴胺能神经传递的结果，男性和女性之间的不同的激素环境。为了验证这一假设，我们将比较和对比的结果，在年轻的成年男性，周期性间情期女性和卵巢切除的女性大鼠。拟议的研究将使我们能够描述激素调节在乙醇戒断恢复中的性别差异的重要性。本课题将通过以下几个方面来验证这一假设：1.在早期（24小时）和后期（3天）戒断时评估几种乙醇戒断行为，包括对药物治疗的反应，2.在这些相同的戒断时间，通过分析GABA-A和NMDA受体的调节，鉴定脑激活中伴随的性别差异，以及3.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，男性和骑自行车的女性之间的不同激素环境调节GABA能和多巴胺能神经传递的适应，赋予从乙醇戒断恢复。从这些拟议的研究结果应该表明，固有的，神经生物学调节，由于激素状态是一个重要的因素影响乙醇的行动，适应是不同的恢复比发展的依赖。增加我们对戒断的性别选择机制的理解应该有助于指导我们改善女性和男性的酒精戒断治疗。