GABA A RECEPTOR MODULATORS IN THE DEVELOPING RAT FOREBRA

发育中的大鼠前脑中的 GABA A 受体调节剂

• 批准号: 6294949
• 负责人: LESLIE P HENDERSON
• 金额: $ 22.65万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-28 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6294949
• 关键词: GABA receptor; age difference; allosteric site; amygdala; androgen analog; animal puberty; benzodiazepines; brain electrical activity; developmental neurobiology; ethanol; female; hypothalamus; laboratory rat; neural transmission; neuropharmacology; polymerase chain reaction; prosencephalon; psychopharmacology; receptor expression; sedative /hypnotic; tranquilizer; voltage /patch clamp

DESCRIPTION: (Adapted from the applicant's Description) Anabolic androgenic steroids (AAS) are synthetic derivatives of testosterone that in recent years have become significant drugs of abuse among preteen and teenage children. AAS are known to elicit detrimental effects on neuroendocrine function, as well as increase psychiatric symptoms, including anxiety, paranoia, hostility, and aggression in adults. However, little is known as to the mechanism of action of these compounds in the central nervous system, and even less is known about how these compounds may act in the developing brain. Neural transmission mediated by GABAA receptor is the primary molecular target for a wide range of both therapeutic and abused drugs, including neurosteroids, benzodiazepines, and ethanol. The investigators have shown recently that AAS induce rapid, reversible, and region-specific modulation of GABAergic currents in the forebrain of prepubertal rats, and thus can be added to the list of substances that act as allosteric modulators of this channel. Both the ontogeny of GABAA receptor subunit gene expression and developmental changes in receptor pharmacology have been well described in the hippocampus and cerebellum during the first two weeks of postnatal development. In contrast, there is a dearth of information delineating developmental changes in receptor pharmacology for other forebrain regions or in the hypothalamus, and few studies have assessed changes in GABAA receptor expression associated with puberty. In particular, no experiments have been performed to determine if sensitivity to AAS is significantly different during the progression from puberty to adulthood. In this application, the investigators will use molecular biological and electrophysiological approaches to determine if, concomitant with puberty, there are significant changes in GABAA receptor subunit expression, as well as the ability of AAS to modulate GABAergic synaptic currents. In addition, the investigators will use electrophysiological and behavioral approaches to determine if chronic AAS exposure in peripubertal versus adult rats induces significant changes in the ability of benzodiazepines or neurosteroids, as well as the AAS, to modulate GABAA receptor currents and to elicit anxiolytic or sedative effects. Together, these studies will demonstrate if puberty is associated with significant changes in the acute or chronic actions of AAS at the GABAA receptor, and thus provide important new information to indicate if adolescents are at increased risk for abuse of AAS or other psychoactive drugs.

描述：（根据申请人的描述改编）合成代谢雄激素 类固醇（AAS）是近年来的睾丸激素的合成衍生物 在青春期和十几岁的孩子中已成为重要的虐待药物。 已知AA会对神经内分泌功能产生不利影响，因为 以及增加精神病症状，包括焦虑，偏执狂，敌对，敌对， 和成人的侵略性。 但是，几乎不知道 这些化合物在中枢神经系统中的作用，甚至更少的是 知道这些化合物如何在发育中的大脑中起作用。 神经 由GABAA受体介导的透射是A的主要分子靶标 广泛的治疗和滥用药物，包括神经类固醇， 苯二氮卓类和乙醇。 调查人员最近表明AAS 诱导GABA能电流的快速，可逆和特定区域的调制 在青春期大鼠的前面，因此可以添加到列表中 充当此通道的变构调节剂的物质。 两者 GABAA受体亚基基因表达和发育变化的个体发育 在受体药理学中，在海马和 小脑在产后发育的前两周。 相比之下， 缺乏信息描述受体的发展变化 其他前脑区域或下丘脑的药理学，少数 研究评估了与 青春期。 特别是，尚未进行实验以确定是否 对AAS的敏感性在进展过程中显着差异 青春期成年。 在此应用程序中，调查人员将使用 分子生物学和电生理方法来确定是否，是否， 与青春期的伴随，GABAA受体发生了重大变化 亚基表达以及AAS调节GABA能的能力 突触电流。 此外，调查人员将使用 电生理和行为方法来确定是否慢性AAS 腹膜与成年大鼠的暴露会引起重大变化 苯二氮卓类药物或神经类固醇以及AAS的能力调节 GABAA受体电流并引起抗焦虑或镇静作用。 这些研究将共同​​证明青春期是否与 AAS在GABAA的急性或慢性作用的显着变化 受体，因此提供重要的新信息，以指示是否是否 青少年滥用AA或其他精神活性的风险增加 毒品。