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: 6515901
• 负责人: LESLIE P HENDERSON
• 金额: $ 23.85万
• 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/6515901
• 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：（改编自申请人的描述）合成代谢雄激素 类固醇（AAS）是睾酮的合成衍生物，近年来 已成为青春期前和青少年儿童中滥用的重要药物。 已知 AAS 会对神经内分泌功能产生有害影响，例如 以及增加精神症状，包括焦虑、偏执、敌意、 和成人的攻击性。 然而，人们对其机制知之甚少 这些化合物在中枢神经系统中的作用更小 了解这些化合物如何在发育中的大脑中发挥作用。 神经 GABAA 受体介导的传输是主要分子靶标 广泛的治疗药物和滥用药物，包括神经类固醇， 苯二氮卓类药物和乙醇。 研究人员最近表明，AAS 诱导 GABA 电流的快速、可逆和区域特异性调节 在青春期前大鼠的前脑中，因此可以添加到 充当该通道的变构调节剂的物质。 两者都 GABAA受体亚基基因表达和发育变化的个体发育 受体药理学在海马体中已得到很好的描述， 小脑在出生后的前两周发育。 相比之下， 缺乏描述受体发育变化的信息 其他前脑区域或下丘脑的药理学，很少有 研究评估了与以下因素相关的 GABAA 受体表达的变化 青春期。 特别是，没有进行任何实验来确定是否 在进展过程中对 AAS 的敏感性显着不同 青春期到成年。 在此应用中，研究人员将使用 分子生物学和电生理学方法来确定是否， 随着青春期的到来，GABAA受体发生显着变化 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患有慢性 AAS 与成年大鼠相比，青春期前后的暴露会引起显着变化 苯二氮卓类药物或神经类固醇以及 AAS 调节的能力 GABAA 受体电流并引发抗焦虑或镇静作用。 这些研究将共同​​证明青春期是否与 AAS 在 GABAA 处的急性或慢性作用发生显着变化 受体，从而提供重要的新信息来表明是否 青少年滥用 AAS 或其他精神活性物质的风险增加 药物。