GABA A RECEPTOR MODULATORS IN THE DEVELOPING RAT FOREBRA

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， 已成为青春期前和青少年儿童滥用的重要药物。 已知AAS会对神经内分泌功能产生有害影响， 并增加精神症状，包括焦虑，偏执，敌意， 和攻击性。 然而，很少有人知道， 这些化合物在中枢神经系统中的作用，甚至更少 这些化合物如何在发育中的大脑中起作用。 神经 由GABAA受体介导的传递是免疫调节的主要分子靶点。 广泛的治疗和滥用药物，包括神经类固醇， 苯二氮卓类药物和乙醇。 研究人员最近发现， 诱导GABA能电流快速、可逆和区域特异性调节 在青春期前大鼠的前脑，因此可以添加到列表中， 作为该通道的变构调节剂的物质。 两者 GABAA受体亚单位基因表达的个体发生和发育变化 在受体药理学中已经在海马体中得到了很好的描述， 小脑在出生后的头两周发育。 与此相反， 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 研究已经评估了GABAA受体表达的变化， 青春期 特别地，没有进行实验来确定是否 AAS的敏感性在进展过程中显著不同， 青春期到成年期 在本申请中，研究人员将使用 分子生物学和电生理学方法来确定， 随着青春期的到来， 亚基表达，以及AAS调节GABA能的能力， 突触电流 此外，研究人员将使用 电生理学和行为学方法来确定慢性AAS 在青春期前后与成年大鼠中的暴露诱导了 苯二氮卓类或神经类固醇以及AAS调节 GABAA受体电流，并引起抗焦虑或镇静作用。 总之，这些研究将证明青春期是否与 AAS在GABAA的急性或慢性作用的显著变化 受体，从而提供重要的新信息，以表明如果 青少年滥用AAS或其他精神活性药物的风险增加 毒品

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.