Sex differences in norepinephrine action in striatal neurons

描述（由申请人提供）：吸毒成瘾对个人、家庭和公共生活造成巨大损失。了解药物成瘾病理和正常纹状体功能的生理机制将最终降低药物滥用的社会和个人成本，使药物滥用的神经生物学成为相关的研究方向。虽然神经调节剂多巴胺是这一领域大多数研究的焦点，但越来越多的证据表明去甲肾上腺素在药物成瘾方面也起着重要作用。我们的试验数据表明，去甲肾上腺素直接作用于纹状体神经元培养从核丘脑和背侧纹状体磷酸化cAMP反应元件结合蛋白（CREB），转录因子直接牵连作为一个分子开关潜在的药物滥用对大脑的长期影响。我们将建立在我们的建议的第一个目标，在那里我们将阐明去甲肾上腺素激活的潜在信号转导通路，并测试该通路是否诱导基因表达的这一结果。药物成瘾最有趣的一个方面是它是性的二态性。目前还没有一个明确的机制来解释药物滥用行为的性别差异。有趣的是，我们发现在成年纹状体中1-肾上腺素能受体是两性异形的。在我们的建议的第二个目标，我们测试的程度，这种性二型性NE行动，以及它是否是通过早期激素暴露诱导。最后，本建议包含一个重要的培训部分。我的最终职业目标是成为一所研究型大学的首席研究员。作为这样一个机构的教授，我希望我的研究计划能够调查具有社会重要性的现象，并涵盖从分子到行为的技术。我将从这个NRSA接受的培训将有助于提供必要的背景，以实现这些职业目标。我将接受分子和细胞神经生物学技术使用方面的培训，并将我的研究范围扩大到药物滥用，性别差异和哺乳动物纹状体神经元的分子生理学机制。 公共卫生相关性：药物成瘾被认为是由纹状体单胺信号的改变引发的。大多数研究都集中在多巴胺的作用上，但越来越多的证据也表明了一个强大的去甲肾上腺素成分。在这项提案中，我们将测试去甲肾上腺素是否可以直接影响与药物成瘾相关的分子事件。初步数据表明，去甲肾上腺素的作用是两性异形的。我们将确定这种二态性的程度，并测试它是否是通过早期激素暴露诱导的。去甲肾上腺素信号的性别差异提供了一个潜在的机制，在药物成瘾行为的性二态性。

DESCRIPTION (provided by applicant): Drug addiction has an enormous toll on personal, family and public life. Understanding the physiological mechanisms underlying drug addiction pathologies and normal striatal function will ultimately reduce the societal and personal cost of drug abuse, making the neurobiology of drug abuse a relevant line of research. While the neuromodulator dopamine is the focus of most research in this area, evidence is accumulating that norepinephrine also plays an essential role in aspects of drug addiction. Our pilot data indicates that norepinephrine acts directly on striatal neurons cultured from the nucleus accumbens and dorsal striatum to phosphorylate cAMP Response Element Binding Protein (CREB), a transcription-factor directly implicated as a molecular switch underlying long-term effects of drug abuse on the brain. We will build on this result in the first aim of our proposal, where we will elucidate the underlying signal transduction pathway that norepinephrine activates, and test whether this pathway induces gene expression. One of the most interesting aspects of drug addiction is that it is sexually dimorphic. There is currently not a clear mechanism to account for sex differences in drug abuse behavior. Interestingly, we find that the ¿1- adrenergic receptor is sexually dimorphic in adult striatum. In the second aim of our proposal we test the extent of this sexual dimorphism in NE action and whether it is induced via early hormone exposure. Finally, this proposal contains a significant training component. My ultimate career goal is to be a principal investigator at a research university. As a professor at such an institution, I want my research program to investigate phenomena of societal importance and to encompass techniques ranging from the molecular to the behavioral. The training that I will receive from this NRSA will help provide necessary background to meet these career goals. I will be trained in the usage of molecular and cellular neurobiological techniques, and broaden my research portfolio into mechanisms underlying drug abuse, sex differences, and the molecular physiology of mammalian striatal neurons. PUBLIC HEALTH RELEVANCE: Drug addiction is believed to be triggered by alterations in striatal monoamine signaling. Most research has focused on the role of dopamine, but accumulating evidence also suggests a strong norepinephrine component. In this proposal, we will test whether norepinephrine can directly affect molecular events related to drug addiction. Preliminary data suggest that norepinephrine action is sexually dimorphic. We will determine the extent of this dimorphism and test whether it is induced via early hormone exposure. The sex difference in norepinephrine signaling provides a potential mechanism underlying sexual dimorphisms in drug addiction behavior.