Cocaine abuse and plasticity in the lateral hypothalamus

可卡因滥用和外侧下丘脑的可塑性

基本信息

批准号：
8989877
负责人：
PIETRO P SANNA
金额：
$ 24.72万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8989877
关键词：
Acute Animal Model Applications Grants Astrocytes Award Basic Science Brain Cells Chronic Cocaine Cocaine Abuse Coupled Cytoplasm Data Development Disease Drug usage Electrophysiology (science)Epilepsy Extracellular Space Food deprivation (experimental)Frequencies GLAST Protein Gene Expression Gene Expression Profiling Genes Glucose Glutamate Transporter Glutamates Glycolysis Heroin Hormones Human Hypothalamic structure Intake Lateral Lead Metabolic Methamphetamine Methods Microdialysis Minor Motivation Na(+)-K(+)-Exchanging ATPase Neurons Nicotine Pattern Pharmaceutical Preparations Play Population Production Property Proteins Rattus Recording of previous events Regulation Relapse Rewards Role Self Administration Self-Administered Sodium Stress Synapses Synaptic Transmission System Testing Therapeutic Whole-Cell Recordings Withdrawal addiction adeno-associated viral vector cell type extracellular functional adaptation gene therapy glucose uptake glycogenolysis hypocretin meetings prevent promoter public health relevance recreational drug use response uptake

项目摘要

DESCRIPTION (provided by applicant): Addiction is a chronic, relapsing disorder characterized by compulsive drug intake and vulnerability to relapse after cessation. In rats with an escalated pattern of cocaine intake, we observed gene expression evidence of remodeling of intrinsic lateral hypothalamic (LH) circuitry, which could contribute to the transition to compulsie drug taking and addiction. In particular, development of compulsive cocaine intake under extended access conditions was characterized by increased expression of genes for pre- and post-synaptic proteins, suggestive of structural reorganization of LH intrinsic circuitry. Careful analysis of these gene expression data suggests the hypothesis behind the present Cutting-Edge Basic Research Awards (CEBRA) grant proposal that such changes are brought about by glutamate-driven metabolic plasticity. In fact, we observed that glial electrogenic Na+ dependent glutamate transporters were increased in the LH of rats with histories of escalated (compulsive) cocaine self-administration. Sodium-coupled re-uptake of glutamate by astrocytes results in the activation of the Na+/K+ ATPase triggering, in turn, glucose uptake by astrocytes and glycogenolysis leading to the production and release of lactate into the extracellular space. Consistently, we observed that cocaine self- administration results in increased extracellular lactate levels and that concomitantly with increased expression of the glial electrogenic Na+ dependent glutamate transporters, several genes involved in lactate transport between astrocytes and neurons also showed increased expression in the LH of rats with histories of escalated cocaine self-administration. To test the present hypothesis, in Specific Aim 1 we will investigate functional adaptations in the lateral hypothalamus by patch-whole cell recording before and after the transition to compulsive cocaine self-administration in orexin and MCH neurons. Even minor metabolic manipulations, such as overnight food deprivation, induce structural and functional synaptic changes in orexin neurons as does passive cocaine administration. In Specific Aim 2 we will investigate the effect of manipulating astrocytic glutamate re-uptake in the LH on the electrophysiology of orexin and MCH neurons by delivery of an adeno- associated viral vector (AAV) over-expressing the astrocyte glutamate transporter GLT1 under an astrocyte- selective promoter. This approach showed promise as an experimental gene therapy strategy for epilepsy.

描述（适用提供）：成瘾是一种慢性，复发性疾病，其特征是强迫性药物摄入和戒烟后脆弱性。在可卡因摄入量升级的大鼠中，我们观察到基因表达的固有下丘脑（LH）回路的基因表达证据，这可能有助于过渡到强制药物服用和成瘾。特别是，在扩展接入条件下强迫性可卡因摄入的发展的特征是在突触前和突触后蛋白的基因表达增加，这表明LH内在回路的结构重组。对这些基因表达数据的仔细分析表明，当前尖端基础研究奖（CEBRA）赠款的假设是，这种变化是由谷氨酸驱动的代谢可塑性带来的。实际上，我们观察到，在大鼠的LH中增加了神经胶质电Na+依赖性谷氨酸转运蛋白，具有升级（强迫性的）可卡因自我给药病史。星形胶质细胞对谷氨酸的钠偶联再摄取会导致Na+/K+ ATPase触发的激活，然后由星形胶质细胞和糖原分解葡萄糖吸收，从而导致渗透率的产生和释放到细胞外空间。 Consistently, we observed that cocaine self-administration results in increased extracellular lactate levels and that concomitantly with increased expression of the glial electrogenic Na+ dependent glutamate transporters, several genes involved in lactoate transport between astrocytes and neurons also showed increased expression in the LH of rats with history of escalated cocaine self-administration.为了检验目前的假设，在特定目标1中，我们将通过在过渡到强迫性可卡因自我给药前和MCH神经元中和之后通过斑块全细胞记录来研究下丘脑侧向下丘脑的功能适应。即使是过夜的食物剥夺，例如较小的代谢操作，也会像被动可卡因一样诱导甲前神经元的结构和功能突触变化。在特定的目标2中，我们将通过在星形胶质细胞促进剂下的星形胶质细胞胶质细胞转运剂，通过递送腺相关病毒载体（AAV）过表达腺相关的病毒载体（AAV），调查LH操纵星形细胞谷氨酸再摄取对Orexin和MCH神经元电生理学的影响。这种方法显示了作为癫痫的实验基因治疗策略的希望。