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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.