SV2C: a novel target for inhibition of methamphetamine action

SV2C：抑制甲基苯丙胺作用的新靶点

基本信息

批准号：
8889500
负责人：
Kristen Stout
金额：
$ 4.31万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8889500
关键词：
Ablation Address Adrenergic Agents Adverse effects Animals Anxiety Area Attenuated Bathing Behavior Behavioral Binding Biological Assay Brain Clinical Trials Cognitive Corpus striatum structure Coupled Couples Couples Therapy Data Disease Dopamine Dose Drug Addiction Drug Targeting Drug abuse Family Genetic Glycoproteins Heroin Dependence High Pressure Liquid Chromatography Investigation Laboratories Lead Measures Mediator of activation protein Mental Depression Methadone Methamphetamine Methamphetamine dependence Microdialysis Midbrain structure Molecular Target Motor Activity Mus Nature Neurons Nucleus Accumbens Pharmaceutical Preparations Pharmacological Treatment Play Positioning Attribute Proteins Psychostimulant dependence Public Health Radioactive Recovery Research Rewards Rodent Role Scanning Self Administration Signal Transduction Slice Synapses Synaptic Vesicles Therapeutic Tissues Treatment Efficacy United States United States Substance Abuse and Mental Health Services Administration Vesicle addiction adrenergic base behavioral response combat cost dopamine system dopamine transporter dopaminergic neuron drug development effective therapy extracellular gastrointestinal in vivo meetings methamphetamine abuse methamphetamine exposure nerve supply neurochemistry neurotransmission neurotransmitter release novel novel therapeutics preference protein function public health relevance research study response social statistics therapeutic development therapeutic target treatment strategy uptake vesicular monoamine transporter vesicular release

项目摘要

DESCRIPTION (provided by applicant): The addictive nature of methamphetamine (METH) is due, at least in part, to drastically increased extracellular dopamine. Though no current therapeutic for METH addiction is available, numerous compounds have been investigated for efficacy in METH addiction recovery. The difficulty in therapeutic development is finding a molecular target that both modulates dopamine release and is preferentially expressed within dopamine neurons to limit adverse effects of treatment. Expression of the synaptic glycoprotein 2C (SV2C) is largely restricted to areas rich in dopaminergic innervation, such as the midbrain and striatum. Additionally, preliminary experiments conducted by the applicant demonstrate the importance of SV2C in normal dopamine release and storage. Genetic ablation of SV2C results in a 50% reduction of vesicular release in striatal brain slices, as measured by fast scan cyclic voltammetry, and a 20% reduction in vesicular storage capacity, as measured by radioactive dopamine uptake. The restricted localization of SV2C coupled with the important role it plays in dopamine neurotransmission identify it as a prime candidate for potential therapeutic development. The purpose of this proposal is to delineate the effect of genetic deletion of SV2C on the neurochemical and behavioral changes associated with METH administration in mice. This project is both timely and highly translational, as compounds that selectively bind SV2C have been created (UCB Pharma), though they have not been investigated for modulation of dopamine signaling.

描述（由申请人提供）：甲基苯丙胺（METH）的成瘾性至少部分归因于细胞外多巴胺的急剧增加。尽管目前还没有针对冰毒成瘾的治疗方法，但已经研究了许多化合物对冰毒成瘾恢复的功效。治疗开发的困难在于找到既调节多巴胺释放又优先在多巴胺神经元内表达以限制治疗副作用的分子靶点。突触糖蛋白 2C (SV2C) 的表达很大程度上局限于富含多巴胺能神经支配的区域，例如中脑和纹状体。此外，申请人进行的初步实验证明了SV2C在正常多巴胺释放和储存中的重要性。通过快速扫描循环伏安法测量，SV2C 的基因消融导致纹状体脑切片中的囊泡释放减少 50%，并且通过放射性多巴胺摄取测量，囊泡存储容量减少 20%。 SV2C 的有限定位加上它在多巴胺神经传递中发挥的重要作用，使其成为潜在治疗开发的主要候选者。该提案的目的是描述 SV2C 基因缺失对小鼠注射 METH 相关神经化学和行为变化的影响。该项目既及时又具有高度转化性，因为选择性结合 SV2C 的化合物已经被创建（UCB Pharma），尽管尚未研究它们对多巴胺信号传导的调节作用。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bioinspired Honokiol Analogs and Their Evaluation for Activity on the Norepinephrine Transporter.

仿生和厚朴酚类似物及其对去甲肾上腺素转运蛋白活性的评估。

DOI：
10.3390/molecules23102536
发表时间：
2018
期刊：
Molecules (Basel, Switzerland)
影响因子：
0
作者：
Stout,Kristen;Bernaskova,Marketa;Miller,GaryW;Hufner,Antje;Schuehly,Wolfgang
通讯作者：
Schuehly,Wolfgang