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Novel mechanisms for correcting opioid-induced synaptic abnormalities

纠正阿片类药物引起的突触异常的新机制

基本信息

批准号：
10610455
负责人：
John A Wemmie
金额：
$ 45.38万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610455
关键词：
ASIC channel Acetazolamide Altitude Sickness Behavior Behavioral Brain Buprenorphine Carbonic Anhydrase IV Carbonic Anhydrase Inhibitors Chronic Clinical Cocaine Dendritic Spines Dose Drug usage Epilepsy Foundations Glutamates Goals Human Incubated Injections Knowledge Maintenance Measures Mediating Methadone Molecular Molecular Target Morphine Mus Nature Neurobiology Neuronal Plasticity Neurons Neurotransmitters Nucleus Accumbens Opiate Addiction Opioid Pathway interactions Persons Pharmaceutical Preparations Physiology Pilot Projects Play Protons Relapse Role Self Administration Signal Pathway Synapses Synaptic Cleft Synaptic Transmission Testing Vesicle Withdrawal addiction carbonate dehydratase conditioned place preference craving drug craving drug of abuse drug relapse drug seeking behavior drug withdrawal experimental study improved inhibitor innovation non-opioid analgesic novel opioid abuse opioid epidemic opioid mortality opioid overdose opioid use disorder opioid withdrawal pharmacologic postsynaptic prevent

项目摘要

Abstract The US is facing a crisis of opioid overdoses and addiction. Current therapies consist largely of alternative opioids (i.e. maintenance with methadone or buprenorphine) and do not correct neurobiological factors that underlie drug craving and relapse. These factors include the long-lasting changes at glutamatergic synapses in the nucleus accumbens (NAc), which both resemble and differ from changes induced by other highly addictive drugs such as cocaine. Our recent studies suggest these synaptic effects of opioids are opposed by acid- sensing ion channels (ASICs). ASICs conduct inward Na+ and Ca2+ current at post-synaptic dendritic spines where they are activated during synaptic transmission by protons released into the synaptic cleft from neurotransmitter-containing vesicles. Because these protons are removed from the synaptic cleft via the actions of carbonic anhydrase 4 (CA4), genetically disrupting CA4 or pharmacologically inhibiting CA4 with acetazolamide (AZD) dramatically increases synaptic ASIC currents. These observations have led to our hypothesis that AZD will reverse synaptic changes following opioid withdrawal by inhibiting CA4 and increasing ASIC activity, and thereby reduce craving and relapse. In this proposal we plan to test this hypothesis by rigorously assessing effects of opioids on synaptic physiology and behavior. Together the experiments in this proposal will pave the way to a better understanding of the neurobiology underlying opioid addiction and to new molecular targets for treating opioid use disorder (OUD). Knowledge gained from these studies could suggest new ways to treat opioid addiction through non-opioidergic mechanisms, for example by manipulating ASICs, brain pH, or carbonic anhydrase, for which a number of inhibitors are already approved for human use, and might be efficiently repurposed.

摘要美国正面临阿片类药物过量和成瘾的危机。目前的治疗主要包括替代疗法，阿片类药物（即美沙酮或丁丙诺啡维持），并且不能纠正导致毒瘾复发这些因素包括：神经核（NAc），既类似于也不同于其他高度成瘾性药物引起的变化。可卡因等毒品。我们最近的研究表明，阿片类药物的这些突触作用被酸- 传感离子通道（ASIC）。ASICs在突触后树突棘上传导内向Na+和Ca 2+电流在突触传递过程中，它们被释放到突触间隙的质子激活，含有神经递质的囊泡。因为这些质子是从突触间隙通过碳酸酐酶4（CA 4）的作用，遗传上破坏CA 4或抑制CA 4，乙酰唑胺（AZD）显著增加突触ASIC电流。这些观察导致我们假设AZD将通过抑制CA 4逆转阿片类药物戒断后的突触变化，增加ASIC活性，从而减少渴望和复发。在本提案中，我们计划测试这一点通过严格评估阿片类药物对突触生理学和行为的影响，提出了这一假说。一起这项提议中的实验将为更好地理解阿片类药物的神经生物学铺平道路成瘾和治疗阿片类药物使用障碍（OUD）的新分子靶点。知识来自这些研究可能会提出通过非阿片类药物机制治疗阿片类药物成瘾的新方法，例如操纵ASIC、大脑pH值或碳酸酐酶，其中许多抑制剂已经被批准供人类使用，并可能被有效地重新利用。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects of acid-sensing ion channel-1A (ASIC1A) on cocaine-induced synaptic adaptations.

DOI：
10.3389/fphys.2023.1191275
发表时间：
2023
期刊：
FRONTIERS IN PHYSIOLOGY
影响因子：
4
作者：
Gupta, Subhash C.;Taugher-Hebl, Rebecca J.;Hardie, Jason B.;Fan, Rong;LaLumiere, Ryan T.;Wemmie, John A.
通讯作者：
Wemmie, John A.

Carbonic anhydrase 4 disruption decreases synaptic and behavioral adaptations induced by cocaine withdrawal.