Investigating a novel regulatory pathway for opioid-induced synaptic plasticity and behavior

研究阿片类药物诱导的突触可塑性和行为的新调控途径

• 批准号: 10292973
• 负责人: John A Wemmie
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292973
• 关键词: AMPA Receptors; ASIC channel; Acids; Acute; Address; Affect; Ambulatory Care Facilities; American; Analgesics; Behavior; Behavioral; Behavioral Paradigm; Brain; Buffers; Carbonic Anhydrase IV; Cations; Chronic; Cocaine; Data; Dendritic Spines; Enzymes; Functional disorder; Glutamate Receptor; Glutamates; Goals; Healthcare; Human; Knowledge; Lead; Measures; Mediating; Molecular; Molecular Target; Morphine; Morphology; Mus; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurons; Neurotransmitters; Nucleus Accumbens; Opiate Addiction; Opioid; Pain; Pain management; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Physiology; Pilot Projects; Play; Protons; Rattus; Regulatory Pathway; Relapse; Risk; Role; Self Administration; Signal Transduction; Structure; Synapses; Synaptic Cleft; Synaptic Transmission; Synaptic plasticity; Testing; United States; Vesicle; Veterans; Wild Type Mouse; Withdrawal; addiction; carbonate dehydratase; cocaine self-administration; conditioned place preference; craving; density; drug of abuse; expectation; experimental study; extracellular; illicit opioid; improved; inhibitor; innovation; mu opioid receptors; non-opioid analgesic; novel; novel therapeutic intervention; novel therapeutics; opioid epidemic; opioid overdose; opioid use disorder; opioid withdrawal; overdose death; overexpression; prescription opioid; presynaptic; prevent; receptor function; reinforced behavior; response; statistics

The United States is in the midst of an opioid epidemic and risk is especially high in veterans. Current therapies consist mainly of alternative opioids, but their efficacy is limited. Thus, new treatments for pain and addiction are in high demand. Improved knowledge of the mechanisms underlying opioid addiction and relapse could help predict who might be a risk for addiction, and help to develop better therapies for those already battling addiction and relapse. The reinforcing effects of opioids depend in large part on the nucleus accumbens (NAc) and mu opioid receptors, which are expressed at glutamatergic synapses on medium spiny neurons in the NAc. Opioids and other drugs of abuse can hijack these synapses and alter their number, morphology, and glutamate receptor subunit composition. These changes are thought to produce abnormal synaptic states that underlie addiction, withdrawal, craving, and relapse. We recently identified a novel signaling mechanism that can influence the synaptic and behavioral effects of opiate drugs. This mechanism involves protons released from presynaptic neurotransmitter-containing vesicles, activation of the post-synaptic acid sensing ion channel, ASIC1A, and pH buffering at the synapse by carbonic anhydrase 4 (CA4). Our previous studies and pilot data suggest that ASIC1A plays a critical role in stabilizing glutamatergic synapses in the NAc, and that loss of ASIC1A increases vulnerability to synaptic abnormalities induced by opioids, as well as by cocaine. Interestingly, reducing pH buffering by disrupting CA4, increases the inward synaptic Na+ currents mediated by ASIC1A and appears to protect against the synaptic rearrangements thought to contribute to addiction, craving, and relapse. Here we propose to extensively test the degree to which CA4 and ASIC1A regulate opioid-induced synaptic abnormalities in the NAc, and influence opioid-reinforced behaviors. Specific Aim 1 proposes to test the effects of opioids on synaptic physiology in mice lacking ASIC1A, CA4, or both. Specific Aim 2 proposes to test effects of opioids in these mice in multiple behavioral paradigms including opioid self-administration, withdrawal, and relapse-related behaviors. We hypothesize that disrupting ASIC1A will alter synaptic and behavioral effects of opioids, disrupting CA4 will protect against these effects, and that effects of CA4 disruption will depend on ASIC1A. Together the experiments in this proposal will pave the way to a better understanding of the neurobiology underlying opioid addiction. Moreover, the knowledge gained from these studies could suggest new ways to treat opioid addiction through non-opioidergic pathways, for example by manipulating brain pH, ASICs, or carbonic anhydrase, for which several inhibitors are already approved for human use.

美国正处于阿片类药物流行之中，退伍军人面临的风险尤其高。当前的 疗法主要包括替代阿片类药物，但其疗效有限。因此，针对疼痛和 成瘾的需求量很大。提高对阿片类药物成瘾和复发机制的了解 可以帮助预测谁可能有成瘾风险，并帮助为那些已经成瘾的人开发更好的治疗方法 与成瘾和复发作斗争。阿片类药物的增强作用很大程度上取决于细胞核 伏隔核 (NAc) 和 mu 阿片受体，在中型多刺的谷氨酸突触上表达 NAc 中的神经元。阿片类药物和其他滥用药物可以劫持这些突触并改变其数量， 形态和谷氨酸受体亚基组成。这些变化被认为会产生异常 突触状态是成瘾、戒断、渴望和复发的基础。我们最近发现了一本小说 可以影响阿片类药物突触和行为效应的信号机制。这个机制 涉及从含有突触前神经递质的囊泡释放质子，激活突触后 酸感应离子通道、ASIC1A 和碳酸酐酶 4 (CA4) 在突触处的 pH 缓冲。我们的 先前的研究和试点数据表明 ASIC1A 在稳定谷氨酸能突触方面发挥着关键作用 在 NAc 中，ASIC1A 的缺失会增加阿片类药物引起的突触异常的脆弱性，如 以及可卡因。有趣的是，通过破坏 CA4 来减少 pH 缓冲，会增加向内突触 Na+ 电流由 ASIC1A 介导，似乎可以防止突触重排（被认为是 导致成瘾、渴望和复发。在这里，我们建议广泛测试 CA4 和 ASIC1A 调节阿片类药物诱导的 NAc 突触异常，并影响阿片类药物强化的行为。 具体目标 1 建议测试阿片类药物对缺乏 ASIC1A、CA4 或 两个都。具体目标 2 建议在多种行为模式下测试阿片类药物对这些小鼠的影响 包括阿片类药物的自我给药、戒断和复发相关行为。我们假设 破坏 ASIC1A 将改变阿片类药物的突触和行为效应，破坏 CA4 将防止这些影响 CA4 破坏的影响将取决于 ASIC1A。本提案中的实验一起进行 将为更好地了解阿片类药物成瘾的神经生物学铺平道路。此外， 从这些研究中获得的知识可能会提出通过非阿片类药物治疗阿片类药物成瘾的新方法 途径，例如通过操纵大脑 pH、ASIC 或碳酸酐酶，其中有几种抑制剂 已经被批准用于人类。