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，退伍军人的风险尤其高。当前 治疗方法主要包括替代阿片类药物，但其疗效有限。因此，新的疼痛和治疗方法 上瘾的需求很大。提高对阿片成瘾和复发的机制的认识 可以帮助预测谁有可能上瘾，并帮助为那些已经上瘾的人开发更好的治疗方法 与毒瘾和旧病复发作斗争。阿片类药物的增强作用在很大程度上依赖于核团 伏隔素(NAC)和MU阿片受体，表达于中棘上的谷氨酸能突触 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它们的数量， 形态和谷氨酸受体亚单位组成。这些变化被认为会产生不正常的 神经突触状态是成瘾、戒断、渴求和复发的基础。我们最近确定了一部小说 影响阿片类药物突触和行为效应的信号机制。这一机制 涉及从含有突触前神经递质的小泡释放质子，激活突触后 酸敏离子通道，ASIC1A，以及由碳酸酐酶4(CA4)在突触处的pH缓冲。我们的 先前的研究和先导数据表明，ASIC1A在稳定谷氨酸能突触方面起着关键作用 而ASIC1A的丢失增加了对阿片类药物诱导的突触异常的易感性，如 以及可卡因。有趣的是，通过破坏CA4来减少pH缓冲，增加了内向突触的Na+ 由ASIC1A介导的电流，似乎能保护神经元免受突触重排 会导致上瘾、渴求和复发。在这里我们建议广泛测试CA4和CA4在多大程度上 ASIC1A调节阿片诱导的NAC突触异常，并影响阿片增强行为。 具体目标1建议测试阿片类药物对ASIC1A、CA4或CA4缺失小鼠突触生理学的影响 两者都有。具体目标2建议在多个行为范式中测试阿片类药物对这些小鼠的影响 包括阿片类药物自我给药、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将保护这些 影响，而CA4中断的影响将取决于ASIC1A。将该提案中的实验结合在一起 将为更好地理解阿片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为通过非阿片类药物治疗阿片成瘾提供新的方法 途径，例如通过操纵大脑pH、ASICs或碳酸氢酶，几种抑制剂 已经被批准用于人类。