Modulation of Synaptic and Behavioral Measures of Addiction by Acid-sensing Ion Channels

酸敏感离子通道对成瘾的突触和行为测量的调节

• 批准号: 9100669
• 负责人: RYAN T LALUMIERE
• 金额: $ 35.86万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9100669
• 关键词: AMPA Receptors; ASIC channel; Acetazolamide; Acids; Addictive Behavior; Affect; Attenuated; Behavior; Behavioral; Brain; Buffers; Carbonic Anhydrase IV; Cocaine; Collaborations; Complement; Control Animal; Data; Dendritic Spines; Dependovirus; Drug Addiction; Drug abuse; Electrophysiology (science); Foundations; Frequencies; Genetic; Goals; Health; Human; Intake; Knowledge; Lead; Life; Mediating; Modeling; Molecular Abnormality; Morphine; Mus; N-Methyl-D-Aspartate Receptors; Nature; Neurons; Nucleus Accumbens; Pharmaceutical Preparations; Physiology; Play; Principal Investigator; Rattus; Relapse; Research Personnel; Rodent; Role; Self Administration; Self-control as a personality trait; Site; Staging; Structure; Synapses; Synaptic Cleft; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; Testing; Therapeutic; Translating; Withdrawal; Work; addiction; behavior measurement; cocaine exposure; craving; drug of abuse; drug relapse; drug reward; drug seeking behavior; drug withdrawal; experience; extracellular; innovation; insight; mouse model; new therapeutic target; novel; novel therapeutics; overexpression; preference; receptor; research study

DESCRIPTION (provided by applicant): Drugs of abuse, such as cocaine, produce long-lasting synaptic adaptations that increase the compulsive nature of addiction, undermine self-control, and increase the likelihood of relapse. Identifying and understanding the molecules that regulate these synaptic changes may suggest novel therapies. Recently, we found that acid-sensing ion channels (ASICs) and brain pH play critical roles in the synaptic plasticity thought to underlie addiction. Our findings suggest that ASIC1a is activated during synaptic transmission in medium-spiny neurons (MSNs) of the nucleus accumbens (NAc), a site firmly implicated in addiction-related behavior. Genetically deleting ASIC1a in mice led to a number of synaptic changes paralleling those previously observed following cocaine withdrawal. Consistent with these synaptic effects, disrupting ASIC1a in mice throughout the body or specifically in the NAc increased conditioned place preference (CPP) to cocaine and to morphine, indicating important behavioral consequences that generalize to multiple drugs of abuse. Confirming the NAc as a key site of ASIC1a action in cocaine-dependent behavior, restoring ASIC1a expression to the NAc of ASIC1a-/- mice reversed the synaptic abnormalities and normalized cocaine CPP. We also tested synaptic and behavioral effects of ASIC1a in rats and found results similar to those in mice. In rats, overexpressing ASIC1a in the NAc doubled the ASIC-mediated synaptic current, and significantly reduced cocaine self- administration. Together, these observations indicate that ASIC1a inhibits addiction-related behavior. Furthermore, these results suggest the hypothesis that ASIC1a and brain pH might be targeted to reduce the synaptic changes underlying addiction and relapse. To test this hypothesis, we propose to explore genetic and pharmacological approaches to increase ASIC1a function at synapses and to determine their ability to affect cocaine-related synaptic physiology and behavior in mice and rats. The planned studies capitalize on novel insight into the roles of ASICs and pH in synaptic transmission, and take advantage of state-of-the-art electrophysiological approaches and an innovative collaboration between principal investigators with extensive experience in ASICs, brain pH, and drug-related behavior. Our planned behavioral analyses include models of craving/relapse using long-access cocaine self-administration in rats, widely considered one of the best models of addiction because animals control their own drug intake, thus facilitating assessment of various stages of drug-seeking behavior. Because ASIC1a structure and function in rodents are nearly identical to those in humans, these studies will be highly relevant to the human brain. Moreover, the knowledge gained through these experiments will inform innovative strategies to interrupt addictive behaviors by targeting ASICs and/or brain pH.

描述（由申请人提供）：可卡因等滥用药物会产生持久的突触适应性，从而增加成瘾的强迫性，破坏自我控制并增加复发的可能性。识别和理解调节这些突触变化的分子可能表明新疗法。最近，我们发现酸性离子通道（ASIC）和脑pH在被认为是突触可塑性中起关键作用。 基础上瘾。我们的发现表明，ASIC1A在伏隔核（NAC）的中跨神经元（MSN）的突触传播过程中被激活，该位点与成瘾相关的行为牢固。小鼠中遗传删除的ASIC1A导致了许多突触变化，与可卡因戒断后先前观察到的那些平行的变化。与这些突触效应一致，在整个身体或NAC中的小鼠中破坏了ASIC1A，或者在NAC中特别增加了调节地位偏好（CPP）对可卡因和吗啡，表明重要的行为后果将推广到多种滥用药物。将NAC确认为可卡因依赖性行为中ASIC1A作用的关键部位，从而恢复ASIC1A表达对ASIC1A - / - 小鼠的NAC的表达逆转了突触异常并归一化可卡因CPP。我们还测试了ASIC1A在大鼠中的突触和行为效应，发现与小鼠相似的结果。在大鼠中，NAC中的ASIC1A过表达使ASIC介导的突触电流翻了一番，并显着降低了可卡因自我给药。这些观察结果共同表明ASIC1A抑制了与成瘾相关的行为。此外，这些结果表明，ASIC1A和脑pH值可能是针对性的，以减少成瘾和复发的突触变化。为了检验这一假设，我们建议探索遗传和药理学方法，以提高突触中的ASIC1A功能，并确定它们影响可卡因相关的突触生理学以及小鼠和大鼠的行为的能力。计划的研究利用了对ASIC和pH在突触传播中的作用的新颖洞察力，并利用了最新的电生理方法，以及在ASIC，脑pH和与药物相关的行为方面具有丰富经验的主要研究人员之间的创新合作。我们计划的行为分析包括使用长期以来可卡因在大鼠中自我管理的渴望/复发模型，这被广泛认为是成瘾的最佳模型之一，因为动物控制着自己的药物摄入量，从而促进了对吸毒行为的各个阶段的评估。由于啮齿动物中的ASIC1A结构和功能几乎与人类的结构和功能几乎相同，因此这些研究将与人脑高度相关。此外，通过这些实验获得的知识将通过瞄准ASIC和/或脑pH来为创新的策略提供创新的策略。