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: 8930129
• 负责人: RYAN T LALUMIERE
• 金额: $ 35.32万
• 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/8930129
• 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; 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; 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）：滥用药物，如可卡因，会产生持久的突触适应，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会提出新的疗法。最近，我们发现酸敏感离子通道 (ASIC) 和大脑 pH 值在突触可塑性中发挥着关键作用。 成瘾的基础。我们的研究结果表明，ASIC1a 在伏隔核 (NAc) 的中棘神经元 (MSN) 的突触传递过程中被激活，该位点与成瘾相关行为密切相关。在小鼠中基因删除 ASIC1a 会导致许多突触变化，与之前在可卡因戒断后观察到的变化相似。与这些突触效应一致，破坏小鼠全身或特别是 NAc 中的 ASIC1a 会增加对可卡因和吗啡的条件性位置偏好 (CPP)，这表明可推广到多种药物滥用的重要行为后果。确认 NAc 是 ASIC1a 在可卡因依赖性行为中发挥作用的关键位点，恢复 ASIC1a-/- 小鼠 NAc 的 ASIC1a 表达可逆转突触异常并使可卡因 CPP 正常化。我们还在大鼠中测试了 ASIC1a 的突触和行为效应，发现结果与小鼠相似。在大鼠中，NAc 中 ASIC1a 的过度表达使 ASIC 介导的突触电流加倍，并显着减少可卡因的自我给药。总之，这些观察结果表明 ASIC1a 抑制与成瘾相关的行为。此外，这些结果表明了这样的假设：ASIC1a 和大脑 pH 值可能是减少成瘾和复发背后的突触变化的目标。为了检验这一假设，我们建议探索遗传和药理学方法来增加突触的 ASIC1a 功能，并确定它们影响小鼠和大鼠与可卡因相关的突触生理和行为的能力。计划中的研究利用对 ASIC 和 pH 在突触传递中的作用的新见解，并利用最先进的电生理学方法以及在 ASIC、大脑 pH 和药物方面拥有丰富经验的主要研究人员之间的创新合作。相关行为。我们计划的行为分析包括在大鼠中使用长期可卡因自我给药的渴望/复发模型，该模型被广泛认为是最好的成瘾模型之一，因为动物控制自己的药物摄入量，从而促进对药物寻求行为的各个阶段的评估。由于啮齿类动物的 ASIC1a 结构和功能与人类几乎相同，因此这些研究将与人类大脑高度相关。此外，通过这些实验获得的知识将为通过针对 ASIC 和/或大脑 pH 值来中断成瘾行为的创新策略提供信息。