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

描述（由申请人提供）：滥用药物，如可卡因，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治疗方法。最近，我们发现酸敏感离子通道（ASIC）和脑pH值在突触可塑性中起着关键作用， 成瘾的根源我们的研究结果表明，ASIC 1a在突触传递过程中被激活，在中棘神经元（MSNs）的神经核（NAc），一个网站坚定地参与成瘾相关的行为。在小鼠中基因缺失ASIC 1a导致了许多突触变化，这些变化与先前在可卡因戒断后观察到的相似。与这些突触效应相一致，在整个身体或特别是在NAc中破坏小鼠的ASIC 1a增加了对可卡因和吗啡的条件性位置偏好（CPP），这表明了推广到多种滥用药物的重要行为后果。证实NAc是可卡因依赖行为中ASIC 1a作用的关键位点，恢复ASIC 1a-/-小鼠NAc的ASIC 1a表达逆转了突触异常并使可卡因CPP正常化。我们还在大鼠中测试了ASIC 1a的突触和行为效应，发现结果与小鼠相似。在大鼠中，在NAc中过表达ASIC 1a使ASIC介导的突触电流加倍，并显着减少可卡因自我给药。总之，这些观察结果表明ASIC 1a抑制了成瘾相关行为。此外，这些结果表明，ASIC 1a和大脑pH值可能是减少成瘾和复发的突触变化的目标。为了验证这一假设，我们建议探索遗传和药理学方法来增加ASIC 1a在突触上的功能，并确定它们影响小鼠和大鼠中可卡因相关突触生理学和行为的能力。计划中的研究利用了对ASIC和pH在突触传递中的作用的新见解，并利用了最先进的电生理方法以及在ASIC，大脑pH和药物相关行为方面具有丰富经验的主要研究者之间的创新合作。我们计划的行为分析包括在大鼠中使用长期接触可卡因自我给药的渴望/复发模型，该模型被广泛认为是成瘾的最佳模型之一，因为动物控制自己的药物摄入量，从而有助于评估药物寻求行为的各个阶段。由于ASIC 1a在啮齿类动物中的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靶向ASIC和/或大脑pH值来中断成瘾行为的创新策略提供信息。

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.