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

描述(申请人提供)：滥用药物，如可卡因，会产生长期的突触适应，增加成瘾的强迫性质，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带来新的治疗方法。最近，我们发现酸敏感离子通道(ASICs)和脑pH在突触可塑性中起关键作用。 根本就是毒瘾。我们的发现表明，ASIC1a在伏隔核(NAC)的中棘神经元(MSN)的突触传递过程中被激活，这是一个与成瘾相关行为密切相关的部位。从基因上删除小鼠的ASIC1a导致了许多突触的变化，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，扰乱小鼠全身或特别是NAC中的ASIC1a增加了对可卡因和吗啡的条件性位置偏爱(CPP)，表明重要的行为后果可概括为多种药物滥用。证实NAC是ASIC1a在可卡因依赖行为中作用的关键部位，恢复ASIC1a在ASIC1a-/-小鼠NAC的表达，逆转了突触异常和可卡因CPP的正常化。我们还在大鼠身上测试了ASIC1a对突触和行为的影响，发现结果与在小鼠身上相似。在大鼠中，在NAC中过表达ASIC1a使ASIC介导的突触电流加倍，并显著减少可卡因的自我给药。总而言之，这些观察表明，ASIC1a抑制了与成瘾相关的行为。此外，这些结果表明，ASIC1a和大脑pH可能是以减少成瘾和复发背后的突触变化为目标的假设。为了验证这一假说，我们建议探索遗传和药理学方法来增加突触的ASIC1a功能，并确定它们影响可卡因相关突触生理和行为的能力。计划中的研究利用了对ASICs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学方法，以及在ASICs、脑pH和药物相关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时间使用可卡因自我管理的大鼠渴望/复发的模型，这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，从而有助于评估寻求药物行为的不同阶段。由于啮齿类动物的ASIC1a结构和功能与人类几乎相同，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为通过靶向ASIC和/或大脑pH来中断成瘾行为的创新策略提供依据。

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.