Investigating role of ASIC2 in synaptic and behavioral responses to drugs of abuse.
Investigating role of ASIC2 in synaptic and behavioral responses to drugs of abuse.
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调查ASIC2在对滥用药物的突触和行为反应中的作用。
DOI：
10.3389/fmolb.2023.1118754
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发表时间：
2023
影响因子：
5
通讯作者：
中科院分区：
文献类型：
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作者：
滥用药物会导致突触重排，这被认为是药物强化行为的原因。酸敏感离子通道（ASICs）被认为可以对抗这些作用，这主要是由于在缺乏ASIC 1A亚基的小鼠中的观察。然而，已知ASIC 2A和ASIC 2B亚基与ASIC 1A相互作用，并且尚未研究它们在滥用药物中的潜在作用。因此，我们测试了在暴露于滥用药物的小鼠中破坏ASIC 2亚基的影响。我们发现Asic 2 −/−小鼠对可卡因和吗啡的条件性位置偏好（CPP）增加，这与Asic 1a −/−小鼠中观察到的相似。由于核神经节核心（NAcc）是ASIC 1A作用的重要位点，我们研究了ASIC 2亚基在那里的表达。通过蛋白质印迹法，ASIC 2A在野生型小鼠中很容易检测到，而ASIC 2B则没有，这表明ASIC 2A是核内的主要亚基。使用腺相关病毒载体（AAV）驱动重组ASIC 2A在Asic 2 −/−小鼠的丘脑核核心中表达，导致接近正常的蛋白质水平。此外，重组ASIC 2A整合与内源性ASIC 1A亚基，形成功能通道中的中型棘神经元（MSN）。然而，与ASIC 1A不同的是，区域限制性恢复的ASIC 2A在延髓核核心不足以影响可卡因或吗啡条件性位置偏爱，这表明ASIC 2的影响不同于ASIC 1A。支持这一对比，我们发现AMPA受体亚基组成和AMPA受体介导的电流与NMDA受体介导的电流（AMPAR/NMDAR）的比值在Asic 2 −/−小鼠中是正常的，并且对可卡因戒断的反应与野生型动物相似。然而，ASIC 2的破坏显着改变树突棘形态，这些影响不同于先前报道的缺乏ASIC 1A的小鼠。我们的结论是，ASIC 2在药物强化行为中起着重要作用，其作用机制可能不同于ASIC 1A。
Drugs of abuse produce rearrangements at glutamatergic synapses thought to contribute to drug-reinforced behaviors. Acid-Sensing Ion Channels (ASICs) have been suggested to oppose these effects, largely due to observations in mice lacking the ASIC1A subunit. However, the ASIC2A and ASIC2B subunits are known to interact with ASIC1A, and their potential roles in drugs of abuse have not yet been investigated. Therefore, we tested the effects of disrupting ASIC2 subunits in mice exposed to drugs of abuse. We found conditioned place preference (CPP) to both cocaine and morphine were increased in Asic2 −/− mice, which is similar to what was observed in Asic1a −/− mice. Because nucleus accumbens core (NAcc) is an important site of ASIC1A action, we examined expression of ASIC2 subunits there. By western blot ASIC2A was readily detected in wild-type mice, while ASIC2B was not, suggesting ASIC2A is the predominant subunit in nucleus accumbens core. An adeno-associated virus vector (AAV) was used to drive recombinant ASIC2A expression in nucleus accumbens core of Asic2 −/− mice, resulting in near normal protein levels. Moreover, recombinant ASIC2A integrated with endogenous ASIC1A subunits to form functional channels in medium spiny neurons (MSNs). However, unlike ASIC1A, region-restricted restoration of ASIC2A in nucleus accumbens core was not sufficient to affect cocaine or morphine conditioned place preference, suggesting effects of ASIC2 differ from those of ASIC1A. Supporting this contrast, we found that AMPA receptor subunit composition and the ratio of AMPA receptor-mediated current to NMDA receptor-mediated current (AMPAR/NMDAR) were normal in Asic2 −/− mice and responded to cocaine withdrawal similarly to wild-type animals. However, disruption of ASIC2 significantly altered dendritic spine morphology, and these effects differed from those reported previously in mice lacking ASIC1A. We conclude that ASIC2 plays an important role in drug-reinforced behavior, and that its mechanisms of action may differ from ASIC1A.
影响因子：
2.5
作者：
Rocca DL;Hanley JG
通讯作者：
Hanley JG