1] Medical Scientist Training Program, University of Iowa, Iowa City, Iowa, USA. [2] Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA. [3].
1] Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA. [2].
Nat Neurosci. 2014 Aug;17(8):1083-91. doi: 10.1038/nn.3750. Epub 2014 Jun 22.
Acid-sensing ion channel 1A (ASIC1A) is abundant in the nucleus accumbens (NAc), a region known for its role in addiction. Because ASIC1A has been suggested to promote associative learning, we hypothesized that disrupting ASIC1A in the NAc would reduce drug-associated learning and memory. However, contrary to this hypothesis, we found that disrupting ASIC1A in the mouse NAc increased cocaine-conditioned place preference, suggesting an unexpected role for ASIC1A in addiction-related behavior. Moreover, overexpressing ASIC1A in rat NAc reduced cocaine self-administration. Investigating the underlying mechanisms, we identified a previously unknown postsynaptic current during neurotransmission that was mediated by ASIC1A and ASIC2 and thus well positioned to regulate synapse structure and function. Consistent with this possibility, disrupting ASIC1A altered dendritic spine density and glutamate receptor function, and increased cocaine-evoked plasticity, which resemble changes previously associated with cocaine-induced behavior. Together, these data suggest that ASIC1A inhibits the plasticity underlying addiction-related behavior and raise the possibility of developing therapies for drug addiction by targeting ASIC-dependent neurotransmission.
酸敏离子通道 1A（ASIC1A）在伏隔核（NAc）中含量丰富，该区域已知在成瘾中起作用。由于 ASIC1A 被认为可以促进联想学习，我们假设在 NAc 中破坏 ASIC1A 会减少与药物相关的学习和记忆。然而，与这一假设相反，我们发现破坏小鼠 NAc 中的 ASIC1A 会增加可卡因条件性位置偏好，这表明 ASIC1A 在成瘾相关行为中具有意想不到的作用。此外，在大鼠 NAc 中过表达 ASIC1A 会减少可卡因自我给药。在研究潜在机制时，我们在神经传递过程中发现了一种以前未知的突触后电流，该电流由 ASIC1A 和 ASIC2 介导，因此非常适合调节突触结构和功能。与这种可能性一致的是，破坏 ASIC1A 改变了树突棘密度和谷氨酸受体功能，并增加了可卡因诱发的可塑性，这类似于以前与可卡因诱导的行为相关的变化。总之，这些数据表明 ASIC1A 抑制了与成瘾相关行为相关的可塑性，并提出了通过靶向 ASIC 依赖性神经传递来开发药物成瘾治疗方法的可能性。
