Novel mechanisms for correcting opioid-induced synaptic abnormalities

摘要 美国正面临阿片类药物过量和成瘾的危机。目前的治疗主要包括替代疗法， 阿片类药物（即美沙酮或丁丙诺啡维持），并且不能纠正 导致毒瘾复发这些因素包括： 神经核（NAc），既类似于也不同于其他高度成瘾性药物引起的变化。 可卡因等毒品。我们最近的研究表明，阿片类药物的这些突触作用被酸- 传感离子通道（ASIC）。ASICs在突触后树突棘上传导内向Na+和Ca2+电流 在突触传递过程中，它们被释放到突触间隙的质子激活， 含有神经递质的囊泡。因为这些质子是从突触间隙通过 碳酸酐酶4（CA4）的作用，遗传上破坏CA4或抑制CA4， 乙酰唑胺（AZD）显著增加突触ASIC电流。这些观察导致我们 假设AZD将通过抑制CA4逆转阿片类药物戒断后的突触变化， 增加ASIC活性，从而减少渴望和复发。在本提案中，我们计划测试这一点 通过严格评估阿片类药物对突触生理学和行为的影响，提出了这一假说。一起 这项提议中的实验将为更好地理解阿片类药物的神经生物学铺平道路 成瘾和治疗阿片类药物使用障碍（OUD）的新分子靶点。知识来自这些 研究可能会提出通过非阿片类药物机制治疗阿片类药物成瘾的新方法，例如 操纵ASIC、大脑pH值或碳酸酐酶，其中许多抑制剂已经被批准 供人类使用，并可能被有效地重新利用。

Abstract The US is facing a crisis of opioid overdoses and addiction. Current therapies consist largely of alternative opioids (i.e. maintenance with methadone or buprenorphine) and do not correct neurobiological factors that underlie drug craving and relapse. These factors include the long-lasting changes at glutamatergic synapses in the nucleus accumbens (NAc), which both resemble and differ from changes induced by other highly addictive drugs such as cocaine. Our recent studies suggest these synaptic effects of opioids are opposed by acid- sensing ion channels (ASICs). ASICs conduct inward Na+ and Ca2+ current at post-synaptic dendritic spines where they are activated during synaptic transmission by protons released into the synaptic cleft from neurotransmitter-containing vesicles. Because these protons are removed from the synaptic cleft via the actions of carbonic anhydrase 4 (CA4), genetically disrupting CA4 or pharmacologically inhibiting CA4 with acetazolamide (AZD) dramatically increases synaptic ASIC currents. These observations have led to our hypothesis that AZD will reverse synaptic changes following opioid withdrawal by inhibiting CA4 and increasing ASIC activity, and thereby reduce craving and relapse. In this proposal we plan to test this hypothesis by rigorously assessing effects of opioids on synaptic physiology and behavior. Together the experiments in this proposal will pave the way to a better understanding of the neurobiology underlying opioid addiction and to new molecular targets for treating opioid use disorder (OUD). Knowledge gained from these studies could suggest new ways to treat opioid addiction through non-opioidergic mechanisms, for example by manipulating ASICs, brain pH, or carbonic anhydrase, for which a number of inhibitors are already approved for human use, and might be efficiently repurposed.