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。目前的治疗方法主要包括替代疗法 阿片类药物(即用美沙酮或丁丙诺啡维持)，并不纠正 吸毒成瘾和复发是其根本原因。这些因素包括脑内谷氨酸能突触的长期变化 伏隔核(NAC)，既类似又不同于其他高度成瘾引起的变化 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效应被酸- 感应离子通道(ASIC)。ASIC在突触后树突棘传导内向Na+和Ca~(2+)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 含有神经递质的小泡。因为这些质子被从突触间隙中移除 碳酸酐酶4(CA4)的作用，基因干扰CA4或药物抑制CA4 乙酰唑胺(AZD)显著增加突触ASIC电流。这些观察结果导致了我们 假设AZD将通过抑制CA4和CA4逆转阿片类药物戒断后的突触变化 增加ASIC活性，从而减少渴求和复发。在这项提案中，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和行为的影响来提出假说。团结在一起 这项提议中的实验将为更好地理解阿片类药物背后的神经生物学铺平道路。 以及治疗阿片使用障碍的新分子靶点(OUD)。从这些项目中获得的知识 研究可以提出通过非阿片能机制治疗阿片成瘾的新方法，例如通过 操纵ASICs、脑pH或碳酸氢酶，许多抑制剂已经被批准用于这些领域 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.