Gupta Subhash C, Taugher-Hebl Rebecca J, Ghobbeh Ali, Jahnke Marshal T, Fan Rong, LaLumiere Ryan T, Wemmie John A
Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA.
Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.
bioRxiv. 2025 Apr 21:2025.01.23.634619. doi: 10.1101/2025.01.23.634619.
The ongoing opioid crisis underscores the need for innovative treatments targeting the neurobiological mechanisms underlying opioid-seeking behaviors and relapse. Here, we explored the role of carbonic anhydrase 4 (CA4) in modulating synaptic adaptations to oxycodone withdrawal in mice. We disrupted CA4 genetically and inhibited it pharmacologically with acetazolamide (AZD), a carbonic anhydrase inhibitor used clinically. We found that oxycodone withdrawal increased AMPAR/NMDAR ratio and synaptic recruitment of calcium-permeable AMPARs in nucleus accumbens core (NAcC) medium spiny neurons (MSNs). Synaptic changes required an extended period of abstinence, generalized to other opioids, including morphine and heroin, were more pronounced in D1 dopamine receptor-expressing MSNs, and were prevented by CA4 disruption. AZD administration and reversed the synaptic alterations, and the effects of AZD depended on CA4 and acid-sensing ion channel-1A. Interestingly, abstinence from oxycodone did not affect dendritic spine density in NAcC MSNs, in contrast to previously observed effects of abstinence from cocaine. Finally, in an oxycodone self-administration paradigm, CA4 disruption and AZD reduced drug-seeking behaviors following 30 days of forced abstinence. Together, these findings identify a critical role for CA4 in synaptic adaptations in opioid withdrawn mice and drug-seeking behavior. Moreover, they suggest pharmacological inhibitors of CA4 may hold therapeutic potential for reducing opioid-seeking and relapse in opioid use disorder.
持续的阿片类药物危机凸显了针对导致阿片类药物寻求行为和复发的神经生物学机制进行创新治疗的必要性。在此，我们探讨了碳酸酐酶4（CA4）在调节小鼠对羟考酮戒断的突触适应性中的作用。我们通过基因手段破坏CA4，并使用临床上使用的碳酸酐酶抑制剂乙酰唑胺（AZD）进行药理学抑制。我们发现，羟考酮戒断会增加伏隔核核心（NAcC）中等棘状神经元（MSN）中AMPAR/NMDAR比率以及钙通透性AMPAR的突触募集。突触变化需要较长时间的禁欲，这种变化可推广到其他阿片类药物，包括吗啡和海洛因，在表达D1多巴胺受体的MSN中更为明显，并且可通过破坏CA4来预防。给予AZD可逆转突触改变，且AZD的作用取决于CA4和酸敏感离子通道-1A。有趣的是，与先前观察到的可卡因戒断效应相反，羟考酮戒断并未影响NAcC MSN中的树突棘密度。最后，在羟考酮自我给药范式中，破坏CA4和给予AZD可减少30天强制禁欲后的药物寻求行为。总之，这些发现确定了CA4在阿片类药物戒断小鼠的突触适应性和药物寻求行为中的关键作用。此外，它们表明CA4的药理学抑制剂可能具有减少阿片类药物使用障碍中阿片类药物寻求和复发的治疗潜力。
