Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, Smętna 12 Street, 31-343 Kraków, Poland.
Int J Mol Sci. 2022 Nov 13;23(22):14011. doi: 10.3390/ijms232214011.
Recent years have provided more and more evidence confirming the important role of Wnt/β-catenin signaling in the pathophysiology of mental illnesses, including cocaine use disorder. High relapse rates, which is a hallmark of drug addiction, prompt the study of changes in Wnt signaling elements (, , and ) in the motivational aspects of cocaine use and early drug-free period (3 days after the last exposure to cocaine). For this purpose, an animal model of intravenous cocaine self-administration and two types of drug-free period (extinction training and abstinence in the home cage) were used. The studies showed that chronic cocaine self-administration mainly disturbs the expression of and (the gene encoding β-catenin) in the examined brain structures (striatum and hippocampus), and the examined types of early abstinence are characterized by a different pattern of changes in the expression of these genes. At the same time, in cocaine self-administrated animals, there were no changes in the level of Wnt5a and β-catenin proteins at the tested time points. Moreover, exposure to cocaine induces a significant reduction in the striatal and hippocampal expression of miR-374 and miR-544, which can regulate Wnt5a levels post-transcriptionally. In summary, previous observations from experimenter-administered cocaine have not been fully validated in the cocaine self-administration model. Yoked cocaine administration appears to disrupt Wnt signaling more than cocaine self-administration. The condition of the cocaine-free period, the routes of drug administration, and the motivational aspect of drug administration play an important role in the type of drug-induced molecular changes observed. Furthermore, in-depth research involving additional brain regions is needed to determine the exact role of Wnt signaling in short-term and long-lasting plasticity as well as in the motivational aspects of cocaine use, and thus to assess its potential as a target for new drug therapy for cocaine use disorder.
近年来，越来越多的证据证实了 Wnt/β-catenin 信号通路在精神疾病的病理生理学中的重要作用，包括可卡因使用障碍。高复发率是药物成瘾的一个标志，这促使人们研究可卡因使用和早期无毒品期（最后一次接触可卡因后 3 天）中 Wnt 信号转导元件（、、和）的变化。为此，采用了静脉内可卡因自我给药的动物模型和两种无毒品期（消退训练和在自家笼子中禁欲）。研究表明，慢性可卡因自我给药主要扰乱了所检查的脑结构（纹状体和海马体）中 和 （编码β-catenin 的基因）的表达，所检查的早期禁欲类型的特征是这些基因表达的变化模式不同。同时，在可卡因自我给药的动物中，在测试的时间点，Wnt5a 和 β-catenin 蛋白的水平没有变化。此外，可卡因暴露会导致纹状体和海马体中 miR-374 和 miR-544 的表达显著减少，这可以调节 Wnt5a 的转录后水平。总之，在可卡因自我给药模型中，实验性给予可卡因的先前观察结果尚未得到充分验证。可卡因伴随给药似乎比可卡因自我给药更能破坏 Wnt 信号。无毒品期的条件、药物给药途径和药物给药的动机方面在观察到的药物诱导的分子变化类型中起着重要作用。此外，需要进行更深入的研究，涉及更多的脑区，以确定 Wnt 信号在短期和长期可塑性以及可卡因使用的动机方面的确切作用，并评估其作为可卡因使用障碍新药物治疗靶点的潜力。
