Munoz Ceiveon, Jayanthi Subramaniam, Ladenheim Bruce, Cadet Jean Lud
Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA, Intramural Research Program, Baltimore, MD, United States.
Front Mol Neurosci. 2023 Jan 13;15:1104657. doi: 10.3389/fnmol.2022.1104657. eCollection 2022.
Methamphetamine (METH) is a popular but harmful psychostimulant. METH use disorder (MUD) is characterized by compulsive and continued use despite adverse life consequences. METH users experience impairments in learning and memory functions that are thought to be secondary to METH-induced abnormalities in the hippocampus. Recent studies have reported that about 50% of METH users develop MUD, suggesting that there may be differential molecular effects of METH between the brains of individuals who met criteria for addiction and those who did not after being exposed to the drug. The present study aimed at identifying potential transcriptional differences between compulsive and non-compulsive METH self-administering male rats by measuring global gene expression changes in the hippocampus using RNA sequencing. Herein, we used a model of METH self-administration (SA) accompanied by contingent foot-shock punishment. This approach led to the separation of animals into shock-resistant rats (compulsive) that continued to take METH and shock-sensitive rats (non-compulsive) that suppressed their METH intake in the presence of punished METH taking. Rats were euthanized 2 h after the last METH SA plus foot-shock session. Their hippocampi were immediately removed, frozen, and used later for RNA sequencing and qRT-PCR analyses. RNA sequencing analyses revealed differential expression of mRNAs encoding cell adhesion molecules (CAMs) between the two rat phenotypes. qRT-PCR analyses showed significant higher levels of , , mRNAs in the compulsive rats in comparison to non-compulsive rats. The present results implicate altered CAM expression in the hippocampus in the behavioral manifestations of continuous compulsive METH taking in the presence of adverse consequences. Our results raise the novel possibility that altered CAM expression might play a role in compulsive METH taking and the cognitive impairments observed in MUD patients.
甲基苯丙胺（METH）是一种流行但有害的精神兴奋剂。甲基苯丙胺使用障碍（MUD）的特征是尽管会产生不良生活后果，但仍强迫性持续使用。甲基苯丙胺使用者在学习和记忆功能方面存在障碍，这被认为是甲基苯丙胺诱导的海马体异常的继发结果。最近的研究报告称，约50%的甲基苯丙胺使用者会发展为MUD，这表明在接触该药物后，符合成瘾标准的个体与未成瘾个体的大脑中，甲基苯丙胺可能存在不同的分子效应。本研究旨在通过RNA测序测量海马体中的全局基因表达变化，确定强迫性和非强迫性自我给药雄性大鼠之间潜在的转录差异。在此，我们使用了一种伴有偶发性足部电击惩罚的甲基苯丙胺自我给药（SA）模型。这种方法将动物分为在有惩罚性甲基苯丙胺摄入时继续服用甲基苯丙胺的抗电击大鼠（强迫性）和抑制甲基苯丙胺摄入的电击敏感大鼠（非强迫性）。在最后一次甲基苯丙胺SA加足部电击实验2小时后，对大鼠实施安乐死。立即取出它们的海马体，冷冻，随后用于RNA测序和qRT-PCR分析。RNA测序分析显示，两种大鼠表型之间编码细胞粘附分子（CAMs）的mRNA存在差异表达。qRT-PCR分析表明，与非强迫性大鼠相比，强迫性大鼠中 、 、 的mRNA水平显著更高。目前的结果表明，在存在不良后果的情况下，持续强迫性服用甲基苯丙胺的行为表现与海马体中CAM表达的改变有关。我们的结果提出了一种新的可能性，即CAM表达的改变可能在强迫性服用甲基苯丙胺以及MUD患者中观察到的认知障碍中起作用。
