Molecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
Autonomic Medicine Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA.
Int J Mol Sci. 2022 Sep 3;23(17):10092. doi: 10.3390/ijms231710092.
Perturbations in striatal dopamine (DA) homeostasis might underlie the behavioral and pathobiological consequences of METH use disorder in humans. To identify potential consequences of long-term METH exposure, we modeled the adverse consequence DSM criterion of substance use disorders by giving footshocks to rats that had escalated their intake of METH during a drug self-administration procedure. Next, DA D1 receptor antagonist, SCH23390 was injected. Thereafter, rats were euthanized to measure several indices of the striatal dopaminergic system. Footshocks split the METH rats into two phenotypes: (i) shock-sensitive that decreased their METH-intake and (ii) shock-resistant that continued their METH intake. SCH23390 caused substantial dose-dependent reduction of METH taking in both groups. Stopping SCH23390 caused re-emergence of compulsive METH taking in shock-resistant rats. Compulsive METH takers also exhibited greater incubation of METH seeking than non-compulsive rats during withdrawal from METH SA. Analyses of DA metabolism revealed non-significant decreases (about 35%) in DA levels in resistant and sensitive rats. However, striatal contents of the deaminated metabolites, DOPAL and DOPAC, were significantly increased in sensitive rats. VMAT2 and DAT protein levels were decreased in both phenotypes. Moreover, protein expression levels of the D1-like DA receptor, D5R, and D2-like DA receptors, D3R and D4R, were significantly decreased in the compulsive METH takers. Our results parallel findings in post-mortem striatal tissues of human METH users who develop Parkinsonism after long-term METH intake and support the use of this model to investigate potential therapeutic interventions for METH use disorder.
纹状体多巴胺（DA）稳态的紊乱可能是人类使用冰毒导致行为和病理生物学后果的基础。为了确定长期使用冰毒的潜在后果，我们通过对在药物自我给药程序中增加冰毒摄入量的大鼠进行电击，来模拟物质使用障碍的不良后果 DSM 标准。然后，注射多巴胺 D1 受体拮抗剂 SCH23390。之后，处死大鼠以测量纹状体多巴胺能系统的几个指标。电击将冰毒大鼠分为两种表型：（i）对电击敏感，减少冰毒摄入量；（ii）对电击耐受，继续摄入冰毒。SCH23390 导致两组大鼠的冰毒摄入量呈显著的剂量依赖性减少。停止 SCH23390 导致电击耐受大鼠强迫性冰毒摄入的重新出现。在停止使用冰毒 SA 期间，强迫性冰毒吸食者也表现出比非强迫性大鼠更大的冰毒寻找潜伏期。DA 代谢分析显示，抵抗和敏感大鼠的 DA 水平有非显著下降（约 35%）。然而，敏感大鼠纹状体中的脱氨代谢物 DOPAL 和 DOPAC 含量显著增加。VMAT2 和 DAT 蛋白水平在两种表型中均降低。此外，强迫性冰毒吸食者的 D1 样多巴胺受体 D5R 和 D2 样多巴胺受体 D3R、D4R 的蛋白表达水平也显著降低。我们的结果与长期摄入冰毒后发展为帕金森病的人类冰毒使用者死后纹状体组织的研究结果相似，支持使用该模型来研究冰毒使用障碍的潜在治疗干预措施。
