96-h methamphetamine self-administration elicits striatal dopamine depletion in male and female rats: a model of binge-like use.

IF 3.3 3区医学 Q2 NEUROSCIENCES

Psychopharmacology Pub Date : 2025-07-24 DOI:10.1007/s00213-025-06850-7

Bo Jarrett Wood, Ethan D Brackett, Nicole M Hall, Christopher E Cannon, Robert D Dayton, Courtney M Keller, Nicholas E Goeders, Kevin S Murnane

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Abstract

Background: Methamphetamine is a psychostimulant with significant public health implications. Chronic methamphetamine use is linked to profound dysregulation of the dopaminergic system, cognitive deficits, and psychiatric symptoms. While traditional experimenter administered "binge" dosing models reliably produce dopaminergic neurotoxicity, they fail to capture the volitional, drug intake characteristic of human methamphetamine use. Although self-administration paradigms better reflect human drug-taking behavior, they have yet to consistently reproduce the neurochemical deficits seen in the non-contingent models.

Methods: In this study, we employed a very long-access (96-h) methamphetamine self-administration model over eight weeks to evaluate whether contingent, volitional drug intake produces dopaminergic neurotoxicity. Male and female rats were given extended access to methamphetamine (0.06 mg/kg/infusion) for 96-h sessions weekly, with saline-yoked controls. Neurochemical analysis focused on striatal dopamine and metabolites to assess drug-induced alterations.

Results: Rats exhibited significant escalation in methamphetamine intake over eight weeks, with no sex differences in total intake. Importantly, striatal dopamine levels were significantly reduced in both male and female methamphetamine self-administering rats compared to saline-yoked controls, representing the first demonstration of dopamine depletion following voluntary administration methamphetamine self-administration. Dopamine depletion was significantly correlated with total methamphetamine intake. Interestingly, no significant changes were observed in dopamine metabolites (DOPAC, HVA).

Conclusions: These findings demonstrate that volitional methamphetamine intake under a 96-h access model induces robust dopaminergic deficits, paralleling those seen in non-contingent binge dosing. This model provides a translationally relevant paradigm, capturing both the behavioral and neurobiological aspects of human methamphetamine use, supporting its utility for investigating neurotoxicity and potential treatments.

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96小时的甲基苯丙胺自我给药引起雄性和雌性大鼠纹状体多巴胺耗竭：一个暴饮暴食的模型。

背景：甲基苯丙胺是一种具有重大公共卫生影响的精神兴奋剂。长期使用甲基苯丙胺与多巴胺能系统的严重失调、认知缺陷和精神症状有关。虽然传统的实验者管理的“暴食”给药模型可靠地产生多巴胺能神经毒性，但它们无法捕捉人类使用甲基苯丙胺的意志性、药物摄入特征。尽管自我给药模式更好地反映了人类服药行为，但它们还没有始终如一地再现非偶然模型中所见的神经化学缺陷。方法：在本研究中，我们采用长达8周的超长时间（96小时）甲基苯丙胺自我给药模型来评估偶然的、自愿的药物摄入是否会产生多巴胺能神经毒性。雄性和雌性大鼠给予甲基安非他明（0.06 mg/kg/输注），每周96小时，与盐水对照。神经化学分析的重点是纹状体多巴胺和代谢物，以评估药物引起的改变。结果：大鼠在八周内甲基苯丙胺摄入量显著增加，总摄入量没有性别差异。重要的是，与盐水对照相比，雄性和雌性自我服用甲基苯丙胺的大鼠纹状体多巴胺水平均显著降低，这是自愿服用甲基苯丙胺后多巴胺消耗的首次证明。多巴胺耗竭与甲基苯丙胺总摄入量显著相关。有趣的是，多巴胺代谢物（DOPAC， HVA）没有明显变化。结论：这些研究结果表明，在96小时获取模型下，自愿摄入甲基苯丙胺会引起强烈的多巴胺能缺陷，与非偶然暴饮暴食中所见的相似。该模型提供了一个翻译相关的范例，捕获了人类使用甲基苯丙胺的行为和神经生物学方面，支持其用于研究神经毒性和潜在治疗的效用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Psychopharmacology 医学-精神病学

CiteScore

7.10

自引率

5.90%

发文量

257

审稿时长

2-4 weeks

期刊介绍： Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.