Bo Jarrett Wood, Ethan D Brackett, Nicole M Hall, Christopher E Cannon, Robert D Dayton, Courtney M Keller, Nicholas E Goeders, Kevin S Murnane
{"title":"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。","authors":"Bo Jarrett Wood, Ethan D Brackett, Nicole M Hall, Christopher E Cannon, Robert D Dayton, Courtney M Keller, Nicholas E Goeders, Kevin S Murnane","doi":"10.1007/s00213-025-06850-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"96-h methamphetamine self-administration elicits striatal dopamine depletion in male and female rats: a model of binge-like use.\",\"authors\":\"Bo Jarrett Wood, Ethan D Brackett, Nicole M Hall, Christopher E Cannon, Robert D Dayton, Courtney M Keller, Nicholas E Goeders, Kevin S Murnane\",\"doi\":\"10.1007/s00213-025-06850-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusions: </strong>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. 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96-h methamphetamine self-administration elicits striatal dopamine depletion in male and female rats: a model of binge-like use.
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.
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.
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