Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline
Methamphetamine (METH) abuse increases worldwide. In addition to its acute life-threatening effects, METH is toxic for dopaminergic neurons, increasing the risk of developing Parkinson's disease. The impact of repeated METH binge consumption on dopaminergic and neurotoxicity markers remains unc...
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Elsevier
2025-04-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125000555 |
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| author | Noelia Granado Liliana Mendieta Yousef Tizabi Mario Gustavo Murer Rosario Moratalla |
| author_facet | Noelia Granado Liliana Mendieta Yousef Tizabi Mario Gustavo Murer Rosario Moratalla |
| author_sort | Noelia Granado |
| collection | DOAJ |
| description | Methamphetamine (METH) abuse increases worldwide. In addition to its acute life-threatening effects, METH is toxic for dopaminergic neurons, increasing the risk of developing Parkinson's disease. The impact of repeated METH binge consumption on dopaminergic and neurotoxicity markers remains unclear. We exposed mice to a repeated “binge-like” METH regime, consisting of three doses over a 6 h interval, repeated three times with 14-day intervals. After the first binge, spontaneous motor activity decreased markedly but remained normal after subsequent binges. Following the first binge, we observed a 25 % loss of nigral dopaminergic cell bodies and significant axon terminal damage as assessed through striatal silver staining, with minimal further degeneration after additional binges. Dopaminergic markers were substantially depleted after the first and second binges, despite partial recovery between binges, dropping to below 20 % of control levels. By one day after the third binge, tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2) stabilized at 50–60 % of control levels, but the dopamine transporter (DAT) remained at only 25 %, showing less recovery. These changes were accompanied by an evolving neuroinflammation pattern, with a transient microglial surge after the first binge and persistent astroglial and temperature responses. Overall, our findings indicate partial recovery of dopaminergic markers and the development of tolerance to METH neurotoxicity. The robust reduction of DAT after the first binge may contribute to this tolerance to subsequence binges by limiting METH entry into neurons thereby mitigating its neurotoxic effects. |
| format | Article |
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| institution | OA Journals |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
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| series | Neurobiology of Disease |
| spelling | doaj-art-1401d55e40ef44a6b93a43659ad42d3d2025-08-20T02:05:28ZengElsevierNeurobiology of Disease1095-953X2025-04-0120710683910.1016/j.nbd.2025.106839Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) declineNoelia Granado0Liliana Mendieta1Yousef Tizabi2Mario Gustavo Murer3Rosario Moratalla4Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, SpainInstituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, SpainDepartment of Pharmacology, Howard University College of Medicine, Washington, DC, USAUniversidad de Buenos Aires, Facultad de Medicina, and CONICET, Instituto de Fisiología y Biofísica (IFIBIO), Buenos Aires, ArgentinaInstituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Corresponding author at: Cajal Institute (CSIC), Avda Dr Arce 37, 28002 Madrid, Spain.Methamphetamine (METH) abuse increases worldwide. In addition to its acute life-threatening effects, METH is toxic for dopaminergic neurons, increasing the risk of developing Parkinson's disease. The impact of repeated METH binge consumption on dopaminergic and neurotoxicity markers remains unclear. We exposed mice to a repeated “binge-like” METH regime, consisting of three doses over a 6 h interval, repeated three times with 14-day intervals. After the first binge, spontaneous motor activity decreased markedly but remained normal after subsequent binges. Following the first binge, we observed a 25 % loss of nigral dopaminergic cell bodies and significant axon terminal damage as assessed through striatal silver staining, with minimal further degeneration after additional binges. Dopaminergic markers were substantially depleted after the first and second binges, despite partial recovery between binges, dropping to below 20 % of control levels. By one day after the third binge, tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2) stabilized at 50–60 % of control levels, but the dopamine transporter (DAT) remained at only 25 %, showing less recovery. These changes were accompanied by an evolving neuroinflammation pattern, with a transient microglial surge after the first binge and persistent astroglial and temperature responses. Overall, our findings indicate partial recovery of dopaminergic markers and the development of tolerance to METH neurotoxicity. The robust reduction of DAT after the first binge may contribute to this tolerance to subsequence binges by limiting METH entry into neurons thereby mitigating its neurotoxic effects.http://www.sciencedirect.com/science/article/pii/S0969996125000555MethamphetamineMulti-dosingBingeNeurotoxicityNeuroinflammationNeuroadaptation |
| spellingShingle | Noelia Granado Liliana Mendieta Yousef Tizabi Mario Gustavo Murer Rosario Moratalla Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline Neurobiology of Disease Methamphetamine Multi-dosing Binge Neurotoxicity Neuroinflammation Neuroadaptation |
| title | Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline |
| title_full | Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline |
| title_fullStr | Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline |
| title_full_unstemmed | Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline |
| title_short | Attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter (DAT) decline |
| title_sort | attenuated neurotoxicity after repeated methamphetamine binges linked to dopamine transporter dat decline |
| topic | Methamphetamine Multi-dosing Binge Neurotoxicity Neuroinflammation Neuroadaptation |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125000555 |
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