Biochemical Neuroadaptations in the Rat Striatal Dopaminergic System after Prolonged Exposure to Methamphetamine Self-Administration
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 foot...
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MDPI AG
2022-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/17/10092 |
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| author | Subramaniam Jayanthi Bruce Ladenheim Patricia Sullivan Michael T. McCoy Irina N. Krasnova David S. Goldstein Jean Lud Cadet |
| author_facet | Subramaniam Jayanthi Bruce Ladenheim Patricia Sullivan Michael T. McCoy Irina N. Krasnova David S. Goldstein Jean Lud Cadet |
| author_sort | Subramaniam Jayanthi |
| collection | DOAJ |
| description | 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. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T01:41:47Z |
| publishDate | 2022-09-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-da54e49e72dd43e8adae62ea75c73bd72023-11-23T13:22:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123171009210.3390/ijms231710092Biochemical Neuroadaptations in the Rat Striatal Dopaminergic System after Prolonged Exposure to Methamphetamine Self-AdministrationSubramaniam Jayanthi0Bruce Ladenheim1Patricia Sullivan2Michael T. McCoy3Irina N. Krasnova4David S. Goldstein5Jean Lud Cadet6Molecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USAMolecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USAAutonomic Medicine Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USAMolecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USADivision for Research Capacity Building, NIGMS, National Institutes of Health, Bethesda, MD 20892, USAAutonomic Medicine Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USAMolecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USAPerturbations 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.https://www.mdpi.com/1422-0067/23/17/10092dopaminedopamine metabolitesDOPALdopamine receptorsdorsal striatummethamphetamine use disorder |
| spellingShingle | Subramaniam Jayanthi Bruce Ladenheim Patricia Sullivan Michael T. McCoy Irina N. Krasnova David S. Goldstein Jean Lud Cadet Biochemical Neuroadaptations in the Rat Striatal Dopaminergic System after Prolonged Exposure to Methamphetamine Self-Administration International Journal of Molecular Sciences dopamine dopamine metabolites DOPAL dopamine receptors dorsal striatum methamphetamine use disorder |
| title | Biochemical Neuroadaptations in the Rat Striatal Dopaminergic System after Prolonged Exposure to Methamphetamine Self-Administration |
| title_full | Biochemical Neuroadaptations in the Rat Striatal Dopaminergic System after Prolonged Exposure to Methamphetamine Self-Administration |
| title_fullStr | Biochemical Neuroadaptations in the Rat Striatal Dopaminergic System after Prolonged Exposure to Methamphetamine Self-Administration |
| title_full_unstemmed | Biochemical Neuroadaptations in the Rat Striatal Dopaminergic System after Prolonged Exposure to Methamphetamine Self-Administration |
| title_short | Biochemical Neuroadaptations in the Rat Striatal Dopaminergic System after Prolonged Exposure to Methamphetamine Self-Administration |
| title_sort | biochemical neuroadaptations in the rat striatal dopaminergic system after prolonged exposure to methamphetamine self administration |
| topic | dopamine dopamine metabolites DOPAL dopamine receptors dorsal striatum methamphetamine use disorder |
| url | https://www.mdpi.com/1422-0067/23/17/10092 |
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