Dopamine-Depleted Dopamine Transporter Knockout (DDD) Mice: Dyskinesia with L-DOPA and Dopamine D1 Agonists
L-DOPA is the mainstay of treatment for Parkinson’s disease (PD). However, over time this drug can produce dyskinesia. A useful acute PD model for screening novel compounds for anti-parkinsonian and L-DOPA-induced dyskinesia (LID) are dopamine-depleted dopamine-transporter KO (DDD) mice. Treatment w...
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MDPI AG
2023-11-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/11/1658 |
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| author | Vladimir M. Pogorelov Michael L. Martini Jian Jin William C. Wetsel Marc G. Caron |
| author_facet | Vladimir M. Pogorelov Michael L. Martini Jian Jin William C. Wetsel Marc G. Caron |
| author_sort | Vladimir M. Pogorelov |
| collection | DOAJ |
| description | L-DOPA is the mainstay of treatment for Parkinson’s disease (PD). However, over time this drug can produce dyskinesia. A useful acute PD model for screening novel compounds for anti-parkinsonian and L-DOPA-induced dyskinesia (LID) are dopamine-depleted dopamine-transporter KO (DDD) mice. Treatment with α-methyl-<i>para</i>-tyrosine rapidly depletes their brain stores of DA and renders them akinetic. During sensitization in the open field (OF), their locomotion declines as vertical activities increase and upon encountering a wall they stand on one leg or tail and engage in climbing behavior termed “three-paw dyskinesia”. We have hypothesized that L-DOPA induces a stereotypic activation of locomotion in DDD mice, where they are unable to alter the course of their locomotion, and upon encountering walls engage in “three-paw dyskinesia” as reflected in vertical counts or beam-breaks. The purpose of our studies was to identify a valid index of LID in DDD mice that met three criteria: (a) sensitization with repeated L-DOPA administration, (b) insensitivity to a change in the test context, and (c) stimulatory or inhibitory responses to dopamine D1 receptor agonists (5 mg/kg SKF81297; 5 and 10 mg/kg MLM55-38, a novel compound) and amantadine (45 mg/kg), respectively. Responses were compared between the OF and a circular maze (CM) that did not hinder locomotion. We found vertical counts and climbing were specific for testing in the OF, while oral stereotypies were sensitized to L-DOPA in both the OF and CM and responded to D1R agonists and amantadine. Hence, in DDD mice oral stereotypies should be used as an index of LID in screening compounds for PD. |
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| language | English |
| last_indexed | 2024-03-09T16:58:15Z |
| publishDate | 2023-11-01 |
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| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-075a966a56634eff9692f284cadfa73e2023-11-24T14:32:09ZengMDPI AGBiomolecules2218-273X2023-11-011311165810.3390/biom13111658Dopamine-Depleted Dopamine Transporter Knockout (DDD) Mice: Dyskinesia with L-DOPA and Dopamine D1 AgonistsVladimir M. Pogorelov0Michael L. Martini1Jian Jin2William C. Wetsel3Marc G. Caron4Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, 354 Sands Building, 303 Research Drive, Durham, NC 27710, USAMount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USAMount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Psychiatry and Behavioral Sciences, Duke University Medical Center, 354 Sands Building, 303 Research Drive, Durham, NC 27710, USADepartment of Cell Biology, Duke University Medical Center, Durham, NC 27710, USAL-DOPA is the mainstay of treatment for Parkinson’s disease (PD). However, over time this drug can produce dyskinesia. A useful acute PD model for screening novel compounds for anti-parkinsonian and L-DOPA-induced dyskinesia (LID) are dopamine-depleted dopamine-transporter KO (DDD) mice. Treatment with α-methyl-<i>para</i>-tyrosine rapidly depletes their brain stores of DA and renders them akinetic. During sensitization in the open field (OF), their locomotion declines as vertical activities increase and upon encountering a wall they stand on one leg or tail and engage in climbing behavior termed “three-paw dyskinesia”. We have hypothesized that L-DOPA induces a stereotypic activation of locomotion in DDD mice, where they are unable to alter the course of their locomotion, and upon encountering walls engage in “three-paw dyskinesia” as reflected in vertical counts or beam-breaks. The purpose of our studies was to identify a valid index of LID in DDD mice that met three criteria: (a) sensitization with repeated L-DOPA administration, (b) insensitivity to a change in the test context, and (c) stimulatory or inhibitory responses to dopamine D1 receptor agonists (5 mg/kg SKF81297; 5 and 10 mg/kg MLM55-38, a novel compound) and amantadine (45 mg/kg), respectively. Responses were compared between the OF and a circular maze (CM) that did not hinder locomotion. We found vertical counts and climbing were specific for testing in the OF, while oral stereotypies were sensitized to L-DOPA in both the OF and CM and responded to D1R agonists and amantadine. Hence, in DDD mice oral stereotypies should be used as an index of LID in screening compounds for PD.https://www.mdpi.com/2218-273X/13/11/1658Parkinson’s diseaseL-DOPAdyskinesiadopaminedopamine transporter knockout micedopamine D1 agonists |
| spellingShingle | Vladimir M. Pogorelov Michael L. Martini Jian Jin William C. Wetsel Marc G. Caron Dopamine-Depleted Dopamine Transporter Knockout (DDD) Mice: Dyskinesia with L-DOPA and Dopamine D1 Agonists Biomolecules Parkinson’s disease L-DOPA dyskinesia dopamine dopamine transporter knockout mice dopamine D1 agonists |
| title | Dopamine-Depleted Dopamine Transporter Knockout (DDD) Mice: Dyskinesia with L-DOPA and Dopamine D1 Agonists |
| title_full | Dopamine-Depleted Dopamine Transporter Knockout (DDD) Mice: Dyskinesia with L-DOPA and Dopamine D1 Agonists |
| title_fullStr | Dopamine-Depleted Dopamine Transporter Knockout (DDD) Mice: Dyskinesia with L-DOPA and Dopamine D1 Agonists |
| title_full_unstemmed | Dopamine-Depleted Dopamine Transporter Knockout (DDD) Mice: Dyskinesia with L-DOPA and Dopamine D1 Agonists |
| title_short | Dopamine-Depleted Dopamine Transporter Knockout (DDD) Mice: Dyskinesia with L-DOPA and Dopamine D1 Agonists |
| title_sort | dopamine depleted dopamine transporter knockout ddd mice dyskinesia with l dopa and dopamine d1 agonists |
| topic | Parkinson’s disease L-DOPA dyskinesia dopamine dopamine transporter knockout mice dopamine D1 agonists |
| url | https://www.mdpi.com/2218-273X/13/11/1658 |
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