Dopamine Transporter Deficient Rodents: Perspectives and Limitations for Neuroscience
Abstract
:1. Introduction
2. Genetically Modified Animals Affecting Function of DAT
3. Impact of DAT Deletion on Neurotransmission and Neuroanatomy
4. Impact of DAT Deficiency on Animal Physiological Phenotype
5. Behavioral Phenotype of Animals with DAT Hypofunction
6. DAT Deficient Animals as Models in Experimental Neuropsychopharmacology
6.1. DTDS
6.2. States Associated with Increased Levels of DA
6.3. States Associated with Decreased Levels of DA
Drug | Mechanism of Action | Animals | Doses | Administration Route | Administration Schedule | Number of Animals per Group | Influencing WT Activity | Reference |
---|---|---|---|---|---|---|---|---|
Nicotine | NAchR agonist | DAT-KO mice F1 | 0.5 and 1 mg/kg | s/c | before testing | 16–24 | ↑ | [46] |
DAT-KO mice | 1 and 3 mg/kg | i/p | before testing | 8–12 | - | [113] | ||
DAT-KD C57BL6/J mice | 40 mg/kg/day | s/c, by mini-osmotic pumps | for 26 days | 27–30 | - | [126] | ||
Choline | α7 agonist | DAT-KO mice F1 | 5 mg/kg | s/c | before testing | 12 | - | [46] |
Epibatidine + Choline | β2 agonist + α7 agonist | DAT-KO mice F1 | 0.5 mcg/kg + 0.5 mg/kg | s/c | before testing | 8 | - | [46] |
β-phenethylamine | TAAR agonist | DAT-KO mice C57BL/6J x 129/SVJ | 10, 30, 50, 70, 100 mg/kg | i/p | 30 min before testing | 10–15 | ↑ | [127] |
Methylphenidate | DAT and NET inhibitor | DAT-KO mice 129/C57 | 30 mg/kg | i/p | before testing | 8 | ↑ | [77] |
DAT-KO rats Wistar Han | 1.2, 2.5, 5 mg/kg | i/p | before testing | 6–19 | [30] | |||
Haloperidol | D2R antagonist | DAT-KO mice 129/C57 | 0.2 mg/kg | i/p | before testing | 6 | ↓ | [77] |
DAT-KO mice C57BL/6 | 0.15, 0.2, 0.3 mg/kg | s/c | 30 min before testing | 10–15 | [71] | |||
DAT HET mice C57BL/6 | 0.1, 0.15, 0.2, 0.3 mg/kg | s/c | 30 min before testing | 10–15 | [71] | |||
DAT-KO rats Wistar Han | 0.5 mg/kg | s/c | before testing | 6–19 | [30] | |||
DAT HET rats Wistar Han | 0.5 mg/kg | s/c | before testing | 4 | [30] | |||
Clozapine | D2-/5-HT2A antagonist | DAT-KO mice C57BL/6 | 2 and 3 mg/kg | s/c | 30 min before testing | 10–15 | ↓ | [71] |
DAT HET mice C57BL/6 | 1, 2, 3 mg/kg | s/c | 30 min before testing | 10–15 | [71] | |||
Raclopride | D2R antagonist | DAT-KO mice C57BL/129SvJ | 0.1 mg/kg | i/p | 10 min before testing | 9–18 | - | [108] |
SCH23390 | D1R antagonist | DAT-KO mice C57BL/129SvJ | 0.01 mg/kg | s/c | 10 min before testing | 9–18 | - | [108] |
Cocaine | DAT, SERT and NET inhibitor | DAT-KO mice 129/C57 | 40 mg/kg | i/p | before testing | 8 | ↑ | [77] |
Amphetamine | DAT, SERT and NET inhibitor, DA and 5-HT receptors agonist | DAT-KO mice C57BL/6 | 1, 3, 10 mg/kg | s/c | before testing | 8–15 | ↑ | [128] |
DAT HET mice C57BL/6 | 1 mg/kg | s/c | before testing | 11–16 | [128] | |||
DAT-KO mice 129/C57 | 0.75 mg/kg | i/p | ? | ? | [77] | |||
2 mg/kg | i/p | before testing | 8 | [77] | ||||
DAT-KO rats Wistar Han | 1, 2, 3, 4 mg/kg | i/p | before testing | 6–19 | [30] | |||
DAT-KD rats F344 | 1 and 2 mg/kg | i/p | 30 min before testing | 7–10 | [72] | |||
DAT-KO mice F1 | 3 mg/kg | i/p | 30 min before testing | 7–11 | [129] | |||
DATKO mice C57Bl/6J | 100 μM/0.5 μL/side | bilateral PFC infusion | before testing | 6–8 | [130] | |||
DAT-KD mice 129 SvyJ | 1, 2, 3 mg/kg | i/p | before testing | 6–8 | [24] | |||
Fluoxetine | SERT inhibitor | DAT-KO mice 129/C57 | 20 mg/kg | s/c | before testing | 6 | - | [77] |
DAT-KO mice C57BL/6 | 20 mg/kg | s/c | before testing | 5 | [128] | |||
DAT-KO mice C57Bl/6J | 20 mg/kg | s/c | before testing | 6–12 | ? | [130] | ||
Quipazine | 5-HT 2A and 5-HT3 agonist | DAT-KO mice 129/C57 | 3 mg/kg | i/p | before testing | 6 | - | [77] |
0.5 mg/kg | i/p | ? | ? | [77] | ||||
5-HTP | serotonine precursor | DAT-KO mice 129/C57 | 50 mg/kg | i/p | before testing | 6 | ↓ | [77] |
10 mg/kg | i/p | ? | ? | - | [77] | |||
L-Tryptophan | serotonine precursor | DAT-KO mice 129/C57 | 100 mg/kg | i/p | before testing | 6 | - | [77] |
10 mg/kg | i/p | ? | ? | [77] | ||||
RO5203648 | partial TAAR1 agonist | DAT-KO rats Wistar Han | 3 mg/kg | i/p | before testing | 6–19 | - | [30] |
RO5166017 | partial TAAR1 agonist | DAT-KO mice C57BL/129SvJ | 0.5 and 1 mg/kg | i/p | before testing | 7–8 | - | [131] |
Apomorphine | DA receptors agonist | DAT-KD mice 129 SvyJ | 0.1, 0.5, 1, 2 mg/kg | s/c | before testing | 6–8 | ↑ | [24] |
Quinpirole | D2/D3 agonist | 0.1, 0.5, 2, 6, 20 mg/kg | i/p | before testing | 6–8 | ↑ | [24] | |
MDMA | DAT, SERT and NET inhibitor, DA and 5-HT receptors agonist | DAT-KO mice C57BL/129SvJ | 20 mg/kg | i/p | 10 min before testing | 7–11 | ↑ | [132] |
SL 327 | MEK inhibitor | DAT-KO mice C57BL/129SvJ | 100 mg/kg | i/p | before testing | 11 | - | [133] |
Reboxetine | NET inhibitor | DAT-KO mice F1 | 5 and 10 mg/kg | i/p | 30 min before testing | 6–18 | - | [129] |
Atomoxetine | DAT-KD rats F344 | 1 and 3 mg/kg | i/p | 30 min before testing | 7–11 | ↓ | [72] | |
Desipramine | DATKO mice C57Bl/6J | 25 mg/kg | i/p | before testing | 6–12 | ? | [130] | |
4 µg/0.5 µL/side | bilateral PFC infusion | |||||||
U99194 | D3 antagonist | DAT-KO mice F1 | 30 and 60 mg/kg | i/p | 30 min before testing | 5–7 | - | [129] |
SB-277011A | D3 antagonist | DAT-KO mice F1 | 3, 10, 30 mg/kg | i/p | 30 min before testing | 5–7 | - | [129] |
LY-341495 | MGluR2 antagonist | DAT-KO rats N157K | 1, 3, 10 mg/kg | i/p | 30 min before testing | 6–9 | - | [72] |
SB 224289 | 5-HT1B antagonist | DAT-KO mice C57BL/129SvJ | 20 mg/kg | i/p | 60 min before testing | 10 | - | [134] |
M100907 | 5-HT2A antagonist | DAT-KO mice C57BL/129SvJ | 0.3 and 1 mg/kg | s/c | 30 min before testing | 10–17 | - | [135] |
Aniracetam | AMPA positive allosteric modulator | DAT-KO mice C57BL/129SvJ | 20 and 50 mg/kg | i/p | before testing | 8–10 | ? | [136] |
CX516 | DAT-KO mice C57BL/129SvJ | 100 mg/kg | s/c | before testing | 6–11 | ? | [136] | |
CX546 | DAT-KO mice C57BL/129SvJ | 50 and 70 mg/kg | s/c | before testing | 6–11 | ? | [136] | |
CX672 | DAT-KO mice C57BL/129SvJ | 1 mg/kg | i/p | before testing | ? | ? | [136] | |
CX776 | DAT-KO mice C57BL/129SvJ | 3 mg/kg | s/c | before testing | ? | ? | [136] | |
Pregnenolone | GABA A and NMDA allosteric modulator | DAT-KO mice C57BL/6 | 30 and 60 mg/kg | i/p | before testing | 10–15 | - | [109] |
Donepezil | cholinesterase inhibitor | DAT-KO mice C57BL/6 | 1 and 3 mg/kg | i/p | 20 min before testing | ? | ↓ | [137] |
Tacrine | DAT-KO mice C57BL/6 | 3, 10, 30 mg/kg | i/p | 20 min before testing | ? | ↓ | [137] | |
VU0152100 | M4 positive allosteric modulator | DAT-KO mice C57BL/6 | 1 mg/kg | i/p | 20 min before testing | 5 | ? | [137] |
AM404 | Anandamide reuptake inhibitor | DAT-KO mice F1 | 0.3, 1, 3 mg/kg | i/p | before testing | 8 | - | [52] |
VDM11 | 2 and 5 mg/kg | i/p | before testing | 6–8 | - | [52] | ||
AA5HT | FAAH inhibitor | 2 and 5 mg/kg | i/p | before testing | 6–8 | - | [52] | |
Valproic acid | Na channels blocker, GABA enhancer | DAT-KD mice 129 SvyJ | 100 mg/kg | i/p | 60 min before testing | 14 | - | [114] |
DAT-KO mice C57BL/129SvJ | 300 mg/kg | i/p | before testing | 8 | ↓ | [138] | ||
LiCl | GSK-3 inhibitor | DAT-KO mice C57BL/129SvJ | 50, 100, 200 mg/kg | i/p | before testing | 9–12 | ? | [138] |
SB 216763 | 3, 5, 10 mg/kg | i/p | before testing | 6–8 | ? | [138] | ||
Indirubin | 10 and 20 mg/kg | i/p | before testing | 8–11 | ? | [138] | ||
Alsterpaullon | 3, 5, 10 mg/kg | i/p | before testing | 8–10 | ? | [138] | ||
TDZD | 30 mg/kg | i/p | before testing | 7 | ? | [138] | ||
ABM300 | CB1R allosteric modulator | DAT-KO mice C57Bl/6J | 10 mg/kg | i/p | 30 min before testing | 10–13 | - | [139] |
Nepicastat | DBH inhibitor | DAT-KO mice C57Bl/6J | 40 mg/kg | i/p | before testing | 6–12 | ? | [130] |
4 µg/0.5 µL/side | bilateral PFC infusion |
7. Conclusions and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Rodent Specie | Stocks and Strains | % of Dopamine Transporter Expression Decrease | Methods and Selectivity | Reference |
---|---|---|---|---|
Mice | C57/B6Jx129/Sv/J and C57/B6J | 100%, DAT-KO | in vivo homologous recombination | [22] |
C57/BLy6J | 100%, DAT-KO | [23] | ||
129 Sv/J | 90%, DAT-KD | [24] | ||
C57/BL6 | 45–50%, DAT lower expresser | Knock-in of hemagglutinin epitope in EL2 | [25] | |
C57BL/6J | Variable (inducible DAT-KD) | Intra-accumbal delivery of DAT shRNA-expressing lentiviral vectors | [26] | |
BALB/c | Intraventricular local nonviral RNA interference | [27] | ||
C57BL6/J | Tetracycline inducible system | [28] | ||
Rats | Fischer 344 | Less than 25%, DAT-KD | N-ethyl-N-nitrosourea-induced spontaneous mutation | [29] |
Wistar Han | 100%, DAT-KO | Zinc finger nuclease technology | [30] | |
Wistar | CRISPR/Cas9 technology | [31] |
Model | Face Validity | Predictive Validity | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Schizophrenia | ADHD | Mania | Drug Dependence | Parkinson Disease | Schizophrenia | ADHD | Mania | Drug Dependence | Parkinson Disease | |
DAT KO | + | + | + | ? | + | ++ | + | ? | ||
DAT KD | - | + | + | + | - | + | ++ | ? | ||
DDD | ++ | ++ |
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Savchenko, A.; Targa, G.; Fesenko, Z.; Leo, D.; Gainetdinov, R.R.; Sukhanov, I. Dopamine Transporter Deficient Rodents: Perspectives and Limitations for Neuroscience. Biomolecules 2023, 13, 806. https://doi.org/10.3390/biom13050806
Savchenko A, Targa G, Fesenko Z, Leo D, Gainetdinov RR, Sukhanov I. Dopamine Transporter Deficient Rodents: Perspectives and Limitations for Neuroscience. Biomolecules. 2023; 13(5):806. https://doi.org/10.3390/biom13050806
Chicago/Turabian StyleSavchenko, Artem, Giorgia Targa, Zoia Fesenko, Damiana Leo, Raul R. Gainetdinov, and Ilya Sukhanov. 2023. "Dopamine Transporter Deficient Rodents: Perspectives and Limitations for Neuroscience" Biomolecules 13, no. 5: 806. https://doi.org/10.3390/biom13050806