• Neuroscience · May 2022

    Dopamine dysregulation and altered responses to drugs affecting dopaminergic transmission in a new dopamine transporter knockout (DAT-KO) rat model.

    • Jordan T Lloyd, Andrew G Yee, Prasanna K Kalligappa, Anower Jabed, Pang Y Cheung, Kathryn L Todd, Rashika N Karunasinghe, Srdjan M Vlajkovic, Peter S Freestone, and Janusz Lipski.
    • Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. Electronic address: jtonylloyd@gmail.com.
    • Neuroscience. 2022 May 21; 491: 43-64.

    AbstractUnder normal conditions, dopamine (DA) clearance after release largely depends on uptake by the DA transporter (DAT). DAT expression/activity is reduced in some neuropsychiatric and neurological disorders. Our aim was to characterize the behavioral, neurochemical and electrophysiological effects of eliminating DAT in a novel knockout rat model we generated using CRISPR/Cas9. Consistent with existing DAT-KO models, our DAT-KO rats displayed increased locomotion, paradoxical calming by amphetamine, and reduced kinetics of DA clearance after stimulated release. Reduced DA kinetics were demonstrated using fast-scan cyclic voltammetry in brain slices containing the striatum or substantia nigra pars compacta (SNc) and in the dorsal striatum in vivo. Cocaine enhanced DA release in wild-type (WT) but not DAT-KO rats. Basal extracellular DA concentration measured with fast-scan controlled-adsorption voltammetry was higher in DAT-KO rats both in the striatum and SNc and was enhanced by L-DOPA (particularly after pharmacological block of monoamine oxidase), confirming that DA release after L-DOPA is not due to DAT reversal. The baseline firing frequency of SNc neurons was similar in both genotypes. However, D2 receptor-mediated inhibition of firing (by quinpirole or L-DOPA) was blunted in DAT-KO rats, while GABAB-mediated inhibition was preserved. We have also provided new data for the DAT-KO rat regarding the effects of slowing DA diffusion with dextran and blocking organic cation transporter 3 with corticosterone. Together, our results validate our DAT-KO rat and provide new insights into the mechanisms of chronic dysregulation of the DA system by addressing several unresolved issues in previous studies with other DAT-KO models.Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.

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