Dopamine Transporter Deficient Rodents: Perspectives and Limitations for Neuroscience

Abstract

The key element of dopamine (DA) neurotransmission is undoubtedly DA transporter (DAT), a transmembrane protein responsible for the synaptic reuptake of the mediator. Changes in DAT’s function can be a key mechanism of pathological conditions associated with hyperdopaminergia. The first strain of gene-modified rodents with a lack of DAT were created more than 25 years ago. Such animals are characterized by increased levels of striatal DA, resulting in locomotor hyperactivity, increased levels of motor stereotypes, cognitive deficits, and other behavioral abnormalities. The administration of dopaminergic and pharmacological agents affecting other neurotransmitter systems can mitigate those abnormalities. The main purpose of this review is to systematize and analyze (1) known data on the consequences of changes in DAT expression in experimental animals, (2) results of pharmacological studies in these animals, and (3) to estimate the validity of animals lacking DAT as models for discovering new treatments of DA-related disorders.

Rats Lacking the Dopamine Transporter Display Inflexibility in Innate and Learned Behavior

“…In Experiment 3, we presented a similar task (operant schedule "progressive ratio 3") to DAT-KO rats. First of all, in accordance with our previous results [12], the DAT-KO rats demonstrated a changed pattern of lever pressing in comparison with the WT rats. The low FRs time between lever pressings was longer in DAT-KO than in WT rats, at a high FR, conversely, knockout rodents performed lever pressings more frequently and the interval between pressings became shorter than in control animals.…”

“…Abnormalities in DA-ergic system functioning lead to the development of different neurological diseases [ 7 , 8 ]. In the search for and development of new therapeutic approaches for the treatment of these diseases, different animal models were created [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. Rodents (mice and rats) with a knockout of the gene encoding the dopamine reuptake transporter protein (DAT-KO) are one of the most popular models of hyperdopaminergia [ 4 , 16 , 17 , 18 ].…”

Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays

“…To evaluate the in vivo pharmacological effect of guanfacine, we used a rodent model of hyperdopaminergia, the dopamine transporter knockout (DAT-KO) rats, that also mimics some phenotypic aspect of ADHD and has certain predictive validity for the search of novel pharmacological agents to control hyperactivity and cognitive processes in patients with this disease [71,72]. In fact, guanfacine demonstrated significant positive effects in tests aimed at evaluating cognitive dysfunction of DAT-KO rats [73].…”

Alterations in surface-based amplitude of low-frequency fluctuations primary open-angle glaucoma link to neurotransmitter profiling and visual impairment severity

“…The dopamine transporter (DAT) demonstrates signi cant performance solely in fALFF, which plays a crucial role in dopamine neurotransmission, and dysfunction in DAT function can contribute to pathological conditions associated with hyperdopaminergic [93] . Gene-modi ed rodents lacking DAT exhibit elevated levels of striatal dopamine, leading to behavioral abnormalities and cognitive de cits [94] .…”