Dopamine transporter knockout rats as the new preclinical model of hyper- and hypo-dopaminergic disorders

Sukhanov, I.; Leo, Damiana; Tur, M.; Belozertseva, Irina; Savchenko, A.; Gainetdinov, Raul R.

doi:10.31363/2313-7053-2019-4-1-84-85

Cited by 4 publications

(8 citation statements)

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“…This fact might be also explained by their hyperactivity and perseverations. The inability of DAT-KO rats to immediately focus their attention on the objects presented may be also related to their attention deficit described earlier (Sukhanov et al, 2019).…”

Section: Discussionmentioning

confidence: 77%

“…The strain of rats with deletion of DAT gene (DAT-KO rats) was developed ( Leo et al, 2018a ) to investigate various aspects of DA system dysfunctions with a particular emphasis on cognitive disorders ( Vengeliene et al, 2017 ; Leo et al, 2018b ; Sukhanov et al, 2019 ). DAT-KO rats were described to have increased locomotor activity, an impaired sensorimotor gating, a deficit in operant nose-poke responding reinforced by food pellets, and decreased Y-maze spontaneous alternation.…”

Section: Introductionmentioning

confidence: 99%

“…It was shown that they can learn the behavioral task in an eight-arm radial maze but perform it much less effectively than the control wild-type (WT) rats ( Kurzina et al, 2020 ). Independently developed DAT deficient rats were also hyperactive, failed to show conditioned fear responses, were unable to learn stimulus–reward associations, and showed anhedonia and impaired cognition and social behaviors ( Vengeliene et al, 2017 ; Sukhanov et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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A New Paradigm for Training Hyperactive Dopamine Transporter Knockout Rats: Influence of Novel Stimuli on Object Recognition

Kurzina

Volnova

Aristova

et al. 2021

Front. Behav. Neurosci.

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Attention deficit hyperactivity disorder (ADHD) is believed to be connected with a high level of hyperactivity caused by alterations of the control of dopaminergic transmission in the brain. The strain of hyperdopaminergic dopamine transporter knockout (DAT-KO) rats represents an optimal model for investigating ADHD-related pathological mechanisms. The goal of this work was to study the influence of the overactivated dopamine system in the brain on a motor cognitive task fulfillment. The DAT-KO rats were trained to learn an object recognition task and store it in long-term memory. We found that DAT-KO rats can learn to move an object and retrieve food from the rewarded familiar objects and not to move the non-rewarded novel objects. However, we observed that the time of task performance and the distances traveled were significantly increased in DAT-KO rats in comparison with wild-type controls. Both groups of rats explored the novel objects longer than the familiar cubes. However, unlike controls, DAT-KO rats explored novel objects significantly longer and with fewer errors, since they preferred not to move the non-rewarded novel objects. After a 3 months’ interval that followed the training period, they were able to retain the learned skills in memory and to efficiently retrieve them. The data obtained indicate that DAT-KO rats have a deficiency in learning the cognitive task, but their hyperactivity does not prevent the ability to learn a non-spatial cognitive task under the presentation of novel stimuli. The longer exploration of novel objects during training may ensure persistent learning of the task paradigm. These findings may serve as a base for developing new ADHD learning paradigms.

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Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A New Paradigm for Training Hyperactive Dopamine Transporter Knockout Rats: Influence of Novel Stimuli on Object Recognition

Kurzina

Volnova

Aristova

et al. 2021

Front. Behav. Neurosci.

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“…Although GBR 12909 also showed proarrhythmic potential in humans, indicating prolonged QTc interval on electrocardiogram (Rothman et al, 2008), clinical GBR 12909 safety studies did not reveal behavioral alterations in humans, unlike other DAT blockers (e.g., cocaine) (Preti, 2000;Tella et al, 1996). However, acute GBR 12909 induced overt hypolocomotion in adult zebrafish, a profile in line with some genetic (e.g., rodent DAT knockout (Cinque et al, 2018;Spielewoy et al, 2001)) or pharmacological (e.g., amphetamine-treated rodents (Cinque et al, 2018;Sukhanov et al, 2019) and zebrafish (Cleal et al, 2021b)) models of DAT deficits. Furthermore, GBR 12909-induced hypolocomotion in zebrafish is unlikely due to putative cardiotoxicity, as no data from studying other cardiotoxic agents link hypolocomotion and cardiotoxicity (Heideman et al, 2005;Wiprich et al, 2020;Yang et al, 2022).…”

Section: Discussionmentioning

confidence: 90%

Behavioral profile of adult zebrafish acutely exposed to a selective dopamine uptake inhibitor, GBR 12909

et al. 2023

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Background: The dopamine transporter (DAT) is the main regulator of dopamine concentration in the extrasynaptic space. The pharmacological inhibition of the DAT results in a wide spectrum of behavioral manifestations, which have been identified so far in a limited number of species, mostly in rodents. Aim: Here, we used another well-recognized model organism, the zebrafish ( Danio rerio), to explore the behavioral effects of GBR 12909, a highly-affine selective DAT blocker. Methods: We evaluated zebrafish locomotion, novelty-related exploration, spatial cognition, and social phenotypes in the novel tank, habituation and shoaling tests, following acute 20-min water immersion in GBR 12909. Results: Our findings show hypolocomotion, anxiety-like state, and impaired spatial cognition in fish acutely treated with GBR 12909. This behavioral profile generally parallels that of the DAT knockout rodents and zebrafish, and it overlaps with behavioral effects of other DAT-inhibiting drugs of abuse, such as cocaine and D-amphetamine. Conclusion: Collectively, our data support the utility of zebrafish in translational studies on DAT targeting neuropharmacology and strongly implicate DAT aberration as an important mechanisms involved in neurological and psychiatric diseases.

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“…The DAT‐KO rat line was developed (Leo, Sukhanov & Gainetdinov, 2018) to investigate various aspects of DA system dysfunction (Sukhanov et al, 2019; Vengeliene et al, 2017). Over the past few years, adult DAT‐KO rats were described to have increased locomotor activity, impaired sensorimotor gating, deficits in operant nose‐poke responding reinforced by food pellets, decreased Y‐maze spontaneous alternation, impairments of working memory, and significant dysregulation in frontostriatal brain‐derived neurotrophic factor function (Adinolfi et al, 2018; Cinque et al, 2018; Kurzina et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Antioxidant system alterations and physiological characteristics of neonatal and juvenile DAT‐KO rats

Apryatin

Traktirov

Karpenko

et al. 2023

J of Neuroscience Research

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Dopamine transporter knockout (DAT‐KO) rats represent a valuable rodent model for studying the molecular and phenotypical outcomes of the effects of excessive dopamine accumulation in the synaptic cleft and the prolonged action of dopamine on neurons. Animals with DAT deficiency are characterized by hyperactivity, stereotypy, cognitive deficits, and impairments in behavioral and biochemical indicators. Several key pathophysiological mechanisms are known to be common to psychiatric, neurodegenerative, metabolic, and other diseases. Among these mechanisms, oxidative stress systems play a particularly important role. One of the main antioxidant systems in the brain is glutathione: specifically, glutathione S‐transferase, glutathione reductase, and catalase play a significant role in the regulation of vital oxidative processes, and their dysfunction has been shown in Parkinson's disease, Alzheimer's disease, and other neurodegenerative diseases. The current study aimed to analyze the dynamics of the activity levels of glutathione reductase and glutathione S‐transferase in erythrocytes, as well as catalase in the blood plasma, of DAT‐deficient, homo‐ and heterozygous, neonatal and juvenile rats (both male and female). Their behavioral and physiological parameters were evaluated at the age of 1.5 months. For the first time, changes in physiological and biochemical parameters were shown in DAT‐KO rats at 1.5 months of postnatal life. The key role of glutathione S‐transferase, glutathione reductase, and catalase in the regulation of oxidative stress in DAT‐KO rats at the 5th week of life was demonstrated. A positive effect of a slightly increased dopamine level on memory function was shown in DAT‐heterozygous animals.

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Dopamine transporter knockout rats as the new preclinical model of hyper- and hypo-dopaminergic disorders

Cited by 4 publications

References 0 publications

A New Paradigm for Training Hyperactive Dopamine Transporter Knockout Rats: Influence of Novel Stimuli on Object Recognition

A New Paradigm for Training Hyperactive Dopamine Transporter Knockout Rats: Influence of Novel Stimuli on Object Recognition

Behavioral profile of adult zebrafish acutely exposed to a selective dopamine uptake inhibitor, GBR 12909

Antioxidant system alterations and physiological characteristics of neonatal and juvenile DAT‐KO rats

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