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

Abstract

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.

Effects of Atomoxetine on Motor and Cognitive Behaviors and Brain Electrophysiological Activity of Dopamine Transporter Knockout Rats

“…In this study we demonstrate, not for the first time [ 22 , 40 , 41 ], the ADHD-like phenotype of DAT-KO rats: in the Hebb–Williams maze, compared to WT, DAT-KO rats made more errors, took a longer time and traveled a longer distance to reach the goal box and exhibited perseverative returns. Errors, time and distance are parameters that may be interpreted in different ways to indicate hyperactivity, impulsivity, deficient attention and working memory, while the number of return runs indicates repetitive (perseverative) behaviors of DAT-KO rats.…”

Attention-deficit/hyperactive disorder updates

“…DAT -knockout rats show impairment in learning the cognitive task, however, their hyperactivity does not prevent the capability to learn a non-spatial cognitive task in the appearance of novel stimuli ( Kurzina et al, 2021 ). Importantly, DAT genetic hypofunction in mice produced alterations consistent with ADHD, but not with schizophrenia or bipolar disorders ( Mereu et al, 2017 ) in one study, but it was shown in another study that DAT silencing in the rat produces abnormalities in the prefrontal-midbrain and in striato-cerebellar circuits leading to motor hyperactivity and compulsive-like behaviors applicable for ADHD, schizophrenia, and obsessive-compulsive disorder ( Reinwald et al, 2022 ).…”

The Lack of Dopamine Transporter Is Associated With Conditional Associative Learning Impairments and Striatal Proteomic Changes

“…Flagel et al (41) showed that novelty-seeking behaviors can be predictive for a behavioral strategy involved in Pavlovian conditioning: high responders to novelty consistently learn a sign-tracking CR whereas low responders to novelty consistently learn a goal-tracking CR. However, there are controversial studies for the DAT-KO rats in novelty detection (23,42).…”

“…Comparable to DAT-KO mice (21), DAT-KO rats weigh less than heterozygote (HT) and wild-type (WT) rats, demonstrating dramatically increased locomotor activity and prominent motor and oral stereotypies (19,22). Mutant rats also display impaired working memory (8), changes in learning an object recognition task (23), and altered male sexual behavior (24).…”