Attention deficit hyperactivity disorder (ADHD) is manifested by a specific set of behavioral deficits such as hyperactivity, impulsivity, and inattention. The dopamine neurotransmitter system is postulated to be involved in the pathogenesis of ADHD. Guanfacine, a selective α2A-adrenoceptor agonist, is prescribed for ADHD treatment. ADHD also is known to be associated with impairment of multiple aspects of cognition, including spatial memory, however, it remains unclear how modulation of the norepinephrine system can affect these deficits. Hyperdopaminergic dopamine transporter knockout (DAT-KO) rats are a valuable model for investigating ADHD. The DAT-KO rats are hyperactive and deficient in spatial working memory. This work aimed to evaluate the effects of noradrenergic drugs on the fulfillment of spatial cognitive tasks by DAT-KO rats. The rats were tested in the Hebb – Williams maze during training and following noradrenergic drugs administration. The efficiency of spatial orientation was assessed as to how fast the animal finds an optimal way to the goal box. Testing in a new maze configuration allowed us to evaluate the effects of drug administration after the acquisition of the task rules. The behavioral variables such as the distance traveled, the time to reach the goal box, and the time spent in the error zones were analyzed. It has been observed that α2A-adrenoceptor agonist Guanfacine (0.25 mg/kg) had only a minimal inhibitory effect on hyperactivity of DAT-KO rats in the maze but significantly ameliorated their perseverative pattern of activity and reduced the time spent in the error zones. In contrast, α2A-adrenoceptor antagonist Yohimbine, at the dose of 1 mg/kg, increased the distance traveled by DAT-KO rats and elevated the number of perseverative reactions and the time spent in the error zones. Guanfacine caused minimal effects in wild-type rats, while Yohimbine altered several parameters reflecting a detrimental effect on the performance in the maze. These data indicate that modulation of α2A-adrenoceptor activity potently affects both dopamine-dependent hyperactivity and cognitive dysfunctions. Similar mechanisms may be involved in the beneficial effects of Guanfacine on cognitive deficits in ADHD patients. This study further supports the translational potential of DAT-KO rats for testing new pharmacological drugs.

Playing a key role in the organization of striatal motor output, the dopamine (DA)-ergic system regulates both innate and complex learned behaviors. Growing evidence clearly indicates the involvement of the DA-ergic system in different forms of repetitive (perseverative) behavior. Some of these behaviors accompany such disorders as obsessive–compulsive disorder (OCD), Tourette’s syndrome, schizophrenia, and addiction. In this study, we have traced how the inflexibility of repetitive reactions in the recently developed animal model of hyper-DA-ergia, dopamine transporter knockout rats (DAT-KO rats), affects the realization of innate behavior (grooming) and the learning of spatial (learning and reversal learning in T-maze) and non-spatial (extinction of operant reaction) tasks. We found that the microstructure of grooming in DAT-KO rats significantly differed in comparison to control rats. DAT-KO rats more often demonstrated a fixed syntactic chain, making fewer errors and very rarely missing the chain steps in comparison to control rats. DAT-KO rats’ behavior during inter-grooming intervals was completely different to the control animals. During learning and reversal learning in the T-maze, DAT-KO rats displayed pronounced patterns of hyperactivity and perseverative (stereotypical) activity, which led to worse learning and a worse performance of the task. Most of the DAT-KO rats could not properly learn the behavioral task in question. During re-learning, DAT-KO rats demonstrated rigid perseverative activity even in the absence of any reinforcement. In operant tasks, the mutant rats demonstrated poor extinction of operant lever pressing: they continued to perform lever presses despite no there being reinforcement. Our results suggest that abnormally elevated DA levels may be responsible for behavioral rigidity. It is conceivable that this phenomenon in DAT-KO rats reflects some of the behavioral traits observed in clinical conditions associated with endogenous or exogenous hyper-DA-ergia, such as schizophrenia, substance abuse, OCD, patients with Parkinson disease treated with DA mimetics, etc. Thus, DAT-KO rats may be a valuable behavioral model in the search for new pharmacological approaches to treat such illnesses.

Study of peculiarities of formation of preference in use of one of forepaws at learning of the manipulatory food-procuring skill has been carried out at different stages of early ontogenesis of white...