Modulation of Spatial Memory Deficit and Hyperactivity in Dopamine Transporter Knockout Rats

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.