Modulation of Spatial Memory Deficit and Hyperactivity in Dopamine Transporter Knockout Rats via α2A-Adrenoceptors

Abstract

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.

Targeting neuroinflammation with Abscisic Acid reduces pain sensitivity in females and hyperactivity in males of an ADHD mice model

“…In addition, in this study, we compared the effect of the dopaminergic lesion and ABA administration between female and male subjects. We found that dopaminergic lesion increased spontaneous activity in two-month-old males in agreement with findings in adolescent male mice [44,58], and in the DAT-KO rats (another model of dopaminergic dysfunction) [59]. Interestingly, the same lesion did not affect female´s activity, to our knowledge, this is the first comparative study, and our finding suggests a sex-dependent effect that may reflect the symptomatology in humans, where hyperactivity is found more prevalent in boys than girls [60].…”

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

“…During the experiments, we measured the following behavioral variables: distance traveled, time to reach the goal box, number of entries into the error zones, time spent in the error zones and number of returns. DAT-KO rats exhibited hyperactivity and stereotypy throughout all stages of the experiment, including the pre-training and training stages, which was described in a previous article [ 26 ].…”

“…Due to the pronounced behavioral phenotype, DAT-KO rats have been proposed as an animal model of attention deficit and hyperactivity disorder (ADHD), following their well-studied mouse counterpart [ 22 , 26 , 27 , 28 ]. In this study, we investigated the behavior and electrophysiological parameters of DAT-KO rats under atomoxetine, which has been shown to improve all three major aspects of ADHD—hyperactivity, inattention and impulsivity [ 15 , 16 ]—through an increase in extracellular levels of DA and NE in NET enriched areas [ 29 , 30 , 31 , 32 ].…”

“…NET blockade has been shown to inhibit hyperactivity in DAT-KO mice [ 13 , 49 ] by nisoxetine and desipramine, see also [ 26 ]. In our study, atomoxetine failed to produce a similar result in DAT-KO rats.…”

“…Despite the previously explored assumption that it is DA that plays the main role in the effects of NET inhibition in DAT-KO and ADHD, we hypothesize that sensorimotor gating and repetitive behaviors are mediated by ATX mainly through NE. This assumption is based on our previous finding that guanfacine, an α2-adrenergic agonist, produced a very similar effect on PPI (unpublished data) and the number of perseverative returns [ 26 ], but did not affect hyperactivity or the number of errors (although the time spent in errors zones decreased) [ 26 ]. Therefore, our findings may indicate a crucial role of prefrontal NE in involuntary attention and repetitive behavior, while hyperactivity and, possibly, attentional deficits are more likely to be mediated by DA in the PFC.…”