Noradrenergic Modulation of Learned and Innate Behaviors in Dopamine Transporter Knockout Rats by Guanfacine

Abstract

Investigation of the precise mechanisms of attention deficit and hyperactivity disorder (ADHD) and other dopamine-associated conditions is crucial for the development of new treatment approaches. In this study, we assessed the effects of repeated and acute administration of α2A-adrenoceptor agonist guanfacine on innate and learned forms of behavior of dopamine transporter knockout (DAT-KO) rats to evaluate the possible noradrenergic modulation of behavioral deficits. DAT-KO and wild type rats were trained in the Hebb–Williams maze to perform spatial working memory tasks. Innate behavior was evaluated via pre pulse inhibition (PPI). Brain activity of the prefrontal cortex and the striatum was assessed. Repeated administration of GF improved the spatial working memory task fulfillment and PPI in DAT-KO rats, and led to specific changes in the power spectra and coherence of brain activity. Our data indicate that both repeated and acute treatment with a non-stimulant noradrenergic drug lead to improvements in the behavior of DAT-KO rats. This study further supports the role of the intricate balance of norepinephrine and dopamine in the regulation of attention. The observed compensatory effect of guanfacine on the behavior of hyperdopaminergic rats may be used in the development of combined treatments to support the dopamine–norepinephrine balance.

A Custom Solution for Acoustic Startle Response Setup with Spike2-Based Data Acquisition Interface

“…The presented software for CED interface offers an affordable and straightforward approach for performing experiments on PPI of acoustic startle response. Similar to earlier articles [ 9 , 10 ], this study showed high effectiveness and valid output results.…”

“…According to the results of experiments in mice (males and females), DAT-KO animals demonstrated a reduced prepulse inhibition compared to WT mice [ 8 , 17 ]. According to the results of our previous experiments in male DAT knockout rats [ 9 , 10 ], ASR in response to single pulses was generally higher than to prepulse+pulse pairs, and PPI in male DAT-KO rats was significantly lower than in male WT rats. The data obtained in female WT and DAT-KO rats show the same tendency; ASR to single pulses is higher than ASR to prepulse+pulse pairs, and PPI in female DAT-KO rats is reduced compared to that in female WT.…”

“…PPI is commonly performed in animal models of human disease to investigate mechanisms of impairment and drug testing. [ 4 , 8 , 9 , 10 ]. Various types of startle stimuli are applied, including acoustic, visual, and tactile [ 3 , 4 ].…”

“…The software has been successfully used in our previous studies, and the results have been published earlier [ 9 , 10 ]. The current paper provides an example of using Spike2-based data acquisition interface to assess PPI in wild-type and knockout rats.…”

Neural Correlates and Molecular Mechanisms of Memory and Learning

“…However, the neural and molecular mechanisms that underlie these cognitive functions are not fully elucidated. For decades, researchers have been fascinated by the neurobiological and molecular basis of acquiring, storing, and retrieving information [ 1 ]. Recent neuroimaging technologies have provided valuable insights into underlying neuroanatomical brain circuits [ 2 , 3 , 4 , 5 , 6 , 7 ].…”