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.

Keywords: ADHD model; attention; dopamine (DA); dopamine transporter knockout (DAT-KO) rats; guanfacine (GF); norepinephrine (NE); spatial working memory.

Figure 1

Samples of the visual tracks in the WT rats (A) and DAT-KO rats (B) in the Hebb–Williams maze. Error zones are indicated in grey color, the circle—the place of food reward.

Figure 2

Comparison of the distance traveled (in cm), (A) and the time for reaching the goal box (in s), (B) of the Hebb–Williams maze in DAT-KO and WT rats after saline, acute (aGF) and repeated (rGF) guanfacine administration. Results are presented as the mean ± SEM, # p < 0.05; ## p < 0.01, Wilcoxon signed rank test; * p < 0.05; two-way ANOVA test combined with Sidak’s multiple comparisons post-hoc test.

Figure 3

Comparison of the percentage of time spent in the Hebb–Williams maze error zones (in %), (A) and the number of return runs (B) by the DAT-KO and WT rats after saline, acute (aGF), and repeated (rGF) guanfacine administration. Results are presented as the mean ± SEM; ### p < 0.001, #### p < 0.0001; * p < 0.05, ** p < 0.01, two-way ANOVA test combined with Sidak’s multiple comparisons post-hoc test.

Figure 4

Comparison of the amplitude of the acoustic startle reaction (ASR, in mV) in DAT-KO and WT rats after saline (A), acute (B) and repeated (C) guanfacine administration. Results are presented as the mean ± SEM; ## p < 0.01, #### p < 0.0001, ** p < 0.01, **** p < 0.0001 according the Mann–Whitney test.

Figure 5

Pre-pulse inhibition (PPI) in DAT-KO and WT rats after saline, acute (aGF) and repeated (rGF) guanfacine administration; comparison of the groups of animals of different genotypes (A) and comparison of the effect of the administered drugs (B). Results are presented as the mean ± SEM; ** p < 0.01 according to Fisher’s LSD post-test; # p < 0.05; ns–(not significant) two-way ANOVA and Dunn’s multiple comparisons post-hoc test.

Figure 6

Power spectra of the brain activity in DAT-KO and WT rats recorded from the striatum (Str) after saline, acute (aGF) and repeated (rGF) guanfacine administration; (A) 1–20 Hz range, (B) 20–75 Hz range. Data are presented as the mean ± SEM. The diagrams represent the following electroencephalographic rhythms (in Hz): delta (0.9–3), theta (4–8), alpha (9–11), lower beta (12–19), higher beta (20–29), lower gamma (30–48), higher gamma (52–74); one-way ANOVA, * p < 0.05; *** p < 0.001; **** p < 0.0001 post test for the linear trend; ** p < 0.01 Dunnett’s multiple comparisons test.

Figure 7

Power spectra of the brain activity of DAT-KO and WT rats recorded from the prefrontal cortex (PFC) after saline, acute (aGF) and repeated (rGF) guanfacine administration; (A) 1–20 Hz range, (B) 20–75 Hz range. Data are presented as mean ± SEM. The diagrams represent the following electroencephalographic rhythms (in Hz): delta (0.9–3), theta (4–8), alpha (9–11), lower beta (12–19), higher beta (20–29), lower gamma (30–48), higher gamma (52–74); one-way ANOVA, **** p < 0.0001 post test for the linear trend; * p < 0.05; ** p < 0.01 Dunnett’s multiple comparisons test.

Figure 8

Coherence of the brain activity in PFC and Str in DAT-KO and WT rats after saline, acute (aGF) and repeated (rGF) guanfacine administration. Degree of coherence is expressed in fractions of one. Data are presented as the mean ± SEM. The diagrams represent the following electroencephalographic rhythms (in Hz): delta (0.9–3), theta (4–8), alpha (9–11), lower beta (12–19), higher beta (20–29), lower gamma (30–48), higher gamma (52–74); two-way ANOVA, ** p < 0.01 **** p < 0.0001 post test for the linear trend and Dunnett’s multiple comparisons test.