Dissociable effects of noradrenaline, dopamine, and serotonin uptake blockade on stop task performance in rats

Abstract

Rationale The stop-signal paradigm measures the ability to stop a motor response after its execution has been initiated. Impairments in inhibiting inappropriate behavior and prolonged stop-signal reaction times (SSRTs) are characteristic of several psychiatric disorders, most notably attention deficit/hyperactivity disorder. While there is relative consensus regarding the anatomical substrates of behavioral inhibition, the neurochemical imbalance responsible for the deficits in stopping displayed by impulsive individuals is still a matter of debate. Objective The aim of this study was to investigate the effects of manipulating brain monoamine levels on stop task parameters. Methods Lister-hooded rats were trained on the rodent version of the stop-signal task and administered different monoamine transporter inhibitors: citalopram, which selectively blocks the serotonin transporter; atomoxetine, which selectively blocks the noradrenaline transporter; and GBR-12909, which selectively blocks the dopamine transporter (DAT), and the alpha-2 adrenergic agonist guanfacine. Results Atomoxetine speeded SSRT and increased accuracy for go-trials. Citalopram slowed go reaction time and decreased go accuracy at the highest dose (1 mg/kg). GBR-12909 speeded go reaction time and impaired both go and stop accuracy. Guanfacine negatively modulated all principal stop and go measures at the highest dose used (0.3 mg/kg). Conclusions The results suggest that atomoxetine exerts its beneficial effects on SSRT via its action on noradrenaline re-uptake, as the specific DAT blocker GBR-12909 and serotonin reuptake blockade had only minor effects on SSRT. The speeding of the go reaction time by dopamine reuptake blockade is consistent with the hypothesis that the hypothetical stop and go processes are modulated by distinct monoaminergic systems.

A Novel Translational Assay of Response Inhibition and Impulsivity: Effects of Prefrontal Cortex Lesions, Drugs Used in ADHD, and Serotonin 2C Receptor Antagonism

“…Our data were consistent with findings in people and previous rat models (Aron et al, 2003;Bari et al, 2009;Bari et al, 2011;Broos et al, 2012;Chamberlain et al, 2006;Eagle et al, 2007;Tannock et al, 1989) and showed that the general ability of these drugs to enhance stopping in the SSRTT extended to mice. The effects of both drugs were dose dependent with the inhibition-promoting effects being lost at higher doses, presumably as a result of a relative reduction in pharmacological selectivity.…”

“…To enable crossspecies comparisons, we used the same dose ranges used in previous SSRTT studies in rats (Bari et al, 2009;Eagle et al, 2007). These doses ranges have been shown to be effective in other behavioral tasks in mice (Davis and Gould, 2007;Griffin et al, 2013) and lead to systematic changes in monoamine release in mouse mPFC assessed using microdialysis (Koda et al, 2010).…”

“…The SSRTT measures the ability to stop or cancel a motor action once started in response to a 'stop-signal' and detects inhibitory deficits in pathological conditions such as ADHD (Alderson et al, 2007;Robbins, 2007). Rats can learn this task and show similar speeds of reaction and sensitivity to task manipulations as people; they also show a similar pattern of effects to drug challenges, most notably recapitulating the inhibitionenhancing properties of the clinically effective drugs methylphenidate and atomoxetine (Bari et al, 2009(Bari et al, , 2011Broos et al, 2012;Eagle et al, 2007).…”

Prenatal Nicotine Exposure Impairs Executive Control Signals in Medial Prefrontal Cortex

“…Taken together, this work points to mPFC as a critical player during response inhibition and suggests that reduced prefrontal activation/function in disorders such as ADHD drive behavioral impairments (Euston et al, 2012). Consistent with this hypothesis, patients diagnosed with ADHD have been successfully treated with the noradrenaline and dopamine (eg, methylphenidate and atomoxetine) reuptake inhibitors (Aron et al, 2003;Bari et al, 2009;Bedard et al, 2003;DeVito et al, 2009;Robinson et al, 2008;Tannock et al, 1989) that have been shown to impact prefrontal cortex in both humans and rats. For instance, in humans, atomoxetine administration increases inferior frontal activity in human participants (Chamberlain et al, 2009) and methylphenidate reverses ADHD-associated hypofrontality (Vaidya et al, 1998).…”

Serotonin and Dopamine: Unifying Affective, Activational, and Decision Functions

“…Thus, studies in rats and humans have shown that manipulating 5-HT does not affect performance on tasks of inhibition that have no clear affective component, such as the stop-signal reaction-time task Cools et al, 2005;Chamberlain et al, 2006;Bari et al, 2009;Eagle et al, 2009), the self-ordered spatial working memory task (Walker et al, 2009), and the go-nogo task (Rubia et al, 2005;Evers et al, 2006) (but see LeMarquand et al, 1999).…”