Prefrontal and Monoaminergic Contributions to Stop-Signal Task Performance in Rats

Abstract

Defining the neural and neurochemical substrates of response inhibition is of crucial importance for the study and treatment of pathologies characterized by impulsivity such as attention-deficit/hyperactivity disorder and addiction. The stop-signal task (SST) is one of the most popular paradigms used to study the speed and efficacy of inhibitory processes in humans and other animals. Here we investigated the effect of temporarily inactivating different prefrontal subregions in the rat by means of muscimol microinfusions on SST performance. We found that dorsomedial prefrontal cortical areas are important for inhibiting an already initiated response. We also investigated the possible neural substrates of the selective noradrenaline reuptake inhibitor atomoxetine via its local microinfusion into different subregions of the rat prefrontal cortex. Our results show that both orbitofrontal and dorsal prelimbic cortices mediate the beneficial effects of atomoxetine on SST performance. To assess the neurochemical specificity of these effects, we infused the ␣2-adrenergic agonist guanfacine and the D 1 /D 2 antagonist ␣-flupenthixol in dorsal prelimbic cortex to interfere with noradrenergic and dopaminergic neurotransmission, respectively. Guanfacine, which modulates noradrenergic neurotransmission, selectively impaired stopping, whereas blocking dopaminergic receptors by ␣-flupenthixol infusion prolonged go reaction time only, confirming the important role of noradrenergic neurotransmission in response inhibition. These results show that, similar to humans, distinct networks play important roles during SST performance in the rat and that they are differentially modulated by noradrenergic and dopaminergic neurotransmission. This study advances our understanding of the neuroanatomical and neurochemical determinants of impulsivity, which are relevant for a range of psychiatric disorders.

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.…”

“…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

“…It has been shown that mPFC is both affected by PNE and is critical for normal performance on stop-signal paradigms (Bari et al, 2011;Schneider et al, 2011;Zhu et al, 2012). Here, we show that PNE makes rats more impulsive and attenuates neural selectivity related to the direction of the response and monitoring of conflict in mPFC.…”

“…This is surprising considering the number of studies that have implicated mPFC in inhibitory control. For instance, perturbation of the rat prelimbic prefrontal cortex reveals stop-signal reaction time deficits (Bari et al, 2011) and increased premature responses during performance of reaction time tasks (Pezze et al, 2014;Risterucci et al, 2003). However, similar approaches have yielded conflicting results (Christakou et al, 2001;Eagle et al, 2008;Eagle and Robbins, 2003).…”

Chronic Corticosterone Exposure during Adolescence Reduces Impulsive Action but Increases Impulsive Choice and Sensitivity to Yohimbine in Male Sprague-Dawley Rats

“…For example, whereas yohimbine-induced impulsivity involves activation of specific signaling cascades in the lOFC (Sun et al, 2010), lesions of the infralimbic region of PFC, not lOFC, have been reported to increase impulsive responding in the face of increasing ITIs on the 5CSRTT (Chudasama et al, 2003). Similarly, behavioral inhibition on the SSRTT may be more dependent on dorsal medial PFC and dorsal striatal activity (Bari et al, 2011;Eagle and Robbins, 2003a;Eagle et al, 2011), whereas choice behavior on the delay-discounting task may be more dependent on a circuit involving the lOFC and ventral striatum (Bezzina et al, 2008;Bezzina et al, 2007;Mobini et al, 2002). Whatever the mechanism, an increase in the likelihood of making impulsive decisions, particularly for immediate 'gratification', could certainly put individuals at a higher risk for developing addictive disorders.…”