Adaptive aspects of impulsivity and interactions with effects of catecholaminergic agents in the 5-choice serial reaction time task: implications for ADHD

Abstract

Background Work in humans has shown that impulsivity can be advantageous in certain settings. However, evidence for so-called functional impulsivity is lacking in experimental animals. Aims This study investigated the contexts in which high impulsive (HI) rats show an advantage in performance compared with mid- (MI) and low impulsive (LI) rats. We also assessed the effects of dopaminergic and noradrenergic agents to investigate underlying neurotransmitter mechanisms. Methods We tested rats on a variable inter-trial interval (ITI) version of the 5-choice serial reaction time task (5CSRTT). Rats received systemic injections of methylphenidate (MPH, 1 mg/kg and 3 mg/kg), atomoxetine (ATO, 0.3 mg/kg and 1 mg/kg), amphetamine (AMPH, 0.2 mg/kg), the alpha-2a adrenoceptor antagonist atipamezole (ATI, 0.3 mg/kg) and the alpha-1 adrenoceptor agonist phenylephrine (PHEN, 1 mg/kg) prior to behavioural testing. Results Unlike LI rats, HI rats exhibited superior performance, earning more reinforcers, on short ITI trials, when the task required rapid responding. MPH, AMPH and ATI improved performance on short ITI trials and increased impulsivity in long ITI trials, recapitulating the behavioural profile of HI. In contrast, ATO and PHEN impaired performance on short ITI trials and decreased impulsivity, thus mimicking the behavioural profile of LI rats. The effects of ATO were greater on MI rats and LI rats. Conclusions These findings indicate that impulsivity can be advantageous when rapid focusing and actions are required, an effect that may depend on increased dopamine neurotransmission. Conversely, activation of the noradrenergic system, with ATO and PHEN, led to a general inhibition of responding.

Noradrenergic deficits contribute to apathy in Parkinson’s disease through the precision of expected outcomes

“…It is possible that the changes in prior weighting are related to atomoxetine-induced changes in arousal (Berridge & Waterhouse, 2003). Atomoxetine can have mild sedative effects, increasing omission errors and decreasing response accuracy specifically in the context of rapid stimulus presentation (Toschi et al, 2021). However, atomoxetine did not affect basic task performance in the current study or in a stopsignal task, either at the group-average level or in relation to individual differences in locus coeruleus CNR (O'Callaghan et al, 2021).…”

Theory of visual attention (TVA) applied to rats performing the 5-choice serial reaction time task: differential effects of dopaminergic and noradrenergic manipulations

“…Milstein et al 2010). Furthermore, we conducted a dose-response study on the effects of 1 and 3 mg/kg MPH on a vITI-5CSRTT paradigm showing that 1 mg/kg (as opposed to 3 mg/kg) MPH improved performance (more rewards earned) on the 5 s ITI (the ITI used in the present study), while not increasing premature responding to the same extend as 3 mg/kg MPH (Toschi et al 2021). The 0.2 mg/kg AMPH dose was chosen based on a previous dose-response study showing improved attention in a signal detection task after an equivalent low-dose AMPH, as opposed to higher doses (1.25 mg/kg), which impaired attention (Turner and Burne 2016).…”

“…Despite clinical studies indicating cognitive enhancing effects of stimulants, studies using the standard 5CSRTT in intact rodents generally fail to find consistent pro-attentional effects on the accuracy variable after clinically relevant (low to moderate) doses of MPH (Navarra et al 2008;Milstein et al 2010) and AMPH (Cole and Robbins 1987;Harrison et al 1999;Van Gaalen et al 2006;Loos et al 2010;Balachandran et al 2018). However, some have reported stimulants to improve attention in low-attention (Robinson 2012;Caballero-Puntiverio et al 2017) and high-impulsive (Caprioli et al 2015) rodents as well as with a variable ITI challenge (Toschi et al 2021), while impairing attention in rats with profound forebrain NA depletion (Cole and Robbins 1987).…”

Noradrenergic deficits contribute to apathy in Parkinson’s disease through the precision of expected outcomes

“…It is possible that the changes in prior weighting are related to atomoxetine-induced changes in arousal [ 103 , 104 ]. However, we note that atomoxetine did not affect self-reported levels of arousal [ 62 ], nor did it affect basic task performance in the current study or in a stop-signal task, either at the group-average level or in relation to individual differences in locus coeruleus CNR [ 62 ].…”