Pay attention to impulsivity: Modelling low attentive and high impulsive subtypes of adult ADHD in the 5-choice continuous performance task (5C-CPT) in female rats

Tomlinson, Anneka; Grayson, Ben; Marsh, Samuel; Harte, Michael K.; Barnes, Sarah; Marshall, Kay; Neill, Joanna C.

doi:10.1016/j.euroneuro.2014.04.008

Cited by 53 publications

(78 citation statements)

References 44 publications

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“…Additionally, the time that is taken to train animals in the task precludes testing animals <P60, hence precluding adolescent animals – a key demographic in ADHD and TS. Given that cognitive control deficits persist even in adult life in both ADHD and TS, animal studies have used adult rats to characterize various subtypes of ADHD based on their 5C-CPT performance (Tomlinson et al, 2014, 2015). …”

Section: Methodological Challengesmentioning

confidence: 99%

“…While some studies have used rodent 5C-CPT to identify rats with low attention and high impulsivity behavior to model the ADHD-combined subtype (Tomlinson et al, 2014; Hayward et al, 2016), others have used rodent 5C-CPT with visual distractors to characterize attentional deficits and behavioral disinhibition resulting from chronic intermittent alcohol exposure (Irimia et al, 2014). …”

Section: Applicationsmentioning

confidence: 99%

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The 5 choice continuous performance test (5C-CPT): A novel tool to assess cognitive control across species

Bhakta

Young

2017

Journal of Neuroscience Methods

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Background Neurodevelopmental disorders including Tourette’s syndrome (TS) and attention deficit hyperactivity disorder (ADHD) are characterized by significant impairment in attention and cognitive control. These cognitive deficits persist throughout development, contribute significantly to socio-occupational impairment, and are relatively impervious to available treatment. A critical challenge in pro-cognitive drug discovery is translatability of findings across species, underscoring the need for developing valid and reliable cross-species cognitive tasks. New Method Here we describe a cross-species 5 choice continuous performance task that was developed to measure cognitive control processes of attention, vigilance, and response inhibition, enabling the translation of findings for pro-cognitive drug discovery across species and delineate neural mechanisms underlying cognitive control construct. Results Construct validity of 5C-CPT has been verified by multiple cross-species studies. Several lines of evidence report consistent findings across species including, deficits resulting from 36-hour sleep deprivation studies, engagement of parietal cortex in human brain imaging and rodent lesion studies, and vigilance decrements over time. Comparison with existing method Unlike the widely used rodent 5 choice serial reaction time task (5CSRTT) and the sustained attention task (SAT), the rodent 5C-CPT includes both target and non-target stimuli that allow measuring of cognitive control elements including response inhibition, an ability to inhibit pre-potent response during non-target trials, detect vigilance decrement and calculate signal detection parameters in rodents analogous to human CPT. Conclusion The cross-species 5C-CPT is a robust translational tool to characterize the neurobiological substrates underlying cognitive control deficits in clinical population including, ADHD and TS and develop targeted pro-cognitive therapeutics.

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Section: Methodological Challengesmentioning

confidence: 99%

Section: Applicationsmentioning

confidence: 99%

The 5 choice continuous performance test (5C-CPT): A novel tool to assess cognitive control across species

Bhakta

Young

2017

Journal of Neuroscience Methods

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“…Female rats were used as they have consistently demonstrated reliable performance in our laboratory in a variety of cognitive tests [40] at all stages of the oestrus cycle [52, 55]. Furthermore, we have thoroughly validated the 5C-CPT in our laboratory using female rats and demonstrated impaired performance following sub-chronic PCP and effects of D1 receptor agonism in “normal” rats [20–23]. All experimentation was conducted in the animal's natural dark-cycle under red lighting.…”

Section: Methodsmentioning

confidence: 99%

“…Dopamine D1 receptor activation has been shown to improve attention/vigilance in a baseline-dependent manner [21, 50]. Other dopamine-related treatments also improve attention in a baseline-dependent manner, such as methylphenidate and atomoxetine [23], and dopamine releasing agents such as nicotine [19] further demonstrating the involvement of dopamine in attentional processing. Dopamine D1 receptor activation attenuates reversal learning and novel object recognition (NOR) deficits induced by sub-chronic PCP administration [51, 52].…”

Section: Introductionmentioning

confidence: 99%

Dopamine D1 receptor activation improves PCP-induced performance disruption in the 5C-CPT by reducing inappropriate responding

Barnes

Young

Bate

et al. 2016

Behavioural Brain Research

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Attentional deficits contribute significantly to the functional disability of schizophrenia patients. The 5-choice continuous performance test (5C-CPT) measures attention in mice, rats, and humans, requiring the discrimination of trial types that either require a response or the inhibition of a response. The 5C-CPT, one version of human continuous performance tests (CPT), enables attentional testing in rodents in a manner consistent with humans. Augmenting the prefrontal cortical dopaminergic system has been proposed as a therapeutic target to attenuate the cognitive disturbances associated with schizophrenia. Using translational behavioural tasks in conjunction with inducing conditions relevant to schizophrenia pathophysiology enable the assessment of pro-attentive properties of compounds that augment dopaminergic activity. Here, using a repeated phencyclidine (PCP) treatment regimen and the 5C-CPT paradigm, we assess the pro-attentive properties of SKF 38393, a dopamine D1 receptor agonist, in rats. We show that repeated PCP treatment induces robust deficits in 5C-CPT performance indicative of impaired attention. Pre-treatment with SKF 38393 partially attenuates the PCP-induced deficits in 5C-CPT performance by reducing false alarm responding and increasing response accuracy. Impaired target detection was still evident in SKF 38393-treated rats however. Thus, augmentation of the dopamine D1 system improves PCP-induces deficits in 5C-CPT performance by selectively reducing aspects of inappropriate responding. These findings provide evidence to support the hypothesis that novel therapies targeting the dopamine D1 receptor system could improve aspects of attentional deficits in schizophrenia patients.

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“…Overall, they showed that drug effects were dependent on individual baseline impulsivity for the majority of studies, including 72% of the studies using amphetamine. Studies using other agents have found evidence for baselinedependent improvement after splitting animals in sub-groups (Mohler et al, 2010;Tomlinson et al, 2014). Previously, it was shown that administration of a D4 antagonist in rats could improve working memory performance in below average, but not above average individuals (Zhang et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Establishing a novel cognitive task in rats of relevance to schizophrenia

Turner¹

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The most debilitating symptoms for patients with neuropsychiatric disorders, such as schizophrenia, are often cognitive deficits; yet they remain largely untreated by current medications. In preclinical animal models, the techniques used to measure cognitive deficits need to be improved to enhance our ability to screen novel drug targets and gain a better understanding of the neurobiological correlates of cognitive dysfunction. Therefore, the aim of this thesis was to develop and test a new high throughput cognitive task in rodents. I have designed a novel Signal Detection Task (SDT) for this purpose.The first aim in developing the SDT was to compare alternative tasks (such as the 5-choice serial reaction time task) and address limitations including the extensive training time required and the lack of control over body position during stimulus presentation.Experiments were then selected to assess the face, construct and predictive validity of the SDT for measuring attentional deficits relevant to schizophrenia. Specifically, I determined if the effects of genetic, environmental, neurobiological and pharmacological manipulations could be detected in rats using this task. The SDT was conducted in rat operant chambers with a series of task variants to probe different components of performance, such as increasing detection difficulty and distraction. Briefly, the studies conducted compared strains (genetics), housing conditions (environment), the impact of a prefrontal cortical lesion (neurobiology) and the effects of amphetamine (pharmacology) on task performance. My findings indicate a relatively short training period was required for rats to perform the SDT with a high level of accuracy compared to other tasks; task acquisition was shown to be dependent on interactions between genetics and environment; prefrontal cortical lesions did not alter baseline performance but impaired attention during distraction and low dose amphetamine significantly improved accuracy. I demonstrated for the first time that the procognitive effects of amphetamine were dependent on baseline attentional performance. In addition, I found that individual variation in baseline performance was related to dopamine metabolism in the striatum.The research outlined in this thesis presents a novel tool for researchers exploring the cognitive phenotype of animal models relevant to neuropsychiatric disorders and for exploring the neurobiology of attention, including mechanisms of action for procognitive medication.ii Declaration by authorThis thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis.

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Pay attention to impulsivity: Modelling low attentive and high impulsive subtypes of adult ADHD in the 5-choice continuous performance task (5C-CPT) in female rats

Cited by 53 publications

References 44 publications

The 5 choice continuous performance test (5C-CPT): A novel tool to assess cognitive control across species

The 5 choice continuous performance test (5C-CPT): A novel tool to assess cognitive control across species

Dopamine D1 receptor activation improves PCP-induced performance disruption in the 5C-CPT by reducing inappropriate responding

Establishing a novel cognitive task in rats of relevance to schizophrenia

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