Putative therapeutic targets for symptom subtypes of adult ADHD: D4 receptor agonism and COMT inhibition improve attention and response inhibition in a novel translational animal model

Tomlinson, Anneka; Grayson, Ben; Marsh, Samuel; Hayward, Andrew; Marshall, Kay; Neill, Joanna C.

doi:10.1016/j.euroneuro.2014.11.016

Cited by 37 publications

(31 citation statements)

References 57 publications

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“…Unfortunately, none of them has yet received clinical approval due to failures of the pharmacokinetics or safety profiles [51]. Similarly, D 4 R agonism has been implicated in the management of cognitive deficits associated with schizophrenia [52] and attention-deficit/hyperactivity disorder [53] and also to reduce the adverse effects of opioids [54].…”

Section: Discussionmentioning

confidence: 99%

Novel Diels–Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases

Paudel

Park

Seong

et al. 2019

IJMS

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In this study, we delineate the human monoamine oxidase (hMAO) inhibitory potential of natural Diels–Alder type adducts, mulberrofuran G (1), kuwanon G (2), and albanol B (3), from Morus alba root bark to characterize their role in Parkinson’s disease (PD) and depression, focusing on their ability to modulate dopaminergic receptors (D1R, D2LR, D3R, and D4R). In hMAO-A inhibition, 1–3 showed mild effects (50% inhibitory concentration (IC50): 54‒114 μM). However, 1 displayed moderate inhibition of the hMAO-B isozyme (IC50: 18.14 ± 1.06 μM) followed by mild inhibition by 2 (IC50: 57.71 ± 2.12 μM) and 3 (IC50: 90.59 ± 1.72 μM). Our kinetic study characterized the inhibition mode, and the in silico docking predicted that the moderate inhibitor 1 would have the lowest binding energy. Similarly, cell-based G protein-coupled receptors (GPCR) functional assays in vector-transfected cells expressing dopamine (DA) receptors characterized 1–3 as D1R/D2LR antagonists and D3R/D4R agonists. The half-maximum effective concentration (EC50) of 1–3 on DA D3R/D4R was 15.13/17.19, 20.18/21.05, and 12.63/‒ µM, respectively. Similarly, 1–3 inhibited 50% of the DA response on D1R/D2LR by 6.13/2.41, 16.48/31.22, and 7.16/18.42 µM, respectively. A computational study revealed low binding energy for the test ligands. Interactions with residues Asp110, Val111, Tyr365, and Phe345 at the D3R receptor and Asp115 and His414 at the D4R receptor explain the high agonist effect. Likewise, Asp187 at D1R and Asp114 at D2LR play a crucial role in the antagonist effects of the ligand binding. Our overall results depict 1–3 from M. alba root bark as good inhibitors of hMAO and potent modulators of DA function as D1R/D2LR antagonists and D3R/D4R agonists. These active constituents in M. alba deserve in-depth study for their potential to manage neurodegenerative disorders (NDs), particularly PD and psychosis.

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Section: Discussionmentioning

confidence: 99%

Novel Diels–Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases

Paudel

Park

Seong

et al. 2019

IJMS

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“…Given that mice with reduced dopamine D 4 receptor expression exhibit response disinhibition (Young et al 2011b), however, agonists at this receptor may remediate response disinhibition that occurs during withdrawal. In fact, D 4 receptor agonist treatment improved response inhibition in rats with high p[FA] during 5C-CPT testing (Tomlinson et al 2015). …”

Section: Discussionmentioning

confidence: 99%

Nicotine withdrawal-induced inattention is absent in alpha7 nAChR knockout mice

et al. 2017

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Rationale Smoking is the leading cause of preventable death in the U.S., but quit attempts result in withdrawal-induced cognitive dysfunction and predicts relapse. Greater understanding of the neural mechanism(s) underlying these cognitive deficits is required to develop targeted treatments to aid quit attempts. Objectives We examined nicotine withdrawal-induced inattention in mice lacking the α7 nicotinic acetylcholine receptor (nAChR) using the 5-choice continuous performance test (5C-CPT). Methods Mice were trained in the 5C-CPT prior to osmotic minipump implantation containing saline or nicotine. Experiment 1 used 40 mg/kg/day nicotine treatment and tested C57BL/6 mice 4, 28, and 52 h after pump removal. Experiment 2 used 14 and 40 mg/kg/day nicotine treatment in α7 nAChR knockout (KO) and wildtype (WT) littermates tested 4 h after pump removal. Subsets of WT mice were sacrificed before and after pump removal to assess changes in receptor expression associated with nicotine administration and withdrawal. Results Nicotine withdrawal impaired attention in the 5C-CPT, driven by response inhibition and target detection deficits. The overall attentional deficit was absent in α7 nAChR KO mice despite response disinhibition in these mice. Synaptosomal glutamate mGluR5 and dopamine D4 receptor expression were reduced during chronic nicotine but increased during withdrawal, potentially contributing to cognitive deficits. Conclusions The α7 nAChR may underlie nicotine withdrawal-induced deficits in target detection but is not required for response disinhibition deficits. Alterations to the glutamatergic and dopaminergic pathways may also contribute to withdrawal-induced attentional deficits, providing novel targets to alleviate the cognitive symptoms of withdrawal during quit attempts.

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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%

“…Evidence suggests that reduced dopamine D4 receptor (DRD4) expression/function is associated with ADHD and TS (Barr et al, 2000, 2001; Grice et al, 1996). Animal studies, revealed impaired 5C-CPT performance with increased response disinhibition and no effect on premature responding in mice with reduced DRD4 expression (Young et al, 2011), and administration of DRD4 agonist improved 5C-CPT performance by enhancing attention, vigilance and response inhibition in rats (Tomlinson et al, 2015). Collectively, these findings reveal the ability of 5C-CPT to distinguish cognitive control elements and allow symptom specific treatment, for example DRD4 agonist may be useful in improving cognitive control deficits in specific subtype of ADHD patients.…”

Section: Applicationsmentioning

confidence: 99%

“…Unlike DRD4 agonist, nicotine consistently improved 5C-CPT performance in mice (Young et al, 2013) similar to improvement in human Conners’ CPT performance (Levin et al, 1998), seen as enhanced responding to target stimuli improving overall d prime. Interestingly, tolcapone, a catechol-O-methyltransferase (COMT) inhibitor enhanced sustained attention via reduced response inhibition in female rats with low attention and high impulsivity (ADHD-C type) (Tomlinson et al, 2015). Given our observations that tolcapone similarly improved 5C-CPT performance by enhancing response inhibition and activated frontal scalp electrodes during correctly identified non-target trials in poorly performing healthy participants (Bhakta et al, 2014), COMT inhibitors may be useful targeted treatments for disorders with evidence of response disinhibition.…”

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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Putative therapeutic targets for symptom subtypes of adult ADHD: D4 receptor agonism and COMT inhibition improve attention and response inhibition in a novel translational animal model

Cited by 37 publications

References 57 publications

Novel Diels–Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases

Novel Diels–Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases

Nicotine withdrawal-induced inattention is absent in alpha7 nAChR knockout mice

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

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