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Cited by 383Attention Deficit Hyperactivity DisorderNeurotransmitter Receptor Influence on BehaviorNeural and Behavioral Psychology Studies

Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders

Open access
Arnsten, Amy F.T., Pliszka, Steven R.·2011·Pharmacology Biochemistry and Behavior
DOI 10.1016/j.pbb.2011.01.020PMC PMC3129015
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Abstract

The primary symptoms of attention deficit/hyperactivity disorder (ADHD) include poor impulse control and impaired regulation of attention. Research has shown that the prefrontal cortex (PFC) is essential for the "top-down" regulation of attention, behavior, and emotion, and that this brain region is underactive in many patients with ADHD. The PFC is known to be especially sensitive to its neurochemical environment; relatively small changes in the levels of norepinephrine and dopamine can produce significant changes in its function. Therefore, alterations in the pathways mediating catecholamine transmission can impair PFC function, while medications that optimize catecholamine actions can improve PFC regulation of attention, behavior, and emotion. This article reviews studies in animals showing that norepinephrine and dopamine enhance PFC function through actions at postsynaptic α(2A)-adrenoceptors and dopamine D1-receptors, respectively. Stimulant medications and atomoxetine appear to enhance PFC function through increasing endogenous adrenergic and dopaminergic stimulation of α(2A)-receptors and D1-receptors. In contrast, guanfacine mimics the enhancing effects of norepinephrine at postsynaptic α(2A)-receptors in the PFC, strengthening network connectivity. Stronger PFC regulation of attention, behavior, and emotion likely contributes to the therapeutic effects of these medications for the treatment of ADHD.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that the prefrontal cortex (PFC) is underactive in ADHD and that optimal catecholamine signaling at postsynaptic α2A-adrenoceptors and dopamine D1-receptors strengthens PFC regulation of attention, behavior, and emotion. Stimulants and atomoxetine increase endogenous NE/DA stimulation, while guanfacine directly mimics NE at PFC α2A-receptors.

Key findings

  • NE strengthens PFC network connections via postsynaptic α2A-receptors on pyramidal cell dendritic spines; blockade of PFC α2A-receptors with yohimbine impairs attention/behavior and induces poor impulse control and locomotor hyperactivity in monkeys.
  • DA acts complementarily through D1-receptors to weaken irrelevant network inputs and reduce “noise,” but PFC neurons require an optimal level of DA because excessive D1 stimulation can disconnect all network inputs and stop cell firing.
  • Stimulants and atomoxetine enhance PFC function by increasing endogenous NE and DA stimulation of α2-receptors and D1-receptors; atomoxetine increases both NE and DA in rat PFC, and therapeutic doses show an inverted U dose-response in monkeys.
  • Guanfacine is the most selective α2A-adrenoceptor agonist available, with weaker presynaptic α2 activity than clonidine (one-tenth), and extended-release guanfacine showed efficacy in 2 short-term, placebo-controlled, double-blind pivotal trials for ADHD symptoms; immediate-release guanfacine also showed promise in 2 trials in children with pervasive developmental disorder accompanied by hyperactivity and impulsiveness.

Methods

  • Narrative review of basic animal and human studies; no new primary data are reported.
  • Evidence synthesized includes rodent and monkey pharmacological, infusion, lesion, iontophoresis, and behavioral studies, plus human imaging, genetic, and clinical trial data.
  • Main analysis is conceptual integration of receptor localization and catecholamine pharmacology with ADHD treatment mechanisms.

Limitations

  • The paper does not state formal limitations; it notes future directions including better understanding of PFC subregions and second messenger actions, and that cognition is not unitary.
  • Evident from the text: this is a narrative review without a systematic search or meta-analysis, and many mechanistic conclusions rely on animal studies.
  • Evident from the text: PET imaging cannot visualize NE or DA changes in PFC, so drug actions in sensory association cortices remain speculative; optimal atomoxetine dose varied widely, which may explain variability in patient response.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.pbb.2011.01.020

Cites

86 of 86 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

40 of 126 cited sources checked · 26 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Animal studies have shown that therapeutic doses of methylphenidate and atomoxetine improve PFC function by increasing endogenous norepinephrine stimulation of α2-receptors and dopamine stimulation of D1-receptors in rats and monkeys.

    “Animal studies have shown that therapeutic doses of methylphenidate and atomoxetine improve PFC function by increasing endogenous NE stimulation of α2-receptors and DA stimulation of D1-receptors in rats (Arnsten and Dudley, 2005) and monkeys (Gamo et al., 2010).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Arnsten and Dudley, 2005 source

      The Discussion reports that therapeutic-range oral methylphenidate improved PFC-related performance in rats and that α2 and D1 receptor antagonists reversed the benefit. But the section on ADHD medications says future studies must test whether low oral doses of atomoxetine likewise improve rat performance. This source therefore does not support the atomoxetine portion attributed to it; the monkey finding is cited separately to Gamo et al. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites Gamo et al., 2010 source
    • Rests on an assumption: Findings about PFC catecholamine mechanisms and drug effects obtained in animals (rats and monkeys) generalize to humans with ADHD.
  • Premisecitation

    There is evidence of delayed maturation of the PFC in children with ADHD.

    “There is evidence of delayed maturation of the PFC in children with ADHD (Shaw et al., 2007).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Shaw et al., 2007 source
  • Premisecitation

    The orbital and ventromedial PFC is essential for the regulation of emotion, such as the inhibition of aggressive impulses.

    “while the orbital and ventromedial PFC is essential for the regulation of emotion, such as the inhibition of aggressive impulses (Best et al., 2002; Izquierdo et al., 2005; Price et al., 1996)”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Best et al., 2002 source
    • cites Izquierdo et al., 2005 source

      In “Responses to a human intruder” (page unavailable), monkeys with orbital prefrontal cortex lesions showed more mild aggression during a threatening stare, which the authors interpret as suggesting a role in modulating aggression. The paper does not establish that the orbital and ventromedial PFC are essential for inhibiting aggressive impulses generally; it studies orbital lesions in rhesus monkeys and describes the aggression difference as modest. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Price et al., 1996 source
  • Premisecitation

    These agents produce an inverted U dose response, whereby higher doses can actually impair PFC cognitive performance in monkeys.

    “These agents produce an inverted U dose response, whereby higher doses can actually impair PFC cognitive performance in monkeys (Gamo et al., 2010).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Gamo et al., 2010 source
  • Premisecitation

    The PFC is especially sensitive to its neurochemical environment; relatively small changes in norepinephrine and dopamine levels can produce significant changes in PFC function.

    “The PFC is known to be especially sensitive to its neurochemical environment; relatively small changes in the levels of norepinephrine and dopamine can produce significant changes in its function.”
    • Also stated in: § The Prefrontal Cortex and Attention Deficit Hyperactivity Disorder · plain
      “However, recurrent PFC network activity is fragile, and extremely sensitive to the neurochemical environment. Thus, small changes in the arousal systems can markedly alter the connectivity of PFC networks (Arnsten et al., 2010).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Arnsten et al., 2010 source

      In “Pathways that strengthen network connections” and “Pathways that weaken network connections” (page unavailable), the paper says that norepinephrine and dopamine help determine PFC functional state, with optimal levels strengthening network firing and excessive levels impairing it. It does not establish that relatively small changes in their levels produce significant changes in PFC function. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • May combine two claims. 39
  • Classified as probably not a substantial claim. 2
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    These lower doses in rats improve PFC attention and working memory function, enhance PFC neuronal response, and reduce locomotor hyperactivity in juveniles.

    “These lower doses in rats improve PFC attention and working memory function, enhance PFC neuronal response, and reduce locomotor hyperactivity in juveniles (Arnsten and Dudley, 2005; Berridge et al., 2006; Kuczenski and Segal, 2002).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Arnsten and Dudley, 2005 source

      The Discussion reports that low oral doses of methylphenidate improved rats’ performance on a task requiring working memory and sustained attention, and says the same dose regimen had been found to decrease locomotor activity. It does not report enhanced PFC neuronal responses or establish reduced locomotor hyperactivity in juveniles; Methods > Animals identifies this study’s rats as young adults. No page numbers are available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites Berridge et al., 2006 source
    • cites Kuczenski and Segal, 2002 source

      The Behavioral responses section (page not available in our copy) reports a small reduction in locomotor activity in adolescent rats given lower oral methylphenidate doses; it was statistically significant only when activity was accumulated over nine hours after three administrations. The Neurotransmitter responses section discusses possible prefrontal-cortex effects but does not report improved attention or working memory, or enhanced PFC neuronal responses, in these rats. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    When administered in appropriate doses, stimulant medications improve PFC function both in healthy human subjects and in animals, including the reduction of locomotor hyperactivity in juvenile rats.

    “When administered in appropriate doses, these medications improve PFC function both in healthy human subjects (Elliott et al., 1997) and in animals (Arnsten and Dudley, 2005), including the reduction of locomotor hyperactivity in juvenile rats (Kuczenski and Segal, 2002).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Elliott et al., 1997 source
    • cites Arnsten and Dudley, 2005 source
    • cites Kuczenski and Segal, 2002 source

      The ‘Behavioral response to acute oral MP’ section reports that oral methylphenidate reduced cumulative locomotor activity in adolescent rats. The Methods describe a typical activity pattern in the control animals, not locomotor hyperactivity, so the source does not establish a reduction of hyperactivity specifically. The PFC and human findings are attached to other citations in the citing sentence. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Recurrent PFC network activity is fragile and extremely sensitive to the neurochemical environment; small changes in arousal systems can markedly alter the connectivity of PFC networks.

    “However, recurrent PFC network activity is fragile, and extremely sensitive to the neurochemical environment. Thus, small changes in the arousal systems can markedly alter the connectivity of PFC networks (Arnsten et al., 2010).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Arnsten et al., 2010 source

  • May combine two claims.

    Premisecitation

    In humans, lower activity of dopamine β-hydroxylase is associated with poor sustained attention, poor executive function, and impulsiveness.

    “In humans, lower activity of dopamine β-hydroxylase, the enzyme that synthesizes NE, is associated with poor sustained attention (Greene et al., 2009), poor executive function (Kieling et al., 2008), and impulsiveness (Hess et al., 2009)”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Greene et al., 2009 source
    • cites Kieling et al., 2008 source
    • cites Hess et al., 2009 source

  • May combine two claims.

    Premisecitation

    In patients with ADHD, white matter tracts linking the PFC to other brain regions appear less well organized, and functional connectivity is reduced.

    “In patients with ADHD, the white matter tracts that link the PFC to other brain regions also appear less well organized (Casey et al., 2007; Makris et al., 2008), and functional connectivity is reduced (Castellanos et al., 2008).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Casey et al., 2007 source
    • cites Makris et al., 2008 source
    • cites Castellanos et al., 2008 source

  • May combine two claims.

    Premisecitation

    Norepinephrine and dopamine enhance PFC function through actions at postsynaptic α2A-adrenoceptors and dopamine D1-receptors, respectively.

    “This article reviews studies in animals showing that norepinephrine and dopamine enhance PFC function through actions at postsynaptic α2A-adrenoceptors and dopamine D1-receptors, respectively.”
    • Also stated in: § Stimulants enhance both DA and NE actions in PFC · plain
      “Animal studies have shown that therapeutic doses of methylphenidate and atomoxetine improve PFC function by increasing endogenous NE stimulation of α2-receptors and DA stimulation of D1-receptors in rats (Arnsten and Dudley, 2005) and monkeys (Gamo et al., 2010).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Arnsten and Dudley, 2005 source
    • cites Gamo et al., 2010 source
    • Rests on an assumption: Findings about PFC catecholamine mechanisms and drug effects obtained in animals (rats and monkeys) generalize to humans with ADHD.

  • May combine two claims.

    Premisecitation

    Depending on task demands, the PFC facilitates sustained attention on a single task or manages rapid shifts in attention to accomplish multiple sequential tasks.

    “Depending on task demands, the PFC facilitates sustained attention on a single task (Wilkins et al., 1987) or manages rapid shifts in attention to accomplish multiple sequential tasks (Robbins, 2007).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Wilkins et al., 1987 source
    • cites Robbins, 2007 source

  • May combine two claims.

    Premisecitation

    The dorsolateral PFC has a smaller volume and reduced activity in patients with ADHD compared with controls.

    “Several imaging studies have shown that the dorsolateral PFC has a smaller volume and reduced activity in patients with ADHD compared with controls (Castellanos et al., 2002; Castellanos et al., 2008; Mostofsky et al., 2002; Rubia et al., 1999; Seidman et al., 2005).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Castellanos et al., 2002 source
    • cites Castellanos et al., 2008 source

      The Results report reduced functional connectivity involving the dorsal anterior cingulate, precuneus, and posterior cingulate in adults with ADHD, not reduced dorsolateral PFC activity. The Discussion mentions diminished volume in the precuneus and posterior cingulate. Searches for dorsolateral PFC volume and activity found no passage in our copy addressing the claimed comparison with controls; section page numbers were not available. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites Rubia et al., 1999 source

      The Stop task results (page unavailable) report reduced activity in right inferior and medioinferior frontal regions in seven adolescent boys with ADHD compared with nine controls; they do not identify the dorsolateral PFC as the affected region. The introduction mentions low frontal volumes from earlier structural studies, but this functional MRI study does not establish a smaller dorsolateral PFC volume. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In humans, both normal subjects and patients with ADHD show improved PFC inhibition of behavior following atomoxetine, consistent with the animal data.

    “In humans, both normal subjects (Chamberlain et al., 2006), and patients with ADHD (Chamberlain et al., 2007) show improved PFC inhibition of behavior following atomoxetine, consistent with the animal data.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Chamberlain et al., 2006 source
    • cites Chamberlain et al., 2007 source

  • May combine two claims.

    Premisecitation

    Lower optimal amounts of atomoxetine enhanced signals via indirectly increasing norepinephrine stimulation of alpha-2A receptors, and/or decreased noise via indirectly increasing dopamine stimulation of D1 receptors.

    “Lower “optimal” amounts of atomoxetine enhanced “signals” (neuronal firing during the delay period for the neuron’s preferred direction) via indirectly increasing NE stimulation of alpha-2A receptors, and/or decreased “noise” (neuronal firing for nonpreferred directions) via indirectly increasing DA stimulation of D1 receptors (Gamo et al., 2010).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Gamo et al., 2010 source

  • May combine two claims.

    Premisecitation

    Optimal doses of atomoxetine improved working memory performance in monkeys, while higher doses impaired performance.

    “Thus, optimal doses improved working memory performance in monkeys, while higher doses impaired performance.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Gamo et al., 2010 source

      The Results (Behavioral Data; page unavailable) report that optimal atomoxetine doses improved spatial working-memory performance in monkeys. The claim overstates the effect of higher doses: the paper says they impaired performance or had no effect, with substantial variation among monkeys. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Guanfacine enhances various PFC functions in animals, including improvements in working memory, behavioral inhibition, and reduced distractibility.

    “Guanfacine enhances various PFC functions in animals, including improvements in working memory (Arnsten et al., 1988), behavioral inhibition (Steere and Arnsten, 1997), and reduced distractibility (Arnsten and Contant, 1992).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Arnsten et al., 1988 source
    • cites Steere and Arnsten, 1997 source
    • cites Arnsten and Contant, 1992 source

  • May combine two claims.

    Premisecitation

    These improvements are observed immediately when guanfacine is infused directly into the PFC and when administered systemically.

    “These improvements are observed immediately when guanfacine is infused directly into the PFC (Mao et al., 1999) and when administered systemically (Arnsten et al., 1988; O'Neill et al., 2000; Rama et al., 1996).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Mao et al., 1999 source
    • cites Arnsten et al., 1988 source
    • cites O'Neill et al., 2000 source

  • May combine two claims.

    Premisenone given

    Norepinephrine acts chiefly at α1-, α2-, and β-receptors; the α2-receptors are further subdivided as α2A, α2B, and α2C.

    “NE acts chiefly at α1-, α2-, and β-receptors; the α2-receptors are further subdivided as α2A, α2B, and α2C.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Extensive projections from the PFC to sensory association cortices allow it to suppress processing of irrelevant distractions and enhance processing of meaningful stimuli.

    “Extensive projections to the sensory association cortices allow the PFC to suppress processing of irrelevant distractions and enhance processing of meaningful stimuli that may not be inherently captivating (e.g. homework) (Barbas et al., 2005; Yamaguchi and Knight, 1990)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Barbas et al., 2005 source
    • cites Yamaguchi and Knight, 1990 source

  • May combine two claims.

    Premisenone given

    The stimulants methylphenidate and amphetamine block reuptake at norepinephrine and dopamine transporters, while atomoxetine more selectively targets the norepinephrine transporter.

    “The stimulants methylphenidate and amphetamine block reuptake at NE and DA transporters, while atomoxetine more selectively targets the NE transporter.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Dopaminergic stimulation of D1-receptors opens ion channels on dendritic spines that receive inputs irrelevant to focused working memory and attention, weakening irrelevant network connections, reducing noisy input, and enhancing the efficiency of PFC function.

    “Dopaminergic stimulation of D1-receptors opens ion channels on a set of dendritic spines that receive inputs irrelevant to focused working memory and attention. Opening channels on these spines weakens irrelevant network connections, reducing noisy input to the neuron and enhancing the efficiency of PFC function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Vijayraghavan et al., 2007 source

  • May combine two claims.

    Premisecitation

    Among α2-receptors, the α2A subtype is the most prevalent in the PFC and is found both presynaptically on noradrenergic terminals and postsynaptically on the dendritic spines of PFC pyramidal cells that receive network inputs.

    “Among the α2-receptors, the α2A subtype is the most prevalent in the PFC and is found both presynaptically on noradrenergic terminals and postsynaptically on the dendritic spines of PFC pyramidal cells that receive network inputs (Aoki et al., 1998; Wang et al., 2007).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Aoki et al., 1998 source
    • cites Wang et al., 2007 source

  • May combine two claims.

    Premisecitation

    α1-Receptor stimulation impairs working memory by activating protein kinase C intracellular signaling, which is thought to be overactive in patients with bipolar disorder.

    “α1-Receptor stimulation impairs working memory by activating protein kinase C intracellular signaling, which is thought to be overactive in patients with bipolar disorder (Birnbaum et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Birnbaum et al., 2004 source

  • May combine two claims.

    Interpretationreasoning

    PFC regulation of posterior cortical and subcortical structures is likely less effective in patients with ADHD, leading to decreased top-down regulation of attention, behavior, and emotion.

    “Thus, PFC regulation of posterior cortical and subcortical structures is likely to be less effective in patients with ADHD, leading to decreased top-down regulation of attention, behavior, and emotion.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Dopamine acts at both the D1 (D1- and D5-receptors) and D2 (D2-, D3-, and D4-receptors) families of receptors.

    “DA acts at both the D1 (D1- and D5-receptors) and D2 (D2-, D3-, and D4-receptors) families of receptors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Blockade of α2A-receptors in the monkey PFC with local yohimbine infusions markedly impairs PFC regulation of attention and behavior, inducing poor impulse control and locomotor hyperactivity.

    “Blockade of α2A-receptors in the monkey PFC with local yohimbine infusions markedly impairs PFC regulation of attention and behavior, inducing poor impulse control and locomotor hyperactivity (Li and Mei, 1994; Ma et al., 2005; Ma et al., 2003).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Li and Mei, 1994 source
    • cites Ma et al., 2005

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Ma et al., 2003

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    The most prominent dopaminergic actions in the PFC arise from actions at D1-receptors, which are found in both superficial and deep layers of the primate PFC.

    “However, the most prominent dopaminergic actions in the PFC arise from actions at D1-receptors, which are found in both superficial and deep layers of the primate PFC (Lidow et al., 1991).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lidow et al., 1991 source

  • May combine two claims.

    Premisecitation

    The cellular networks of the PFC maintain representations of goals and rules and use remembered information to guide attention, actions, and emotion.

    “The cellular networks of the PFC are able to maintain representations of goals and rules and use remembered information to guide attention, actions, and emotion (Goldman-Rakic, 1995).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Goldman-Rakic, 1995 source

  • May combine two claims.

    Premisecitation

    Studies in animals indicate that norepinephrine engages predominantly α2-receptors in the PFC when the subject is alert and interested, while actions at α1-receptors and possibly β-receptors are predominant under stressful conditions.

    “Studies in animals indicate that NE engages predominantly α2-receptors in the PFC when the subject is alert and interested (Li and Mei, 1994), while actions at α1-receptors and possibly β-receptors are predominant under stressful conditions (Birnbaum et al., 2004; Ramos et al., 2005).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Li and Mei, 1994 source
    • cites Birnbaum et al., 2004 source
    • cites Ramos et al., 2005 source

  • May combine two claims.

    Premisecitation

    Under conditions of alert interest, there is moderate tonic firing and increased phasic firing of norepinephrine and dopamine to relevant stimuli.

    “In contrast, under conditions of alert interest, there is moderate tonic firing, and increased phasic firing of NE and DA to relevant stimuli (Aston-Jones et al., 2000; Aston-Jones et al., 1994; Finlay et al., 1995; Foote et al., 1980; Schultz, 1998).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Aston-Jones et al., 2000 source
    • cites Aston-Jones et al., 1994
    • cites Schultz, 1998 source

  • May combine two claims.

    Premisecitation

    Excessive doses of stimulants impair PFC function, which may account for the cognitive inflexibility observed when patients with ADHD are administered these doses of stimulant medication.

    “However, excessive doses of stimulants impair PFC function, which may account for the cognitive inflexibility observed when patients with ADHD are administered these doses of stimulant medication (Dyme et al., 1982).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dyme et al., 1982 source

  • May combine two claims.

    Premisecitation

    Recent studies have found slower maturation of the PFC in typically developing adolescents with weaker impulse control, indicating that this is a dimensional characteristic related to the integrity of PFC gray matter.

    “Recent studies have found slower maturation of PFC in typically developing adolescents with weaker impulse control, indicating that this is a dimensional characteristic related to the integrity of PFC gray matter (Shaw et al., 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shaw et al., 2010

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Higher doses of stimulants induce hyperactivity and addiction in rat models, but these doses exceed those given clinically.

    “Higher doses of stimulants induce hyperactivity and addiction in rat models, but these doses exceed those given clinically (Segal and Kuczenski, 1987).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Segal and Kuczenski, 1987 source

  • May combine two claims.

    Premisecitation

    D2-receptors in the PFC are concentrated in layer V neurons where they increase response-related firing.

    “D2-receptors in the PFC are concentrated in layer V neurons where they also increase response-related firing (Wang et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wang et al., 2004 source

  • May combine two claims.

    Interpretationreasoning

    Basic studies of catecholamine actions in the PFC have helped understand how genetic insults in catecholamine signaling pathways may lead to ADHD symptoms and how current medications may alleviate weak attention and impulse control in ADHD and related disorders.

    “Basic studies of catecholamine actions in the prefrontal cortex (PFC) have helped us understand how genetic insults in catecholamine signaling pathways may lead to symptoms of Attention Deficit Hyperactivity Disorder (ADHD), and how current medications may alleviate symptoms of weak attention and impulse control in ADHD and related disorders.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Findings about PFC catecholamine mechanisms and drug effects obtained in animals (rats and monkeys) generalize to humans with ADHD.

  • The quote only partly states this claim.

    Interpretationreasoning

    The lesser effect of these doses on subcortical dopamine release may explain why they do not cause addiction when used as prescribed.

    “which may explain why they do not cause addiction when they are used as prescribed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Delayed maturation of the PFC may vary in degree, which may explain why ADHD continues into adulthood for some individuals yet may resolve in others.

    “This delayed maturation may vary in degree, which may explain why ADHD continues into adulthood for some individuals, yet may resolve in others.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Dopamine D1-receptor overstimulation may lead to disconnection of all network inputs and the cell may stop firing.

    “In addition, DA D1-receptor overstimulation (eg, under a stressful condition) may lead to disconnection of all network inputs and the cell may stop firing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    D1-receptors have fundamental excitatory effects on PFC function but also modify inputs to pyramidal cells.

    “D1-receptors have fundamental excitatory effects on PFC function, but also modify inputs to pyramidal cells (Vijayraghavan et al., 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Vijayraghavan et al., 2007 source

  • May combine two claims.

    Interpretationcitation

    The optimal dose of atomoxetine varied widely, which may explain variability of drug response in patients.

    “Interestingly, the optimal dose varied widely, which may explain variability of drug response in patients (Castellanos and Kelly, 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Castellanos and Kelly, 2010 source

  • May combine two claims.

    Interpretationcitation

    The finding that stimulant medication can normalize gray matter volume in the developing PFC of patients with ADHD counters fears that stimulant medications could interfere with brain development.

    “This finding counters fears that stimulant medications could interfere with brain development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Guanfacine mimics noradrenergic actions at α2A-receptors, and its activity at postsynaptic α2-receptors may restore PFC function in patients with ADHD.

    “Not only does guanfacine mimic noradrenergic actions at α2A-receptors, its activity at postsynaptic α2-receptors may restore PFC function in patients with ADHD (Biederman et al., 2008; Scahill et al., 2001).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Biederman et al., 2008 source
    • cites Scahill et al., 2001 source
    • Rests on an assumption: Findings about PFC catecholamine mechanisms and drug effects obtained in animals (rats and monkeys) generalize to humans with ADHD.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Improved understanding of catecholamine actions in the prefrontal cortex has helped lead to new treatments for ADHD.

    “In summary, improved understanding of catecholamine actions in the PFC has helped to lead to new treatments for ADHD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Yohimbine blockade of α2-receptors in the PFC recreates the symptoms of ADHD: inducing locomotor hyperactivity, poor impulse control, and weaker working memory.

    “Conversely, yohimbine blockade of α2-receptors in the PFC recreates the symptoms of ADHD: inducing locomotor hyperactivity (Ma et al., 2005), poor impulse control (Ma et al., 2003), and weaker working memory (Li and Mei, 1994).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ma et al., 2005

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Ma et al., 2003

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Li and Mei, 1994 source

  • May combine two claims.

    Premisecitation

    The sedative effects of guanfacine may arise from a variety of actions, including stimulation of presynaptic α2A-receptors on noradrenergic cell bodies and terminals as well as postsynaptic α2B-receptors in the thalamus.

    “The sedative effects of guanfacine may arise from a variety of actions, including stimulation of presynaptic α2A-receptors on noradrenergic cell bodies and terminals as well as postsynaptic α2B-receptors in the thalamus (Berridge et al., 2003; McCormick et al., 1991).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Berridge et al., 2003 source
    • cites McCormick et al., 1991 source

  • May combine two claims.

    Premisecitation

    Guanfacine is the most selective α2A-adrenoceptor agonist currently available, with higher affinity for the α2A- than for the α2B- or α2C-adrenoceptor subtypes.

    “Guanfacine is the most selective α2A-adrenoceptor agonist currently available, with higher affinity for the α2A- than for the α2B- or α2C-adrenoceptor subtypes (Uhlén et al., 1995; Uhlen and Wikberg, 1991)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Uhlén et al., 1995 source
    • cites Uhlen and Wikberg, 1991 source
42 of 42

  • The paper relies on this without support.

    Findings about PFC catecholamine mechanisms and drug effects obtained in animals (rats and monkeys) generalize to humans with ADHD.

    “This article reviews studies in animals showing that norepinephrine and dopamine enhance PFC function through actions at postsynaptic α2A-adrenoceptors and dopamine D1-receptors, respectively.”
    “Animal studies have shown that therapeutic doses of methylphenidate and atomoxetine improve PFC function by increasing endogenous NE stimulation of α2-receptors and DA stimulation of D1-receptors in rats (Arnsten and Dudley, 2005) and monkeys (Gamo et al., 2010).”

  • The paper relies on this without support.

    The therapeutic effects of ADHD medications are mediated by their actions on PFC catecholamine receptors rather than by other brain regions or mechanisms.

    “Stronger PFC regulation of attention, behavior, and emotion likely contributes to the therapeutic effects of these medications for the treatment of ADHD.”

  • The paper relies on this without support.

    Altered top-down prefrontal cortical control of behavior, thought and emotion is central to most neuropsychiatric disorders.

    “As altered “top-down” PFC control of behavior, thought and emotion is central to most neuropsychiatric disorders, these studies are relevant to many cognitive disorders.”

  • The paper relies on this without support.

    Cognition is not a unitary phenomenon.

    “We must respect that cognition is not a unitary phenomenon, and that different brain circuits and cognitive operations may have distinct neurochemical needs.”
4 of 4

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Authors
Arnsten, A. F. T., & Pliszka, S. R.
Affiliations
  • Yale University (US)
  • The University of Texas at San Antonio Health Science Center (US)
Corresponding author
Arnsten, Amy F.T.
ORCID
Venue
Pharmacology Biochemistry and Behavior
Publisher
Elsevier BV
Published
2011-08
Volume
99
Issue
2
Pages
211-216
ISSN
0091-3057 (ISSN-L)
DOI
10.1016/j.pbb.2011.01.020
PMC
PMC3129015
OpenAlex
W1964309132
Semantic Scholar
b6177bb3cb85433b0e8670a0a0b0ae0b05cbc5d7
Cited by
383
References
86
Citations by year
2026: 22 · 2025: 23 · 2024: 35 · 2023: 30 · 2022: 32 · 2021: 22 · 2020: 24 · 2019: 22 · 2018: 23 · 2017: 19 · 2016: 26 · 2015: 26 · 2014: 21 · 2013: 33 · 2012: 19
FWCI
3.41
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Pharmacology Biochemistry and Behavior (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Food and Drug Administration
  • National Institute on Alcohol Abuse and Alcoholism (RL1AA017536)
  • National Institute on Aging (P01AG030004, R01 AG006036, AG06036, R37 AG006036)
  • National Center for Research Resources (U54RR024350)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
Keywords
attention deficit hyperactivity disorder, prefrontal cortex, catecholamines, norepinephrine, dopamine, dopamine D1 receptor, stimulant medication, atomoxetine, guanfacine, impulse control, prefrontal connectivity
MeSH terms
Atomoxetine Hydrochloride, Central Nervous System Stimulants, Animals, Attention Deficit Disorder with Hyperactivity, Catecholamines, Dopamine, Humans, Models, Neurological, Norepinephrine, Propylamines, Guanfacine, Prefrontal Cortex, Receptors, Catecholamine, Adrenergic Uptake Inhibitors, Adrenergic alpha-2 Receptor Agonists

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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