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Cited by 366Attention Deficit Hyperactivity DisorderNeurotransmitter Receptor Influence on BehaviorNeural and Behavioral Psychology Studies

Methylphenidate improves prefrontal cortical cognitive function through α2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in Attention Deficit Hyperactivity Disorder

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Arnsten, Amy FT, Dudley, Anne G·2005·Behavioral and Brain Functions
DOI 10.1186/1744-9081-1-2PMC PMC1143775
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Abstract

Background: Methylphenidate (MPH) is the classic treatment for Attention Deficit Hyperactivity Disorder (ADHD), yet the mechanisms underlying its therapeutic actions remain unclear. Recent studies have identified an oral, MPH dose regimen which when given to rats produces drug plasma levels similar to those measured in humans. The current study examined the effects of these low, orally-administered doses of MPH in rats performing a delayed alternation task dependent on prefrontal cortex (PFC), a brain region that is dysfunctional in ADHD, and is highly sensitive to levels of catecholamines. The receptor mechanisms underlying the enhancing effects of MPH were explored by challenging the MPH response with the noradrenergic α2 adrenoceptor antagonist, idazoxan, and the dopamine D1 antagonist, SCH23390. Results: MPH produced an inverted U dose response whereby moderate doses (1.0–2.0 mg/kg, p.o.) significantly improved delayed alternation performance, while higher doses (2.0–3.0 mg/kg, p.o.) produced perseverative errors in many animals. The enhancing effects of MPH were blocked by co-administration of either the α2 adrenoceptor antagonist, idazoxan, or the dopamine D1 antagonist, SCH23390, in doses that had no effect on their own. Conclusion: The administration of low, oral doses of MPH to rats has effects on PFC cognitive function similar to those seen in humans and patients with ADHD. The rat can thus be used as a model for examination of neural mechanisms underlying the therapeutic effects of MPH on executive functions in humans. The efficacy of idazoxan and SCH23390 in reversing the beneficial effects of MPH indicate that both noradrenergic α2 adrenoceptor and dopamine D1 receptor stimulation contribute to cognitive-enhancing effects of MPH.

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Crossref · 10.1186/1744-9081-1-2

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  • 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).”

    From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Arnsten and Dudley, 2005

    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)

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  • 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).”

    From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Arnsten and Dudley, 2005

    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)

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  • Stimulants may upregulate neuroimaging activation patterns in the left cerebellum compared to controls given their indirect phosphorylation of the glutamate receptor through modulating the release of norepinephrine.

    “Our study reveals that stimulants may upregulate neuroimaging activation patterns in the left cerebellum compared to controls given their indirect phosphorylation of the glutamate receptor through modulating the release of norepinephrine”

    From Overlapping and differential neuropharmacological mechanisms of stimulants and nonstimulants for attention-deficit/hyperactivity disorder: A comparative neuroimaging analysis (2024) · cites this paper as Arnsten & Dudley, 2005

    The Background and Discussion (pages unavailable) say that methylphenidate and amphetamine increase norepinephrine in the rat prefrontal cortex. The paper does not link this effect to glutamate-receptor phosphorylation or report increased left-cerebellar neuroimaging activation relative to controls; the latter is framed as the citing authors’ own finding. (LLM, conf=0.84)

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  • Children with ADHD tend to show impaired planning abilities that can be restored with MPH.

    “This observation is in line with previous research demonstrating that children with ADHD tend to show impaired planning abilities (e.g., Clarke, Prior, & Kinsella, 2000) that can be restored with MPH (e.g., Arnsten & Dudley, 2005).”

    From Implementation Intentions Facilitate Response Inhibition in Children with ADHD (2008) · cites this paper as Arnsten & Dudley, 2005

    The Background links prefrontal dysfunction in ADHD to poor planning. The Discussion reports that MPH improves several cognitive functions in children and adults with ADHD, but it does not say that MPH restores planning abilities in children. The study’s own MPH results concern delayed alternation in rats, not planning in children; page numbers are unavailable in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • NE strengthens network connectivity of the PFC and maintains persistent firing of PFC neurons during working memory tasks through stimulation of postsynaptic α2-adrenoceptors.

    “Further, recent physiological studies have shown that NE strengthens network connectivity of the PFC and maintains persistent firing of PFC neurons during working memory tasks through stimulation of postsynaptic α2-adrenoceptors (Arnsten and Dudley, 2005).”

    From The Effects of Methylphenidate on Goal-directed Behavior in a Rat Model of ADHD (2015) · cites this paper as Arnsten and Dudley, 2005

    The Background (page unavailable) says NE improves working memory through postsynaptic α2A adrenoceptors in the PFC. The Discussion (page unavailable) reports that blocking α2 receptors reduces delay-related PFC neuronal activity, supporting the point about persistent activity during working memory. Our copy does not say that NE strengthens PFC network connectivity. (LLM, conf=0.86)

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Cites

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Research works printed but not linked: 1

  1. Arnsten AFT Castellanos FX Martin A, Scahill L, Charney D and Leckman J Neurobiology of attention regulation and its disorders Textbook of Child and Adolescent Psychopharmacology 2002 NY, Oxford Univ. Press 99 109

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Authors
Arnsten, A. F., & Dudley, A. G.
Affiliations
Yale University (US)
Corresponding author
Arnsten, Amy FT
ORCID
Venue
Behavioral and Brain Functions
Publisher
Springer Science and Business Media LLC
Published
2005-04-22
Volume
1
Issue
1
Pages
2-2
ISSN
1744-9081 (ISSN-L)
DOI
10.1186/1744-9081-1-2
PMC
PMC1143775
OpenAlex
W2124264649
Cited by
363
References
70
Citations by year
2026: 3 · 2025: 7 · 2024: 10 · 2023: 9 · 2022: 17 · 2021: 7 · 2020: 8 · 2019: 14 · 2018: 13 · 2017: 19 · 2016: 18 · 2015: 16 · 2014: 27 · 2013: 28 · 2012: 27
FWCI
15.31
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Behavioral and Brain Functions (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Shire
  • National Institutes of Health (5r21mh066393-03)
  • National Institute of Mental Health (R21-MH066393)
  • National Institute on Drug Abuse
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
methylphenidate, attention deficit hyperactivity disorder, prefrontal cortex, delayed alternation, executive function, alpha2-adrenoceptors, dopamine D1 receptor, idazoxan, SCH 23390, noradrenergic signaling, dopamine signaling, perseverative errors, dose-response relationship, rat model

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