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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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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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“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
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“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
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“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
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“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
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“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
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“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).”
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
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“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.”
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
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Metadata
- Authors
- Arnsten, A. F., & Dudley, A. G.
- Affiliations
- Yale University (US)
- Corresponding author
- Arnsten, Amy FT
- Venue
- Behavioral and Brain Functions
- Published
- 2005-04-22
- Volume
- 1
- Issue
- 1
- Pages
- 2-2
- ISSN
- 1744-9081 (ISSN-L)
- 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
- gold
- doi.org
- 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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