The DOI matches its Crossref record; 137 of the 139 references it cites were found in a registry or an index; 10 of the 73 sources its claims cite were checked for support.
Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks
Open accessAbstract
The symptoms of attention-deficit/hyperactivity disorder (ADHD) involve impairments in prefrontal cortical top-down regulation of attention and behavior. All current pharmacological treatments for ADHD facilitate catecholamine transmission, and basic research suggests that these compounds have prominent actions in the prefrontal cortex (PFC). The dorsolateral PFC is especially sensitive to levels of norepinephrine and dopamine, whereby either too little or too much markedly impairs PFC function. Recent physiological studies have shown that norepinephrine strengthens PFC network connectivity and maintains persistent firing during a working memory task through stimulation of postsynaptic α(2A)-adrenoceptors on PFC neurons. Conversely, dopamine acts at D1 receptors to narrow spatial tuning, sculpting network inputs to decrease noise (i.e., stabilization of the representation). The stimulant medications and atomoxetine appear to enhance PFC function by indirectly increasing these catecholamine actions through blockade of norepinephrine and/or dopamine transporters. 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.
Overview
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Written from the paper’s full text.
TL;DR
This review argues that dorsolateral prefrontal cortex function depends on an inverted-U level of norepinephrine and dopamine, with norepinephrine α2A receptors strengthening network connectivity and dopamine D1 receptors narrowing spatial tuning. ADHD medications likely work by indirectly increasing or mimicking these catecholamine actions to improve prefrontal top-down regulation.
Key findings
- Norepinephrine and dopamine both show inverted-U effects on dorsolateral prefrontal working memory: moderate arousal-related release improves function, while depletion/fatigue or stress-level release impairs it. Norepinephrine α2A stimulation enhances delay-period firing for preferred directions by inhibiting cAMP-HCN signaling, whereas α1/β1 stimulation under stress impairs prefrontal function.
- Dopamine D1/5 stimulation has a complementary sculpting role: optimal levels suppress firing to nonpreferred directions and sharpen spatial tuning, while high D1/5 stimulation suppresses all firing and impairs working memory. D2 receptors mainly affect response-related firing rather than delay-period firing.
- ADHD medications act through catecholamine mechanisms: methylphenidate blocks norepinephrine and dopamine transporters and is more potent for norepinephrine than dopamine in rat prefrontal cortex; atomoxetine blocks the norepinephrine transporter and raises both norepinephrine and dopamine in prefrontal cortex; guanfacine directly mimics norepinephrine at postsynaptic α2A receptors. Atomoxetine at 40 mg increased right inferior prefrontal activity during a stop-signal task, while a much higher dose impaired go/no-go performance.
- Blocking α2 receptors in monkey dorsolateral prefrontal cortex reproduces ADHD-like symptoms: yohimbine infusions induced locomotor hyperactivity, no-go commission errors, and working memory deficits. Genetic variants in dopamine β-hydroxylase and the α2A receptor have been associated with ADHD and impaired prefrontal executive function.
Methods
- Narrative review synthesizing basic and clinical literature on catecholamine modulation of dorsolateral prefrontal cortical networks, with emphasis on working memory circuits.
- Evidence base includes monkey electrophysiology and iontophoresis during spatial working memory tasks, rodent biochemistry and slice physiology, and human pharmacological, imaging, and genetic studies.
- Main analysis is conceptual integration of receptor-specific mechanisms (α2A, α1, β, D1/5, D2) and medication effects; no systematic search or meta-analysis is described.
Limitations
- Stated in the paper: PET imaging cannot detect dopamine interactions with receptors in prefrontal cortex; available D1 drugs act at both D1 and D5, so pharmacological studies cannot separate these mechanisms; D2 response-cell microcircuitry is less understood and it is unknown whether GABA interneurons influence response cells; D1 agonists likely cannot reproduce the dynamic range of endogenous dopamine; the proposed atomoxetine dose-response hypothesis remains to be tested.
- Stated in the paper: human guanfacine evidence is mixed, with some studies showing cognitive improvement and at least one (Muller et al.) finding no effects on executive or memory functions in healthy volunteers.
- Evident from the text: this is a narrative review rather than a primary study, with much mechanistic evidence from nonhuman animals and a focus on dorsolateral prefrontal spatial working memory; human causal and prefrontal receptor imaging data are limited.
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Claims the paper makes
31 No full text of the sources · 11 Own interpretation · 6 Partly supported · 2 Supported · 1 Supported so far · 1 Not checked yet · 1 No basis given · accuracy not yet measured
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“The stimulant medications and atomoxetine appear to enhance PFC function by indirectly increasing these catecholamine actions through blockade of norepinephrine and/or dopamine transporters.”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > Abstract
What the sources say
- Not checked — no full text of the sourcecites [83] Berridge, 2006, Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function, Biol Psychiatry source
- Supportedcites [90] Bymaster, 2002, Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: A potential mechanism for efficacy in attention deficit/hyperactivity disorder, Neuropsychopharmacology source
The Discussion proposes that enhanced prefrontal catecholamine neurotransmission contributes to the efficacy of both psychostimulants and atomoxetine. It identifies atomoxetine as an NE-transporter inhibitor and reports that methylphenidate, a psychostimulant with affinity for the DA transporter, also raises prefrontal NE and DA. The paper presents improved PFC function as a proposed mechanism, consistent with the citing sentence’s hedge. Page numbers were not available in our copy. (LLM, conf=0.90)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Every source the paper cites for this claim was checked and supports it.
In the paper
“Research in rodent medial PFC has shown that D2 receptor stimulation can reduce GABAergic inputs to pyramidal cells (130).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > D2 Receptor Mechanisms
What the sources say
- Supportedcites [130] Seamans, 2001, Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons, J Neurosci source
The Materials and Methods describe recordings from pyramidal neurons in rat prelimbic–infralimbic PFC slices, matching rodent medial PFC. The Discussion reports that D2 receptor activation reduced evoked GABAergic inhibitory currents in those neurons. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Supported
In the paper
“In contrast to α2A receptors, infusion of an α1 agonist directly into the dorsolateral PFC impairs working memory performance (42).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > The Underappreciated Role of Norepinephrine
What the sources say
- Not checked — no full text of the sourcecites [42] Mao, 1999, Local infusion of an alpha-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys, Biol Psychiatry source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Guanfacine administration to children with ADHD and tics improved performance of a Conners’ Continuous Performance Test task that requires sustained attention, working memory, and behavioral inhibition (95).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > NE Mechanisms and ADHD Medications
What the sources say
- Not checked — no full text of the sourcecites [95] Scahill, 2001, A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder, Am J Psychiatry source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This research began with the landmark discovery that depletion of catecholamines from the dorsolateral PFC was as detrimental as ablation of the cortical tissue itself (4).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > The Strength of Network Connections Is Rapidly Altered by the Neurochemical Environment: Integrating Arousal and Cognition
What the sources say
- Not checked — no full text of the sourcecites [4] Brozoski, 1979, Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey, Science source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Dopamine has an inverted U-shaped influence on working memory abilities via actions at the D1 receptor family in both animals (100) and humans (105).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > D1/5 Receptor Mechanisms
What the sources say
- Not checked — no full text of the sourcecites [100] Arnsten, 2009, Dopamine's influence on prefrontal cortical cognition: Actions and circuits in behaving primates source
- Not checked — no full text of the sourcecites [105] Gibbs, 2006, A functional magnetic resonance imaging study of the effects of pergolide, a dopamine receptor agonist, on component processes of working memory, Neuroscience source
plaindirect- Asserted: passes — The authors put it forward as true.
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A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“In contrast, guanfacine mimics the enhancing effects of norepinephrine at postsynaptic α2A-receptors in the PFC, strengthening network connectivity.”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > Abstract
What the sources say
- Not checked — no full text of the sourcecites [35] Arnsten, 1985, Alpha 2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates, Science source
- Not checked — no full text of the sourcecites [41] Cai, 1993, Reserpine impairs spatial working memory performance in monkeys: Reversal by the alpha 2-adrenergic agonist clonidine, Brain Res source
- Not checked — no full text of the sourcecites [42] Mao, 1999, Local infusion of an alpha-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys, Biol Psychiatry source
- Not checked — no full text of the sourcecites [43] Ramos, 2006, Alpha2A-adrenoceptor stimulation improves prefrontal cortical regulation of behavior through inhibition of cAMP signaling in aging animals, Learn Mem source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Stronger PFC regulation of attention, behavior, and emotion likely contributes to the therapeutic effects of these medications for the treatment of ADHD.”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Biochemical studies in rats have consistently shown that both DA and NA release are increased in the medial PFC during acute stress exposure (30–32).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > The Strength of Network Connections Is Rapidly Altered by the Neurochemical Environment: Integrating Arousal and Cognition
What the sources say
- Not checked — no full text of the sourcecites [30] Roth, 1988, Stress and the mesocorticolimbic dopamine systems, Ann NY Acad Sci source
- Not checked — no full text of the sourcecites [31] Deutch, 1990, The determinants of stress-induced activation of the prefrontal cortical dopamine system, Prog Brain Res source
- Not checked — no full text of the sourcecites [32] Finlay, 1995, Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: Effects of diazepam, Neuroscience source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Recent physiological studies have shown that norepinephrine strengthens PFC network connectivity and maintains persistent firing during a working memory task through stimulation of postsynaptic α2A-adrenoceptors on PFC neurons.”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > Abstract
What the sources say
- Not checked — no full text of the sourcecites [57] Wang, 2007, Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex, Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 20
- Probably not a substantial claim. 1
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Systemic administration of an α1 agonist that crosses the blood brain barrier also impairs working memory performance, while administration of an α1 antagonist, e.g., prazosin, can protect working memory performance during stress (37,50,51).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > The Underappreciated Role of Norepinephrine
What the sources say
- Partly supportedcites [37] Birnbaum, 1999, A role for norepinephrine in stress-induced cognitive deficits: Alpha-1-adrenoceptor mediation in the prefrontal cortex, Biol Psychiatry sourceExperimental — accuracy not yet measured
The Discussion reports that α1 stimulation in the prefrontal cortex impairs spatial working memory and that intra-PFC urapidil reversed a pharmacological stressor’s effect on response accuracy in rats (page not available in our copy). It does not establish that a blood–brain-barrier-crossing α1 agonist was administered systemically, or that prazosin protected working memory during stress; its prazosin example concerns performance under nonstress conditions. (LLM, conf=0.86)
- Partly supportedcites [50] Arnsten, 1997, The alpha-1 adrenergic agonist, cirazoline, impairs spatial working memory performance in aged monkeys, Pharmacol Biochem Behav sourceExperimental — accuracy not yet measured
The Drug Administration and Results sections report systemic cirazoline treatment in aged monkeys, impaired spatial working memory, and reversal of that impairment by prazosin (page numbers unavailable). The Discussion proposes that α1 mechanisms may contribute to cognitive impairment during stress, but the paper does not show that prazosin protects working memory during stress. It describes cirazoline's brain penetrance as purported rather than directly demonstrating it. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [51] Arnsten, 1999, Alpha-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function, Biol Psychiatry source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Like methylphenidate, atomoxetine also blocks the NE transporter (Figure 2E), and as the NE transporter clears both NE and DA in the PFC, this increases extracellular levels of both catecholamines (90).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > NE Mechanisms and ADHD Medications
What the sources say
- Partly supportedcites [90] Bymaster, 2002, Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: A potential mechanism for efficacy in attention deficit/hyperactivity disorder, Neuropsychopharmacology sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) reports that atomoxetine inhibits the NE transporter, that this transporter takes up dopamine in the PFC, and that atomoxetine increases extracellular NE and dopamine there. It presents transporter-mediated dopamine clearance as a proposed explanation, however, and says other interactions may also contribute; the citing sentence states that causal explanation more definitively than the paper does. (LLM, conf=0.82)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“A common misconception is that methylphenidate is a selective DA transporter blocker, when in actuality it blocks both NE and DA transporters. Indeed, methylphenidate has more potent effects on NE than DA in the rat PFC (83) (84).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > NE Mechanisms and ADHD Medications
What the sources say
- Not checked — no full text of the sourcecites [83] Berridge, 2006, Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function, Biol Psychiatry source
- Partly supportedcites [84] Berridge, 2011, Psychostimulants as cognitive enhancers: The prefrontal cortex, catecholamines, and attention-deficit/hyperactivity disorder, Biol Psychiatry sourceExperimental — accuracy not yet measured
The section “Neurochemical Actions of Low-Dose Psychostimulants” (page not supplied) states that methylphenidate blocks both NE and DA reuptake and increases both in the rat PFC. It does not say that its effects on NE are more potent than its effects on DA in the rat PFC. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Data from studies of monkey dorsolateral PFC demonstrate an inverted-U dose-response: moderate levels of NE released during alert, nonstressed waking improve working memory performance by engaging postsynaptic, α2A receptors (35,36), whereas high levels of NE released during stress impair PFC function via stimulation of lower affinity α1 (37) and β1 receptors (38).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > The Underappreciated Role of Norepinephrine
What the sources say
- Not checked — no full text of the sourcecites [35] Arnsten, 1985, Alpha 2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates, Science source
- Not checked — no full text of the sourcecites [36] Li, 1994, Delayed-response deficit induced by local injection of the alpha 2-adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys, Behav Neural Biol source
- Partly supportedcites [37] Birnbaum, 1999, A role for norepinephrine in stress-induced cognitive deficits: Alpha-1-adrenoceptor mediation in the prefrontal cortex, Biol Psychiatry sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [38] Ramos, 2005, The beta-1 adrenergic antagonist, betaxolol, improves working memory performance in rats and monkeys, Biol Psychiatry source
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Norepinephrine has the highest affinity for α2 adrenergic receptors and lower affinity for α1 and β receptors (34).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > The Underappreciated Role of Norepinephrine
What the sources say
- Supportedcites [34] Arnsten, 2000, Through the looking glass: Differential noradenergic modulation of prefrontal cortical function, Neural Plast source
The discussion and Fig. 4 caption (pp. 141–142) state that norepinephrine has higher affinity for α2A receptors than for α1 or β receptors. The claim paraphrases this comparison, using the broader α2 label for the α2A subtype specified in the paper. (LLM, conf=0.93)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Cognitive studies in animals have shown that either blockade of D1/5 receptors or excessive stimulation of D1/5 receptors in the PFC impairs spatial working memory (106–108).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > D1/5 Receptor Mechanisms
What the sources say
- Not checked yetcites [106] Arnsten, 1990, Stress impairs prefrontal cortex cognitive function in monkeys: Role of dopamine, Soc Neurosci Abstr
- Not checked — no full text of the sourcecites [107] Sawaguchi, 1991, D1 dopamine receptors in prefrontal cortex: Involvement in working memory, Science source
- Partly supportedcites [108] Zahrt, 1997, Supranormal stimulation of D1 dopamine receptors in the rodent prefrontal cortex impairs spatial working memory performance, J Neurosci sourceExperimental — accuracy not yet measured
The paper reports that excessive D1 receptor stimulation in rat PFC impaired delayed-alternation performance, a spatial working-memory task. Its introduction also describes evidence that insufficient D1 stimulation impairs PFC cognition, but this study’s antagonist dose alone did not impair performance (Experiment 2, page unavailable). The passages identify D1 receptors, not D1/5 receptors, so the D5 part of the claim is not established by this source. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The D2 receptors are less prevalent in monkey dorsolateral PFC and are concentrated on layer V neurons, the layer that projects to striatum and the superior colliculus (98,122,123).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > D2 Receptor Mechanisms
What the sources say
- Not checked — no full text of the sourcecites [98] Lidow, 1998, Layer V neurons bear the majority of mRNAs encoding the five distinct dopamine receptor subtypes in the primate prefrontal cortex, Synapse source
- Partly supportedcites [122] Lidow, 1989, Dopamine D2 receptors in the cerebral cortex: Distribution and pharmacological characterization with [3H]raclopride, Proc Natl Acad Sci U S A sourceExperimental — accuracy not yet measured
The Discussion reports that D2 binding sites are considerably less concentrated in primate cortex than in the neostriatum, and the Results report binding in monkey prefrontal cortex. The paper does not establish that receptors are concentrated on layer V neurons or identify layer V projections to the striatum and superior colliculus; it measures binding by cortical region, not neuronal layer. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [123] Lidow, 1991, Distribution of dopaminergic receptors in the primate cerebral cortex: quantitative autoradiographic analysis using [3H]raclopride, [3H]spiperone and [3H]SCH23390, Neuroscience source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“Dopamine neurons have not been followed as methodically with regard to states of arousal but have been shown to fire related to prediction of reward (28).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > The Strength of Network Connections Is Rapidly Altered by the Neurochemical Environment: Integrating Arousal and Cognition
What the sources say
- Not checked — no full text of the sourcecites [28] Schultz, 1998, The phasic reward signal of primate dopamine neurons, Adv Pharmacol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Stimulation of α2A receptors increases delay-related firing of PFC neurons via inhibition of cyclic adenosine mono-phosphate (cAMP) (57), while stimulation of α1 receptors decreases delay-related firing via activation of phosphatidylinositol protein kinase C signaling (58).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > The Underappreciated Role of Norepinephrine
What the sources say
- Not checked — no full text of the sourcecites [57] Wang, 2007, Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex, Cell source
- Not checked — no full text of the sourcecites [58] Birnbaum, 2004, Protein kinase C overactivity impairs prefrontal cortical regulation of working memory, Science source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Stimulation of α2A receptors strengthens firing for the neuron’s preferred direction by inhibiting cAMP production, which, in turn, reduces cAMP opening of potassium channels, increasing the efficacy of nearby synaptic inputs (Figure 2E).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > The Underappreciated Role of Norepinephrine
What the sources say
- Not checked — no full text of the sourcecites [57] Wang, 2007, Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex, Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“The dorsolateral PFC is especially sensitive to levels of norepinephrine and dopamine, whereby either too little or too much markedly impairs PFC function.”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > Abstract
What the sources say
- Not checked — no full text of the sourcecites [4] Brozoski, 1979, Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey, Science source
- Not checked — no full text of the sourcecites [5] Arnsten, 1985, Stress produces opioid-like effects on investigatory behavior, Pharmacol Biochem Behav source
- Not checked — no full text of the sourcecites [6] Roberts, 1994, 6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: Possible interactions with subcortical dopamine, J Neurosci source
- Not checked — no full text of the sourcecites [7] Robbins, 2007, Differential regulation of fronto-executive function by the monoamines and acetylcholine, Cereb Cortex source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Either depletion of NE (35) or blockade of α2A receptors in PFC (36) impairs working memory performance in monkeys, suggesting that endogenous NE plays a large role in strengthening working memory performance.”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > The Underappreciated Role of Norepinephrine
What the sources say
- Not checked — no full text of the sourcecites [35] Arnsten, 1985, Alpha 2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates, Science source
- Not checked — no full text of the sourcecites [36] Li, 1994, Delayed-response deficit induced by local injection of the alpha 2-adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys, Behav Neural Biol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Norepinephrine neurons in the locus coeruleus are silent during rapid eye movement sleep and have low tonic firing during slow wave sleep, moderate tonic firing and pronounced phasic firing to relevant stimuli during nonstressed waking, and high tonic firing with dysregulated phasic firing during stress (27).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > The Strength of Network Connections Is Rapidly Altered by the Neurochemical Environment: Integrating Arousal and Cognition
What the sources say
- Not checked — no full text of the sourcecites [27] Aston-Jones, 1999, Role of locus coeruleus in attention and behavioral flexibility, Biol Psychiatry source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These studies have revealed that NE and DA have complementary effects on the strength of PFC network connections, with NE strengthening connectivity via α2A receptor stimulation and DA sculpting network inputs via D1 receptors.”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Iontophoresis of an α2A agonist such as guanfacine onto PFC neurons enhances neuronal firing during the delay period for the neurons’ preferred direction (Figure 3A), while blockade of α2A receptors markedly reduces PFC neuronal firing during the delay period (indeed, high doses can silence a neuron) (57,61).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > The Underappreciated Role of Norepinephrine
What the sources say
- Not checked — no full text of the sourcecites [57] Wang, 2007, Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex, Cell source
- Not checked — no full text of the sourcecites [61] Li, 1999, Alpha-2 adrenergic modulation of prefrontal cortical neuronal activity related to spatial working memory in monkeys, Neuropsychopharmacology source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“All medications currently approved for the treatment of ADHD influence NE transmission (Figure 2E), and all can improve at least some aspects of PFC function (82).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > NE Mechanisms and ADHD Medications
What the sources say
- Not checked — no full text of the sourcecites [82] Chamberlain, 2011, Translational approaches to frontostriatal dysfunction in attention-deficit/hyperactivity disorder using a computerized neuropsychological battery, Biol Psychiatry source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Animal studies have also shown that the enhancing effects of methylphenidate and atomoxetine on working memory performance involve D1/5 receptor stimulation, as well as the NE α2 receptor actions described above.”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > DA Mechanisms and ADHD Medications
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Studies of catecholamine actions on dorsolateral PFC microcircuitry have revealed intricate and powerful mechanisms to regulate the strength of persistent neuronal firing and the degree of neuronal tuning.”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > Conclusions
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Iontophoresis of D2 drugs onto PFC neurons has no effect on delay cell firing during the delay period in a working memory task but has marked effects on response cell firing in relationship to the eye movement response (124).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > D2 Receptor Mechanisms
What the sources say
- Not checked — no full text of the sourcecites [124] Wang, 2004, Selective D2 receptor actions on the functional circuitry of working memory, Science source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“On the other hand, stimulants likely enhance motivation and other striatal functions not engaged by NE medications (135).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > DA Mechanisms and ADHD Medications
What the sources say
- Not checked — no full text of the sourcecites [135] Cousins, 1996, Nucleus accumbens dopamine depletions alter relative response allocation in a T-maze cost/benefit task, Behav Brain Res source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Thus, DA and NE have complementary roles: NE α2A receptor stimulation enhances network firing for shared, preferred inputs (i.e., increasing signals [57]), whereas D1 receptor stimulation sculpts neuronal firing by decreasing firing to nonpreferred inputs (i.e., decreasing noise [109]).”
§ Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks > D1/5 Receptor Mechanisms
What the sources say
- Not checked — no full text of the sourcecites [57] Wang, 2007, Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex, Cell source
- Not checked — no full text of the sourcecites [109] Vijayraghavan, 2007, Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory, Nat Neurosci source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Many symptoms of ADHD arise from dysfunction of the prefrontal cortex and its connections with cortical and subcortical brain regions.
“As described in this special issue, many of the symptoms of attention-deficit/hyperactivity disorder (ADHD) are thought to arise from dysfunction of the prefrontal cortex (PFC) and its connections with cortical and subcortical brain regions.”
The paper relies on this without support.
Prefrontal cortex networks are able to represent information in the absence of bottom-up external stimulation, but this fragile process is tremendously dependent on the correct neurochemical environment.
“Prefrontal cortex networks are able to represent information in the absence of bottom-up external stimulation, but this fragile process is tremendously dependent on the correct neurochemical environment, whereby arousal pathways coordinate cognitive state with environmental events.”
Claims other papers make about this one
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The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“microdialysis studies suggest that atomoxetine may selectively increase dopamine levels in the prefrontal cortex, via the norepinephrine transporter or perhaps via a secondary signaling mechanism [23].”
From Atomoxetine Effects on Executive Function as Measured by the BRIEF-A in Young Adults with ADHD: A Randomized, Double-Blind, Placebo-Controlled Study (2014) · cites this paper as [23]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“However, excessive DA stimulation might cause PFC dysfunction leading to impaired inhibition of undesirable behavior, and a deficit in sustaining attention, as these two behaviors are highly regulated by dopaminergic release in the PFC (Russell, 2003; Brennan and Arnsten, 2008; Arnsten, 2011).”
From The Effects of Methylphenidate on Goal-directed Behavior in a Rat Model of ADHD (2015) · cites this paper as Arnsten, 2011
In the citing paper
“Reduced catecholamine transmission has been linked to ADHD, while overamplified noradrenergic transmission is associated with PTSD 46.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [46]
In the citing paper
“Stimulation of D1R produces an inverted-U dose response on PFC neuronal firing and cognitive performance during working memory tasks 46.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [46]
In the citing paper
“Norepinephrine (NE) and dopamine (DA) are believed to modulate attention and other cognitive capabilities105, generally with dose–response following classic inverted-U shaped curves.”
From Paying attention to attention in depression (2019) · cites this paper as [105]
In the citing paper
“both neuromodulators have distinct roles to facilitate information processing in the prefrontal cortex [33, 34].”
In the citing paper
“Although much previous work on cognitive functioning has stressed the importance of intact dopaminergic levels, particularly with respect to functions mediated by prefrontal cortex, such as working memory, it is now being recognized that norepinephrine plays a similarly important role [33]”
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Cited by
Sorted by citations
Items 401–494 of 494
The cognitive fatigue experienced by batters is modulated by the strike rate of a twenty20 innings
Lopes, T., Goble, D., Kerr, S., & Olivier, B. (2025) · International Journal of Sport and Exercise Psychology · doi:10.1080/1612197x.2025.2510257 · Cited by 1
“…exercise of very high intensity, at or beyond the athlete’s lactate threshold (Borer, 2003), causes excessive endocrinological catecholamine release and the oversaturation of norepinephrine in the PFC – impairing the signal–noise ratio by activating low-affinity α 1 -receptors (Arnsten, 2011).”
Involvement of Dopamine in Cognitive Improvement by Aerobic Exercise
Ando, S., Fujimoto, T., Sudo, M., & Tashiro, M. (2025) · Advances in neurobiology · doi:10.1007/978-981-95-0066-6_10 · Cited by 2
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“Larger pupil size has been associated with increased Locus Coeruleus activity and secretion of noradrenaline (Murphy et al. 2014), a catecholamine known for being involved in the modulation of cortical activity, particularly in the prefrontal cortex (Aston-Jones and Cohen 2005; Arnsten 2011).”
Kutter, E. F., Viswanathan, P., & Nieder, A. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2600210123 · Cited by 1
“D1 receptors (D1Rs) enhance the stability and maintenance of task - relevant information by boosting signal - to - noise ratios and strengthening recurrent excitation in prefrontal networks, thereby supporting selective activity and resistance to distraction (23, 36–40).”
Distinct activity in prefrontal projections promotes temporal control of action
Ding, X., Weber, M. A., Butler, T. C., Bova, A. S., Guerrero, S. G., Hunter, C. M., Cole, R. C., Stutt, H. R., McMurrin, M. S., Spicer, M. M., et al. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2538059123 · Cited by 3
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“Dopaminergic signalling is particularly important for coordinating activity within interconnected cortical and subcortical brain regions involved in executive function [18].”
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Carboni, E., Cadeddu, R., & Rosa, A. (2012) · InTech eBooks · doi:10.5772/51221 · Cited by 1
“, 2011), schizophrenia (Arnsten, 2011), and Parkinson’s disease (Luft and Schwarz, 2009).”
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Kilian, B., & Sidiropoulos, K. (2023) · Springer eBooks · doi:10.1007/978-3-662-65726-3_3 · Cited by 1
Rogóż, Z., Kamińska, K., Lorenc‐Koci, E., & Wąsik, A. (2024) · Pharmacological Reports · doi:10.1007/s43440-024-00626-0 · Cited by 1
“Several studies confirm that the activity of DA neurons is important for learning, and disruption of DA transmission is suspected to underlie several psychiatric conditions including schizophrenia, depression, and attention-deficit hyperactivity disorder [30–32].”
BackgroundSahlholm, K., Svensson, P., Malo, M., et al. (2025) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5c00270 · Cited by 1
Endogenous conversion of alcohol to norepinephrine and epinephrine may contribute to hangover
Fitzgerald, P. J., Właź, P., & Socała, K. (2025) · Medical Hypotheses · doi:10.1016/j.mehy.2025.111716 · Cited by 1
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Milivojevic, V., Sinha, R., & Fox, H. C. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-803750-8.00069-5 · Cited by 1
Management and treatment of attention-deficit/hyperactivity disorder
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Intervention, Treatment, and Management of ADHD
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The role of the medial prefrontal cortex in delay discounting
Beckwith, S. W. (2017) · Purdue e-Pubs (Purdue University System) · doi:10.7912/c2365b · Cited by 1
“This parallels the inverted “U” model of prefrontal function where an optimal level of DA neuromodulation is needed (Arnsten, 2011, Cools and D’Esposito, 2011; Floresco et al., 2013).”
BackgroundRole of prefrontal cortex and cholinergic modulation in attentional performance in rats
Fisher, B. M. (2017) · Apollo (University of Cambridge) · doi:10.17863/cam.21750 · Cited by 1
“Within the mPFC in rats, cholinergic, monoaminergic and catecholamine neurotransmitter systems modulate cortical networks and cognitive functions; which resembles aspects of the primate dorsolateral PFC (Hasselmo 1995; Arnsten 1997; Robbins 2000; Arnsten 2011; for review see Uylings et al. 2003).”
BackgroundAli, S. A., Ali, S. N., & Khan, R. (2023) · Preprints.org · doi:10.20944/preprints202304.0170.v1 · Cited by 1
Desor, F., Hajj, A. E., Herzine, A., Djelti, F., Bombail, V., Denis, I., Oster, T., Malaplate, C., Lanhers, M., Yen, F. T., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.27.582228 · Cited by 1
“ADHD is characterized by poor impulse control, weak sustained attention, and heightened distractibility, and has been linked to deficits in prefrontal cortex functioning [31].”
BackgroundHeinbockel, H., Leicht, G., Wagner, A. D., & Schwabe, L. (2024) · eLife · doi:10.7554/elife.100525 · Cited by 1
“This idea is in line with previous reports of inverted U-shaped relationships between noradrenergic arousal and memory processes ( Arnsten, 2011 ; Hernaus et al., 2017 ; Birnbaum et al., 1999 ; Li and Mei, 1994 ).”
Biernacki, K., Zhai, T., Hill, J., McConnell, E., Salmeron, B. J., Kaiser, R. H., & Janes, A. C. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.30.679567 · Cited by 1
“These current findings fit with the literature as engagement of the dlPFC is sensitive to variance in dopamine and norepinephrine function [64,65].”
Behavioral impulsivity and hallucinations : insights from Parkinson's disease
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VTA neurons correlates with stimulus detection Distinct prestimulus and poststimulus activation of
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Pasquini, J., Palermo, G., Pavese, N., & Ceravolo, R. (2026) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-026-01499-x
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Central neural circuits and their associated mechanisms of inter-organ crosstalk
Kang, L., Salas-Hernandez, J. L., & Xu, R. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1830768
“…function is encoded by spatial localization (Macgillavry et al., 2013; Ferreira et al., 2020), temporal dynamics (Booker et al., 2017; Ren et al., 2022; Gonzalez-Hernandez et al., 2024), and molecular combinations (Gamo et al., 2015; Arnsten, 2011), which is a process called molecular cross-coding.”
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Blunted modulation of hierarchical brain organization in opioid use disorderPreprint
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Mechanistic insights into combined prefrontal tDCS and vagal nerve stimulation for stress regulation
Roy, S., & Vanderhasselt, M. (2026) · Frontiers in Psychology · doi:10.3389/fpsyg.2026.1872276
“Elevated NE release under stress activates lower-affinity α 1 and β -adrenoreceptors, triggering intracellular cascades (including PKA and PKC signaling) that can destabilize persistent cortical firing and raise the threshold for LTP induction (Arnsten, 2011).”
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“…through α 1-and β -adrenergic receptors, thereby increasing the probability of successfully reinstating memory cues; however, excessively high or low NE release disrupts the retrieval process, leading to reduced retrieval efficiency or diminished accuracy (Fukabori and Iguchi, 2020; Arnsten, 2011).”
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The therapeutic potential of COMT inhibition: cognition and beyond
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Human cognitive responses to high temperature in normoxic and hypobaric environments
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Metadata
- Authors
- Arnsten, A. F. T.
- Affiliations
- Yale University (US)
- Corresponding author
- Arnsten, Amy F.T.
- ORCID
- Arnsten, Amy F.T.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 69
- Issue
- 12
- Pages
- e89-e99
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3145207
- OpenAlex
- W2091646494
- Cited by
- 493
- References
- 139
- Citations by year
- 2026: 40 · 2025: 40 · 2024: 33 · 2023: 30 · 2022: 14 · 2021: 24 · 2020: 26 · 2019: 32 · 2018: 30 · 2017: 34 · 2016: 36 · 2015: 49 · 2014: 36 · 2013: 26 · 2012: 33
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (RL1AA017536)
- National Institute on Aging (R37AG006036, P01AG030004, R01AG006036, AG06036)
- National Institute of Mental Health (P50MH068789)
- 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, dorsolateral prefrontal cortex, catecholamines, norepinephrine, dopamine, alpha2A-adrenoceptor, dopamine D1 receptor, network connectivity, working memory, atomoxetine, guanfacine, stimulant medication, norepinephrine transporter, dopamine transporter
- MeSH terms
- Atomoxetine Hydrochloride, Adrenergic alpha-Agonists, Animals, Arousal, Attention Deficit Disorder with Hyperactivity, Catecholamines, Cognition, Humans, Memory, Short-Term, Methylphenidate, Models, Neurological, Neural Pathways, Synaptic Transmission, Propylamines, Guanfacine, Prefrontal Cortex, Adrenergic Uptake Inhibitors
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