The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.
Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory
Abstract
Dopamine (DA) D1 receptor (D1R) stimulation in prefrontal cortex (PFC) produces an 'inverted-U' dose-response, whereby either too little or too much D1R stimulation impairs spatial working memory. This response has been observed across species, including genetic linkages with human cognitive abilities, PFC activation states and DA synthesis. The cellular basis for the inverted U has long been sought, with in vitro intracellular recordings supporting a variety of potential mechanisms. The current study demonstrates that the D1R agonist inverted-U response can be observed in PFC neurons of behaving monkeys: low levels of D1R stimulation enhance spatial tuning by suppressing responses to nonpreferred directions, whereas high levels reduce delay-related firing for all directions, eroding tuning. These sculpting actions of D1R stimulation are mediated in monkeys and rats by cyclic AMP intracellular signaling. The evidence for an inverted U at the cellular level in behaving animals promises to bridge in vitro molecular analyses with human cognitive experience.
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In the citing paper
“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.”
From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Vijayraghavan et al., 2007
In the citing paper
“In the PFC, DA plays a role complementary to that of NE, decreasing PFC neuronal activity in response to irrelevant stimuli. (Vijayraghavan et al., 2007).”
From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Vijayraghavan et al., 2007
In the citing paper
“D1-receptors have fundamental excitatory effects on PFC function, but also modify inputs to pyramidal cells (Vijayraghavan et al., 2007).”
From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Vijayraghavan et al., 2007
In the citing paper
“As a result, PFC neurons require a specific amount of DA to function optimally (Arnsten et al., 2009; Vijayraghavan et al., 2007).”
From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Vijayraghavan et al., 2007
In the citing paper
“Similar results are observed at the cellular level, whereby Sp-cAMPS, high doses of D1 agonist or a phosphodiesterase inhibitor all suppress neuronal firing in monkeys performing a working memory task, whereas inhibition of cAMP or gentle blockade of HCN channels restores normal firing patterns60,68.”
From Stress signalling pathways that impair prefrontal cortex structure and function (2009) · cites this paper as [68]
In the citing paper
“Conversely, we propose that in an ODR task, D1 receptors suppress neuronal responses to non-preferred directions by increasing cAMP production68 and opening HCN channels on spines that receive network inputs from cells that are tuned to these other directions (FIG. 4a).”
From Stress signalling pathways that impair prefrontal cortex structure and function (2009) · cites this paper as [68]
In the citing paper
“The impairment in working memory that is induced by stress exposure or excessive D1 receptor stimulation can be prevented by blocking cAMP activity or HCN channels in the PFC60,68 (A.F.T.A., unpublished observations) or can be mimicked by administering the cAMP analogue Sp-cAMPS96.”
From Stress signalling pathways that impair prefrontal cortex structure and function (2009) · cites this paper as [68]
In the citing paper
“The inverted U-shaped relationship can also be observed at the cellular level (FIG. 2b), where an optimal level of D1 receptor stimulation enhances spatial tuning by suppressing delay-related firing to the neurons’ non-preferred directions in the ODR task68.”
From Stress signalling pathways that impair prefrontal cortex structure and function (2009) · cites this paper as [68]
In the citing paper
“Conversely, dopamine acts at D1 receptors to narrow spatial tuning, sculpting network inputs to decrease noise (i.e., stabilization of the representation).”
From Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks (2011) · cites this paper as [109]
In the citing 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]).”
From Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks (2011) · cites this paper as [109]
In the citing paper
“This inverted U-shaped relationship can be observed at the cellular level (Figure 3B), where an optimal level of D1/5 receptor stimulation enhances spatial tuning by suppressing delay-related firing to the neurons’ nonpreferred directions (109).”
From Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks (2011) · cites this paper as [109]
In the citing paper
“In contrast to moderate D1/5 receptor stimulation, high doses of D1/5 agonist suppress all neuronal firing (Figure 3B, right side of curve).”
From Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks (2011) · cites this paper as [109]
In the citing paper
“Conversely, inhibition of Ca2+–PKC or cAMP–PKA signaling, or blockade of HCN channels, can rescue PFC delay-cell firing and working memory functions57,60,62.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [60]
In the citing paper
“Norepinephrine α1-ARs activate Ca2+–protein kinase C (PKC) signaling, which reduces delay-cell firing in the primate dlPFC57, while high levels of dopamine D1R stimulation reduce dlPFC delay-cell firing by increasing cAMP–protein kinase A (PKA) signaling60.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [60]
In the citing paper
“As is the case with selective attention, dopamine D1 receptors also appear to modulate visuo-spatial working memory-related activity in the monkey PFC (e.g. [19])”
From Linking ADHD to the Neural Circuitry of Attention (2017) · cites this paper as [19]
In the citing paper
“With nonhuman primates we can, for example, interrogate how catecholaminergic circuits in the prefrontal cortex contribute to ADHD-linked behaviors (e.g. [19,47])”
From Linking ADHD to the Neural Circuitry of Attention (2017) · cites this paper as [19]
In the citing paper
“Dopaminergic signalling has a role in the top-down regulation of spatial attention, and D1 dopaminergic receptors modulate response amplitude and selectivity in the dorsolateral prefrontal cortex for preferred spatial locations during working memory tasks204,205.”
From Mechanisms underlying gain modulation in the cortex (2020) · cites this paper as [204]
In the citing paper
“Dopaminergic signalling has a role in the top-down regulation of spatial attention, and D1 dopaminergic receptors modulate response amplitude and selectivity in the dorsolateral prefrontal cortex for preferred spatial locations during working memory tasks204,205.”
From Mechanisms underlying gain modulation in the cortex (2020) · cites this paper as [204]
In the citing paper
“Dopamine effects on behavior follow an inverted U-shaped dose-response curve, with both deficient and excessive amounts of dopamine activity predicting poor cognitive tasks performance (24,25).”
From Influence of the COMT genotype on working memory and brain activity changes during development (2011) · cites this paper as [24]
In the citing paper
“PFC functioning and WM performance have been suggested to follow an inverted-U curve function of dopamine levels (24), with adult rs4680 Met/Met individuals near the apex of this curve (2).”
From Influence of the COMT genotype on working memory and brain activity changes during development (2011) · cites this paper as [24]
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Metadata
- Authors
- Vijayraghavan, S., Wang, M., Birnbaum, S. G., Williams, G. V., & Arnsten, A. F. T.
- Affiliations
- Yale University (US)
- Venue
- Nature Neuroscience
- Published
- 2007-02-04
- Volume
- 10
- Issue
- 3
- Pages
- 376-384
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2046835548
- Cited by
- 1,013
- References
- 50
- Citations by year
- 2026: 29 · 2025: 27 · 2024: 55 · 2023: 53 · 2022: 48 · 2021: 50 · 2020: 53 · 2019: 49 · 2018: 47 · 2017: 50 · 2016: 58 · 2015: 69 · 2014: 61 · 2013: 73 · 2012: 68
- FWCI
- 22.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (P50MH068789)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- dopamine D1 receptor, prefrontal cortex, spatial working memory, neuronal firing patterns, spatial tuning, cAMP signaling, monkeys, rats
- MeSH terms
- Action Potentials, Cyclic AMP, Analysis of Variance, Animals, Behavior, Animal, Dose-Response Relationship, Drug, Drug Interactions, Iontophoresis, Macaca mulatta, Male, Memory, Short-Term, Neurons, Neuropsychological Tests, Sensitivity and Specificity, Thionucleotides, Dopamine Agents, Rats, Sprague-Dawley, Prefrontal Cortex, Receptors, Dopamine D1, Maze Learning, Rats
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