Key role of the dopamine D
            <sub>4</sub>
            receptor in the modulation of corticostriatal glutamatergic neurotransmission

Bonaventura, Jordi; Quiroz, César; Cai, Ning-Sheng; Rubinstein, Marcelo; Tanda, Gianluigi; Ferré, Sergi

doi:10.1126/sciadv.1601631

Cited by 50 publications

(77 citation statements)

References 30 publications

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“…21,22 In the present study, we aimed at a more motor-involved striatal area, the dorsal striatal area that receives innervation from the agranular motor cortex (Fig 1A). This corticostriatal projection has been anatomically well defined from different studies analyzing striatal neuronal activation upon cortical-electrical stimulation.…”

Section: Resultsmentioning

confidence: 99%

“…21,22 It could then be demonstrated that adenosine A 2A receptors (A2AR) play a strong facilitatory role, since perfusion through the microdialysis probe of the selective A2AR antagonist MSX-3, completely counteracted optogenetically-induced corticostriatal glutamate release. 21 In agreement with a functional upregulation of A2AR being involved with the increased sensitivity of corticostriatal terminals induced by BID (see Discussion and refs.…”

Section: Resultsmentioning

confidence: 99%

“…We have recently reported results obtained with the optogenetic-microdialysis technique in knock-in mice expressing the long intracellular domain of D4.7, the product of a polymorphic variant of the D4R gene ( DRD4 ) associated with attention deficit hyperactivity disorder (ADHD). 22 When compared with the wild-type mouse D4R, the expanded intracellular domain of the humanized D4R conferred a gain of function, blunting optogenetically-induced corticostriatal glutamate release. 22 These results confirmed a key role of striatal D4R localized in glutamatergic terminals in the control of corticostriatal transmission.…”

Section: Resultsmentioning

confidence: 99%

“…D4R can be particularly seen as the main therapeutic target, since it is more selectively expressed by corticostriatal neurons than D2SR and it has been recently shown to play a main role as a mediator of dopamine modulation of corticostriatal neurotransmission. 22 On the other hand, D2SR has a more widespread expression, including the dopamine cells, where it acts as autoreceptor. 47 In addition, a selective D2SR ligand devoid of activity for the striatal postsynaptic D2LR, might be difficult to obtain.…”

Section: Discussionmentioning

confidence: 99%

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Targeting hypersensitive corticostriatal terminals in restless legs syndrome

Yepes

Guitart

Rea

et al. 2017

Annals of Neurology

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Objective The first aim was to demonstrate a previously hypothesized increased sensitivity of corticostriatal glutamatergic terminals in the rodent with brain iron deficiency (BID), a pathogenetic model of Restless Legs Syndrome (RLS). The second aim was to determine if these putative hypersensitive terminals could constitute a significant target for drugs effective in RLS, including dopamine agonists (pramipexole and ropinirole) and α2δ ligands (gabapentin). Methods A recently introduced in vivo optogenetic-microdialysis approach was used, which allows the measurement of the extracellular concentration of glutamate upon local light-induced stimulation of corticostriatal glutamatergic terminals. The method also allows to analyze the effect of local perfusion of compounds within the same area being sampled for glutamate. Results BID rats showed hypersensitivity of corticostriatal glutamatergic terminals (lower frequency of optogenetic stimulation to induce glutamate release). Both hypersensitive and control glutamatergic terminals were significant targets for locally perfused pramipexole, ropinirole and gabapentin, which significantly counteracted optogenetically-induced glutamate release. The use of selective antagonists demonstrated the involvement of dopamine D4 and D2 receptor subtypes on the effects of pramipexole. Interpretation Hypersensitivity of corticostriatal glutamatergic terminals can constitute a main pathogenetic mechanism of RLS symptoms. Selective D4 receptor agonists, by specifically targeting these terminals, should provide a new efficient treatment with less secondary effects.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting hypersensitive corticostriatal terminals in restless legs syndrome

Yepes

Guitart

Rea

et al. 2017

Annals of Neurology

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“…The specific subtype of EAA receptor activated was crucial to the direction of effect. The basic work provided a foundation to expand and explore how other combinations and receptor subtypes influenced one another (Bonaventura et al, 2017). The increase in NMDA receptor-mediated responses was obtained by application of SKF 38,393, a D 1 receptor agonist.…”

Section: Dopamine-g Lutamate Inter Ac Ti On S: P Oss Ib Le Influen mentioning

confidence: 99%

Translating striatal activity from brain slice to whole animal neurophysiology: A guide for neuroscience research integrating diverse levels of analysis

Cromwell

2019

J of Neuroscience Research

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An important goal of this review is highlighting research in neuroscience as examples of multilevel functional and anatomical analyses addressing basic science issues and applying results to the understanding of diverse disorders. The research of Dr. Michael Levine, a leader in neuroscience, exemplifies this approach by uncovering fundamental properties of basal ganglia function and translating these findings to clinical applications. The review focuses on neurophysiological research connecting results from in vitro and in vivo recordings. A second goal is to utilize these research connections to produce novel, accurate descriptions for corticostriatal processing involved in varied, complex functions. Medium spiny neurons in striatum act as integrators combining input with baseline activity creating motivational “events.” Basic research on corticostriatal synapses is described and links developed to issues with clinical relevance such as inhibitory gating, self‐injurious behavior, and relative reward valuation. Work is highlighted on dopamine–glutamate interactions. Individual medium spiny neurons express both D1 and D2 receptors and encode information in a bivalent manner depending upon the mix of receptors involved. Current work on neurophysiology of reward processing has taken advantage of these basic approaches at the cellular and molecular levels. Future directions in studying physiology of reward processing and action sequencing could profit by incorporating the divergent ways dopamine modulates incoming neurochemical signals. Primary investigators leading research teams should mirror Mike Levine's efforts in “climbing the mountain” of scientific inquiry by performing analyses at different levels of inquiry, integrating the findings, and building comprehensive answers to problems unsolvable without this bold approach.

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Animal models of attention‐deficit hyperactivity disorder (ADHD)

Rahi

Kumar

2021

Intl J of Devlp Neuroscience

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Attention‐deficit hyperactivity disorder (ADHD) is a heterogeneous neuropsychiatric disorder characterized by three primary symptoms hyperactivity, attention deficit, and impulsiveness, observed in both children and adults. In childhood, this disorder is more common in boys than in girls, and at least 75% will continue to suffer from the disorder until adulthood. Individuals with ADHD generally have poor academic, occupational, and social functioning resulting from developmentally inappropriate levels of hyperactivity and impulsivity, as well as impaired ability to maintain attention on motivationally relevant tasks. Very few drugs available in clinical practice altogether abolish the symptoms of ADHD, therefore, to find new drugs and target it is essential to understand the neuropathological, neurochemical, and genetic alterations that lead to the progression of ADHD. With this contrast, an animal study is the best approach because animal models provide relatively fast invasive manipulation, rigorous hypothesis testing, as well as it provides a better angle to understand the pathological mechanisms involved in disease progression. Moreover, animal models, especially for ADHD, serve with good predictive validity would allow the assessment and development of new therapeutic interventions, with this aim, the present review collect the various animal models on a single platform so that the research can select an appropriate model to pursue his study.

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Key role of the dopamine D ₄ receptor in the modulation of corticostriatal glutamatergic neurotransmission

Abstract: The function of the dopamine D4 receptor and the product of a clinically significant gene polymorphic variant is revealed.

Cited by 50 publications

References 30 publications

Targeting hypersensitive corticostriatal terminals in restless legs syndrome

Targeting hypersensitive corticostriatal terminals in restless legs syndrome

Translating striatal activity from brain slice to whole animal neurophysiology: A guide for neuroscience research integrating diverse levels of analysis

Animal models of attention‐deficit hyperactivity disorder (ADHD)

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Key role of the dopamine D 4 receptor in the modulation of corticostriatal glutamatergic neurotransmission

Abstract: The function of the dopamine D4 receptor and the product of a clinically significant gene polymorphic variant is revealed.

Cited by 50 publications

References 30 publications

Targeting hypersensitive corticostriatal terminals in restless legs syndrome

Targeting hypersensitive corticostriatal terminals in restless legs syndrome

Translating striatal activity from brain slice to whole animal neurophysiology: A guide for neuroscience research integrating diverse levels of analysis

Animal models of attention‐deficit hyperactivity disorder (ADHD)

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Product

Resources

About

Key role of the dopamine D ₄ receptor in the modulation of corticostriatal glutamatergic neurotransmission