Dopamine–Glutamate Interactions Controlling Prefrontal Cortical Pyramidal Cell Excitability Involve Multiple Signaling Mechanisms
Open accessAbstract
Although the importance of dopamine (DA) for prefrontal cortical (PFC) cognitive functions is widely recognized, the nature of DA actions in the PFC remains controversial. A critical component in DA actions is its modulation of glutamate transmission, which can be different when specific receptors are activated. To obtain a clear picture of cellular mechanisms involved in these interactions, we studied the effects of DA–glutamate coactivation on pyramidal cell excitability in brain slices obtained from developmentally mature rats using whole-cell patch-clamp recordings. Bath application of NMDA, AMPA, and the D1 agonist SKF38393 induced concentration-dependent excitability increases, whereas bath application of the D2 receptor agonist quinpirole induced a concentration-dependent excitability decrease. The NMDA-mediated response was potentiated by SKF38393. This NMDA–D1 synergism required postsynaptic intracellular Ca 2+and protein kinase A (PKA) and was independent of membrane depolarization. On the other hand, the excitatory effects of both NMDA and AMPA were attenuated by a D2 agonist. Surprisingly, the D2–NMDA interaction was also blocked by the GABA A antagonists bicuculline and picrotoxin, suggesting that the inhibitory action of D2 receptors on NMDA-induced responses in the PFC may be mediated by GABAergic interneurons. In contrast, the D2–AMPA interaction involves inhibition of PKA and activation of phospholipase lipase C–IP 3 and intracellular Ca 2+at a postsynaptic level. Thus, the modulatory actions of D1 and D2 receptors on PFC pyramidal cell excitability are mediated by multiple intracellular mechanisms and by activation of GABA A receptors, depending on the glutamate receptor subtypes involved.
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Noradrenergic and dopaminergic projections towards forebrain regions, as well as dopaminergic-glutamatergic and dopaminergic-cholinergic interactions, control PFC maturation and functioning.
“The same holds true for noradrenergic and dopaminergic projections towards forebrain regions as well as dopaminergic-glutamatergic and dopaminergic-cholinergic interactions controlling PFC maturation and functioning [227, 228, 231].”
From Development of prefrontal cortex (2022) · cites this paper as [227]
The Introduction (page unavailable) says dopaminergic neurons project to the PFC and that dopamine–glutamate interactions may be essential for PFC function. The paper studies those interactions in developmentally mature rats, but does not establish that they control PFC maturation or address noradrenergic projections or dopamine–cholinergic interactions. (LLM, conf=0.87)
Experimental — accuracy not yet measuredDuring embryonic development there is convergence of the various neurotransmitter signaling pathways and they influence each other's development and functioning.
“There is, furthermore, ample evidence now that during embryonic development there is convergence of the various neurotransmitter signaling pathways and influence each other’s development and functioning [153, 227–231].”
From Development of prefrontal cortex (2022) · cites this paper as [227]
The Introduction says dopamine affects glutamate function, and the Discussion examines their interactions in prefrontal neurons. But the study used developmentally mature rats (postnatal days 42–65); it does not establish convergence during embryonic development or that neurotransmitter pathways influence one another’s development. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAscending neuromodulatory neurotransmitter systems, such as dopaminergic and cholinergic projections, have exactly the right characteristics: they are driven by activity in presynaptic connections and can affect activity through classical neuromodulatory effects at the post-synaptic membrane, while also enabling potentiation of connection strengths.
“Happily, the ascending neuromodulatory neurotransmitter systems, such as dopaminergic and cholinergic projections, have exactly the right characteristics: they are driven by activity in presynaptic connections and can affect activity though classical neuromodulatory effects at the post-synaptic membrane [65], while also enabling potentiation of connection strengths [66],[67].”
From Hierarchical Models in the Brain (2008) · cites this paper as [65]
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- Authors
- Tseng, K. Y., & O'Donnell, P.
- Affiliations
- Albany Medical College (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-06-02
- Volume
- 24
- Issue
- 22
- Pages
- 5131-5139
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6729185
- OpenAlex
- W2057749702
- Cited by
- 402
- References
- 45
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 4 · 2023: 9 · 2022: 14 · 2021: 14 · 2020: 8 · 2019: 19 · 2018: 14 · 2017: 13 · 2016: 23 · 2015: 18 · 2014: 21 · 2013: 20 · 2012: 27
- FWCI
- 9.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health (MH57683)
- National Institute of Mental Health (MH57683, R56MH057683, R01MH057683)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- dopamine-glutamate interaction, prefrontal cortex, dopamine D1 receptor, dopamine D2 receptor, NMDA receptor, AMPA receptors, protein kinase A, intracellular calcium, GABAergic interneurons, GABAA receptor, synaptic modulation
- MeSH terms
- Action Potentials, Animals, Calcium, Dopamine, Dose-Response Relationship, Drug, Drug Synergism, Male, Reaction Time, Signal Transduction, N-Methylaspartate, Rats, Sprague-Dawley, Prefrontal Cortex, Receptors, Dopamine D1, Receptors, Dopamine D2, Cyclic AMP-Dependent Protein Kinases, Pyramidal Cells, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Patch-Clamp Techniques, Dopamine Agonists, Dopamine Antagonists, Excitatory Amino Acid Agonists, Glutamic Acid, GABA Antagonists, Rats, Dopamine D2 Receptor Antagonists, In Vitro Techniques
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