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Cited by 302Neuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on BehaviorSchizophrenia research and treatment

Mechanisms of Dopamine Activation of Fast-Spiking Interneurons That Exert Inhibition in Rat Prefrontal Cortex

Gorelova, Natalia, Seamans, Jeremy K., Yang, Charles R.·2002·Journal of Neurophysiology
DOI 10.1152/jn.00335.2002
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Abstract

Prefrontal cortical dopamine (DA) modulates pyramidal cell excitability directly and indirectly by way of its actions on local circuit GABAergic interneurons. DA modulation of interneuronal functions is implicated in the computational properties of prefrontal networks during cognitive processes and in schizophrenia. Morphologically and electrophysiologically distinct classes of putative GABAergic interneurons are found in layers II-V of rat prefrontal cortex. Our whole cell patch-clamp study shows that DA induced a direct, TTX-insensitive, reversible membrane depolarization, and increased the excitability of fast-spiking (FS) interneurons. The DA-induced membrane depolarization was reduced significantly by D1/D5 receptor antagonist SCH 23390, but not by the D2 receptor antagonist (−)sulpiride, D4 receptor antagonists U101958 or L-745870, α1-adrenoreceptor antagonist prazosin, or serotoninergic receptor antagonist mianserin. The D1/5 agonists SKF81297 or dihydrexidine, but not D2 agonist quinpirole, also induced a prolonged membrane depolarization. Voltage-clamp analyses of the voltage-dependence of DA-sensitive currents, and the effects of changing [K+]O on reversal potentials of DA responses, revealed that DA suppressed a Cs+-sensitive inward rectifier K+current and a resting leak K+current. D1/D5, but not D2 agonists mimicked the suppressive effects of DA on the leak current, but the DA effects on the inward rectifier K+current were not mimicked by either agonist. In a subgroup of FS interneurons, the slowly inactivating membrane outward rectification evoked by depolarizing voltage steps was also attenuated by DA. Collectively, these data showed that DA depolarizes FS interneurons by suppressing a voltage-independent ‘leak’ K+current (via D1/D5 receptor mechanism) and an inwardly rectifying K+current (via unknown DA mechanisms). Additional suppression of a slowly inactivating K+current led to increase in repetitive firing in response to depolarizing inputs. This D1-induced increase in interneuron excitability enhances GABAergic transmission to PFC pyramidal neurons and could represent a mechanism via which DA suppresses persistent firing of pyramidal neurons in vivo.

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  • Prior to adolescence, D2 stimulation elicits either no effect or only weak inhibition on interneurons; in adult animals, stimulation of D2 receptors is strongly excitatory and results in robust firing of interneurons and potent inhibition of their pyramidal cell targets.

    “Prior to adolescence, D2 stimulation elicits either no effect or only weak inhibition on interneurons. However, in adult animals stimulation of D2 receptors is strongly excitatory and therefore results in robust firing of interneurons and potent inhibition of their pyramidal cell targets.”

    From A role for synaptic plasticity in the adolescent development of executive function (2013) · cites this paper as [62]

  • Recent evidence has established that D2 dopamine receptors on interneurons undergo a profound maturational change during adolescence.

    “recent evidence has established that D2 dopamine receptors on interneurons undergo a profound maturational change during adolescence.62, 63, 64”

    From A role for synaptic plasticity in the adolescent development of executive function (2013) · cites this paper as [62]

  • In juvenile rats, D1 agonists increase GABA interneuron firing, whereas D2 agonists have either a weak inhibitory effect or no effect.

    “In juvenile rats, D 1 agonists increase GABA interneuron firing, whereas D 2 agonists have either a weak inhibitory effect or no effect.12,13”

    From Adolescent Onset of Cortical Disinhibition in Schizophrenia: Insights From Animal Models (2011) · cites this paper as [13]

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Authors
Gorelova, N., Seamans, J. K., & Yang, C. R.
Affiliations
  • University of British Columbia (CA)
  • Medical University of South Carolina (US)
  • Eli Lilly (United States) (US)
ORCID
Seamans, Jeremy K.
Venue
Journal of Neurophysiology
Publisher
American Physiological Society
Published
2002-12-01
Volume
88
Issue
6
Pages
3150-3166
ISSN
  • 0022-3077 (ISSN-L)
  • 1522-1598
DOI
10.1152/jn.00335.2002
OpenAlex
W2033043582
Cited by
302
References
99
Citations by year
2026: 7 · 2025: 5 · 2024: 9 · 2023: 6 · 2022: 15 · 2021: 8 · 2020: 4 · 2019: 6 · 2018: 14 · 2017: 13 · 2016: 15 · 2015: 12 · 2014: 8 · 2013: 14 · 2012: 10
FWCI
4.30
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Neurophysiology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords
dopamine, fast-spiking interneurons, prefrontal cortex, GABAergic interneurons, dopamine D1/D5 receptors, interneuron excitability, membrane depolarization, inward rectifier potassium current, dopamine D2 receptor, repetitive firing, schizophrenia
MeSH terms
Action Potentials, Animals, Dopamine, Electrophysiology, Interneurons, Male, Neural Inhibition, Reaction Time, Potassium Channels, Rats, Sprague-Dawley, Prefrontal Cortex, Receptors, Dopamine D1, Patch-Clamp Techniques, Potassium Channels, Inwardly Rectifying, Receptors, Dopamine D5, Rats, In Vitro Techniques

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