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Cited by 34Neurotransmitter Receptor Influence on BehaviorTreatment of Major DepressionNeuroscience and Neuropharmacology Research

Noradrenaline activation of hippocampal dopamine D 1 receptors promotes antidepressant effects

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Kobayashi, Katsunori, Shikano, Kisako, Kuroiwa, Mahomi, Horikawa, Mio, Ito, Wakana, Nishi, Akinori, Segi-Nishida, Eri, Suzuki, Hidenori·2022·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2117903119PMC PMC9388128
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Abstract

Dopamine D 1 receptors (D 1 Rs) in the hippocampal dentate gyrus (DG) are essential for antidepressant effects. However, the midbrain dopaminergic neurons, the major source of dopamine in the brain, only sparsely project to DG, suggesting possible activation of DG D 1 Rs by endogenous substances other than dopamine. We have examined this possibility using electrophysiological and biochemical techniques and found robust activation of D 1 Rs in mouse DG neurons by noradrenaline. Noradrenaline at the micromolar range potentiated synaptic transmission at the DG output and increased the phosphorylation of protein kinase A substrates in DG via activation of D 1 Rs and β adrenergic receptors. Neuronal excitation preferentially enhanced noradrenaline-induced synaptic potentiation mediated by D 1 Rs with minor effects on β-receptor–dependent potentiation. Increased voluntary exercise by wheel running also enhanced noradrenaline-induced, D 1 R-mediated synaptic potentiation, suggesting a distinct functional role of the noradrenaline–D 1 R signaling. We then examined the role of this signaling in antidepressant effects using mice exposed to chronic restraint stress. In the stressed mice, an antidepressant acting on the noradrenergic system induced a mature-to-immature change in the DG neuron phenotype, a previously proposed cellular substrate for antidepressant action. This effect was evident only in mice subjected to wheel running and blocked by a D 1 R antagonist. These results suggest a critical role of noradrenaline-induced activation of D 1 Rs in antidepressant effects in DG. Experience-dependent regulation of noradrenaline–D 1 R signaling may determine responsiveness to antidepressant drugs in depressive disorders.

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Cited by

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Authors
Kobayashi, K., Shikano, K., Kuroiwa, M., Horikawa, M., Ito, W., Nishi, A., Segi-Nishida, E., & Suzuki, H.
Affiliations
  • Nippon Medical School (JP)
  • Tokyo University of Science (JP)
  • Kurume University (JP)
  • Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Tokyo 125-8585, Japan
Corresponding author
Kobayashi, Katsunori
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2022-08-08
Volume
119
Issue
33
Pages
e2117903119-e2117903119
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2117903119
PMC
PMC9388128
OpenAlex
W4290725205
Cited by
34
References
5
Citations by year
2026: 8 · 2025: 7 · 2024: 10 · 2023: 9
FWCI
2.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
MEXT | Japan Society for the Promotion of Science (19K06961)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
norepinephrine, dopamine D1 receptor, dentate gyrus, antidepressant effects, synaptic potentiation, protein kinase A phosphorylation, beta-adrenergic receptors, chronic restraint stress, wheel running, neuronal excitation, depression, noradrenergic signaling
MeSH terms
Animals, Antidepressive Agents, Depressive Disorder, Dopamine, Norepinephrine, Receptors, Dopamine D1, Dentate Gyrus, Mice, Dopaminergic Neurons

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