Cited by 246Circadian rhythm and melatoninNeurotransmitter Receptor Influence on BehaviorParkinson's Disease Mechanisms and Treatments

The DOI matches its Crossref record; 72 of the 73 references it cites were found in a registry or an index; 1 of the 38 sources its claims cite were checked for support.

Endogenous Dopamine Regulates the Rhythm of Expression of the Clock Protein PER2 in the Rat Dorsal Striatum via Daily Activation of D2Dopamine Receptors

Open access

Abstract

A role for dopamine (DA) in the regulation of clock genes in the mammalian brain is suggested by evidence that manipulations of DA receptors can alter the expression of some clock genes outside the suprachiasmatic nucleus (SCN), the master circadian clock. The role of endogenous DA in the regulation of clock gene expression is unknown. Here, we demonstrate a direct relationship between extracellular DA levels and the rhythm of expression of the clock protein PERIOD2 (PER2) in the dorsal striatum of the male Wistar rat. Specifically, we show that the peak of the daily rhythm of extracellular DA in the dorsal striatum precedes the peak of PER2 by ∼6 h and that depletion of striatal DA by 6-hydroxydopamine or α-methyl-para-tyrosine or blockade of D 2 DA receptors by raclopride blunts the rhythm of striatal PER2. Furthermore, timed daily activation of D 2 DA receptors, but not D 1 DA receptors, restores and entrains the PER2 rhythm in the DA-depleted striatum. None of these manipulations had any effect on the PER2 rhythm in the SCN. Our findings are consistent with the idea that the rhythm of expression of PER2 in the dorsal striatum depends on daily dopaminergic activation of D 2 DA receptors. These observations may have implications for circadian abnormalities seen in Parkinson's disease.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

Endogenous dopamine in the rat dorsal striatum regulates the daily rhythm of PER2, primarily via daily activation of D2 dopamine receptors. Depleting or blocking dopamine blunts striatal PER2, while timed D2/3 agonist treatment restores and entrains the rhythm without affecting the SCN.

Key findings

  • Extracellular dopamine in the dorsal striatum peaks in the middle of the dark phase and precedes the dorsal striatum PER2 peak by ~6 h; PER2 peaks at ZT1 in dorsal striatum but at ZT13 in the SCN.
  • Unilateral 6-OHDA lesions of the medial forebrain bundle blunt the dorsal striatum PER2 rhythm on the lesioned side, with significant reductions at ZT1 and ZT19, while SCN PER2 is unaffected.
  • AMPT treatment reduced dorsal striatum dopamine content by 95% at ZT13 and 88% at ZT1, reduced PER2 at ZT1, and slightly increased PER2 at ZT13; SCN PER2 was unchanged.
  • Chronic raclopride (D2 antagonist) reduced dorsal striatum PER2 at ZT1, whereas SCH 23390 (D1 antagonist) had no effect. Daily quinpirole (D2/3 agonist) at ZT1 restored and reversed the PER2 rhythm in 6-OHDA-lesioned striatum, increasing PER2 at ZT13; daily SKF 81297 (D1 agonist) and continuous quinpirole infusion had no effect.

Methods

  • Male Wistar rats (n = 172 total) housed on a 12 h light/dark cycle; experiments used unilateral 6-OHDA medial forebrain bundle lesions, AMPT injections, osmotic minipumps for D1/D2 antagonists or agonists, and daily agonist injections.
  • PER2 and PER1 immunoreactive nuclei were counted in dorsal striatum and SCN; DAT staining confirmed lesions; RT-PCR measured Per2 transcription; in vivo microdialysis measured extracellular dorsal striatum dopamine; wheel-running activity was monitored.
  • Analyses used mixed-model or two-way ANOVA with ZT and treatment/lesion as factors, followed by Bonferroni-corrected post hoc tests or t tests; α = 0.05.

Limitations

  • The paper states that the mechanisms whereby dopamine depletion and D2 receptor activation suppress and restore PER2 remain unresolved, and it leaves open a possible role for noradrenaline because AMPT also prevents noradrenaline synthesis.
  • Evident from the text: the dopamine rhythm was measured in only three rats, and several experimental groups had small n values (e.g., 2–3 per ZT in some conditions), limiting precision.
  • Evident from the text: the phase relationship between dopamine and PER2 is correlational, and the study does not identify the molecular pathway linking D2 receptor activation to Per2 transcription.

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Integrity signals

Registry

Crossref · 10.1523/jneurosci.2128-10.2010

Cites

72 of 72 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

102 Own result · 25 Own interpretation · 17 Not checked yet · 5 Own method · 1 Supported so far · 1 No basis given

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Show all 109 claims

  • Probably not a substantial claim. 13
  • It may state two separate claims as one. 31
42 of 42
  • The paper relies on this without support.

    Raclopride acts selectively as a D2 dopamine receptor antagonist.

    “blockade of D 2 DA receptors by raclopride”
  • The paper relies on this without support.

    Quinpirole acts selectively as a D2/3 dopamine receptor agonist.

    “D 1 and D 2/3 DA receptor agonists, delivered either by timed daily injection”
  • The paper relies on this without support.

    Unilateral 6-OHDA injection into the MFB selectively destroys dopaminergic inputs to the dorsal striatum without affecting other neurotransmitter systems.

    “One hour before surgery, rats were injected intraperitoneally with desipramine (2.5 mg/kg) to protect noradrenergic fibers from the 6-OHDA toxin.”
  • The paper relies on this without support.

    AMPT selectively inhibits tyrosine hydroxylase and depletes dopamine without affecting other catecholamines.

    “injections of the tyrosine hydroxylase inhibitor ␣-methyl-para-tyrosine (AMPT)”
4 of 4

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Citations

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Metadata

Authors
Hood, S., Cassidy, P., Cossette, M.-P., Weigl, Y., Verwey, M., Robinson, B., Stewart, J., & Amir, S.
Affiliations
Concordia University (CA)
Corresponding author
Amir, Shimon
Venue
The Journal of Neuroscience
Published
2010-10-20
Volume
30
Issue
42
Pages
14046-14058
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W1994354389
Cited by
246
References
73
Citations by year
2026: 11 · 2025: 11 · 2024: 13 · 2023: 17 · 2022: 17 · 2021: 20 · 2020: 17 · 2019: 13 · 2018: 28 · 2017: 20 · 2016: 14 · 2015: 14 · 2014: 12 · 2013: 13 · 2012: 12
FWCI
5.63
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Concordia University
  • Canadian Institutes of Health Research
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
dopamine, dopamine D2 receptor, Per2, clock genes, circadian rhythm, dorsal striatum, extracellular dopamine, 6-hydroxydopamine, alpha-methyl-p-tyrosine, raclopride, suprachiasmatic nucleus, Parkinson's disease, circadian entrainment
MeSH terms
Animals, Cell Count, Chromatography, High Pressure Liquid, Corpus Striatum, Dopamine, Gene Expression Regulation, Immunohistochemistry, Male, Medial Forebrain Bundle, Motor Activity, RNA, Suprachiasmatic Nucleus, Sympathectomy, Chemical, Sympatholytics, Tyrosine 3-Monooxygenase, Oxidopamine, Rats, Wistar, Receptors, Dopamine D2, Microdialysis, Reverse Transcriptase Polymerase Chain Reaction, Rats, Period Circadian Proteins, Dopamine D2 Receptor Antagonists

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