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

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
Hood, Suzanne, Cassidy, Pamela, Cossette, Marie-Pierre, Weigl, Yuval, Verwey, Michael, Robinson, Barry, Stewart, Jane, Amir, Shimon·2010·The Journal of Neuroscience
DOI 10.1523/jneurosci.2128-10.2010PMC PMC6634752
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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.

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.

Model-written summary. Check it against the paper before relying on it.

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.

Claims the paper makes

0 of 38 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Depletion of striatal DA by 6-OHDA or AMPT or blockade of D2 DA receptors by raclopride blunts the rhythm of striatal PER2.

    “depletion of striatal DA by 6-hydroxydopamine or ␣-methyl-para-tyrosine or blockade of D 2 DA receptors by raclopride blunts the rhythm of striatal PER2”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Raclopride acts selectively as a D2 dopamine receptor antagonist.
    • Rests on an assumption: Unilateral 6-OHDA injection into the MFB selectively destroys dopaminergic inputs to the dorsal striatum without affecting other neurotransmitter systems.
    • Rests on an assumption: AMPT selectively inhibits tyrosine hydroxylase and depletes dopamine without affecting other catecholamines.
  • Findingown data

    The peak of the daily rhythm of extracellular DA in the dorsal striatum precedes the peak of PER2 by approximately 6 hours.

    “the peak of the daily rhythm of extracellular DA in the dorsal striatum precedes the peak of PER2 by ϳ6 h”
    Quote in the paperSubstantial claim
  • Findingown data

    None of the manipulations (6-OHDA, AMPT, raclopride, D2/D1 agonists) had any effect on the PER2 rhythm in the SCN.

    “None of these manipulations had any effect on the PER2 rhythm in the SCN.”
    Quote in the paperSubstantial claim
  • Findingown data

    There is a direct relationship between extracellular DA levels and the rhythm of expression of PER2 in the dorsal striatum of the male Wistar rat.

    “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.”
    Quote in the paperSubstantial claim
  • Findingown data

    In the SCN, the rhythm of PER2 expression peaks in the evening, in antiphase to that in the dorsal striatum.

    “In the SCN, the rhythm of PER2 expression peaks in the evening, in antiphase to that in the dorsal striatum (Figs. 1, 2b).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 31
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingown data

    Timed daily activation of D2 DA receptors, but not D1 DA receptors, restores and entrains the PER2 rhythm in the DA-depleted striatum.

    “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”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Quinpirole acts selectively as a D2/3 dopamine receptor agonist.

  • May combine two claims.

    Findingown data

    The rhythm of PER2 expression in the dorsal striatum peaks in the morning at ZT1 and reaches its trough in the evening at ZT13.

    “the rhythm of PER2 expression in the dorsal striatum peaks in the morning, at the beginning of the light phase (ZT1), and reaches its trough in the evening, at the beginning of the dark phase (ZT13).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The 6-OHDA injection severely blunted the rhythm of PER2 expression in the lesioned hemisphere, but did not affect the normal PER2 rhythm on the intact side.

    “the 6-OHDA injection severely blunted the rhythm of PER2 expression in the lesioned hemisphere, but did not affect the normal PER2 rhythm on the intact side”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Wheel-running activity occurs primarily in the dark phase and is absent during the light phase.

    “wheel-running activity occurs primarily in the dark phase and is absent during the light phase.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the SCN, the normal rhythm of PER1 expression is similar to the rhythm of PER2 and peaks near ZT13.

    “In the SCN, the normal rhythm of PER1 expression is similar to the rhythm of PER2 and peaks near ZT13.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the dorsal striatum, the normal rhythm of PER1 expression approximates the rhythm of PER2 in this region and peaks near ZT1.

    “the normal rhythm of PER1 expression approximates the rhythm of PER2 in this region and peaks near ZT1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Daily quinpirole injections restored the daily variation of PER2 expression in the lesioned striatum while suppressing nighttime activity, but had no effect on PER2 expression in the intact hemisphere.

    “daily quinpirole injections restored the daily variation of PER2 expression in the lesioned striatum while suppressing nighttime activity, but had no effect on PER2 expression in the intact hemisphere.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither daily injections nor continuous infusions of a D1 DA agonist were effective.

    “Neither daily injections nor continuous infusions of a D 1 DA agonist were effective.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Chronic delivery of quinpirole or SKF 81297 at the doses used did not alter the effect of lesions on PER2 expression in the dorsal striatum nor did they alter PER2 expression in the intact hemisphere.

    “chronic delivery of quinpirole (Fig. 12b) or SKF 81297 (Fig. 12c) at the doses used did not alter the effect of lesions on PER2 expression in the dorsal striatum nor did they alter PER2 expression in the intact hemisphere.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AMPT depletion of catecholamines strongly reduced PER2 expression in the dorsal striatum, as well as in M1 and DG.

    “AMPT depletion of catecholamines strongly reduced PER2 expression in this region, as well as in M1 and DG, which receive NA inputs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Daily injections of a D2 DA receptor agonist restored and shifted the daily peak of PER2 in the lesioned striatum.

    “Daily injections of a D 2 DA receptor agonist, given to induce a peak of activation of DA receptors at a time of day when DA levels are normally low, not only restored, but shifted the daily peak of PER2 in the lesioned striatum.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    When striatal DA was depleted unilaterally using 6-OHDA, the peak expression of PER2 on the lesioned side was strongly suppressed and the daily rhythm of PER2 in this region was blunted both 2 and 4 weeks after surgery.

    “When striatal DA was depleted unilaterally using 6-OHDA, the peak expression of PER2 on the lesioned side was strongly suppressed and the daily rhythm of PER2 in this region was blunted both 2 and 4 weeks after surgery.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Unilateral depletion of striatal DA did not disrupt the daily activity rhythm even though the level of nighttime activity was reduced.

    “Unilateral depletion of striatal DA, which strongly blunted the rhythm of PER2 expression on the lesioned side, did not disrupt the daily activity rhythm even though the level of nighttime activity was reduced.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Daily fluctuations in wheel-running activity peak at night, preceding the peak of PER2 in the striatum.

    “The daily fluctuations in extracellular striatal DA levels (c) and wheelrunning activity (d) peak at night, preceding the peak of PER2 in the striatum.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Extracellular DA levels in the dorsal striatum are lowest during the middle of the light phase and highest in the middle of the dark phase.

    “In vivo microdialysis sampling in the dorsal striatum shows that extracellular DA levels are lowest during the middle of the light phase and highest in the middle of the dark phase”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Daily fluctuations in extracellular striatal DA levels peak at night, preceding the peak of PER2 in the striatum.

    “The daily fluctuations in extracellular striatal DA levels (c) and wheelrunning activity (d) peak at night, preceding the peak of PER2 in the striatum.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the SCN, PER2 expression is greatest at ZT13 (near the beginning of the dark phase) and lowest during the light phase.

    “in the SCN, PER2-IR nuclei are most abundant around ZT13”
    • Also stated in: § Functional significance of PER2 regulation by DA · plain
      “In the SCN, PER2 expression is greatest at ZT13, near the beginning of the dark phase, and is lowest during the light phase.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither quinpirole nor SKF 81297 treatment affected daily wheel-running activity.

    “Neither treatment affected daily wheel-running activity”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Wheel-running activity is greatest during the dark phase and virtually absent during the light phase.

    “Wheel-running activity is also greatest during the dark phase and is virtually absent during the light phase”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the dorsal striatum, PER2 expression is greatest at ZT1 (near the beginning of the light phase) and lowest during the dark phase.

    “In the dorsal striatum, PER2-IR nuclei are most abundant around ZT1”
    • Also stated in: § Functional significance of PER2 regulation by DA · plain
      “In the dorsal striatum, PER2 expression is greatest at ZT1, near the beginning of the light phase, and is lowest during the dark phase”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Circadian rhythms of physiology and behavior are generated by a core set of clock genes, which regulate their own expression in a 24 h transcriptional-translational feedback cycle.

    “Circadian rhythms of physiology and behavior are generated by a core set of clock genes, which regulate their own expression in a 24 h transcriptional-translational feedback cycle (for review, see Reppert and Weaver, 2001;Ko and Takahashi, 2006).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Reppert and Weaver, 2001

      Not checked in the free run.

    • cites Ko and Takahashi, 2006

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    The role of endogenous DA in the regulation of clock gene expression is unknown.

    “The role of endogenous DA in the regulation of clock gene expression is unknown.”
    • Also stated in: § Introduction · hedged
      “There is no direct evidence, however, that endogenous DA regulates rhythmic expression of clock genes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The specificity of the PER2 and PER1 primary antibodies was previously confirmed with blocking experiments.

    “The specificity of the PER2 and PER1 primary antibodies was previously confirmed with blocking experiments, in which addition of the PER2 peptide or the PER1 peptide (1 g/ml in PBS) to the primary incubation solution prevented staining of PER2 or PER1 expression, respectively, in the tissue (Hastings et al., 1999;Field et al., 2000).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hastings et al., 1999

      Not checked in the free run.

    • cites Field et al., 2000

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The rhythms of PER2 expression in the SCN, extracellular DA levels in the dorsal striatum, and wheel running are in phase with one another, but are in antiphase to the rhythm of PER2 expression in the dorsal striatum.

    “Thus, the rhythms of PER2 expression in the SCN, extracellular DA levels in the dorsal striatum, and wheel running are in phase with one another, but are in antiphase to the rhythm of PER2 expression in the dorsal striatum.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    We found no differences between the two PER2 primary antibodies in the pattern or amount of staining for PER2 in a number of different brain regions.

    “We found no differences between these primary antibodies in the pattern or amount of staining for PER2 in a number of different brain regions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Extra-SCN rhythms can be influenced independently by a variety of other signals, including steroid hormones, stressors, and restricted feeding schedules.

    “Although signals from the SCN are required to maintain and coordinate rhythmic gene expression in the brain and periphery, these extra-SCN rhythms can also be influenced independently by a variety of other signals, including steroid hormones, stressors, and restricted feeding schedules (Takahashi et al., 2001;Wakamatsu et al., 2001;Perrin et al., 2006;Segall et al., 2006;Angeles-Castellanos et al.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Takahashi et al., 2001

      Not checked in the free run.

    • cites Wakamatsu et al., 2001

      Not checked in the free run.

    • cites Perrin et al., 2006

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Per2 plays a critical role in the regulation of the 24 h rhythm by serving as the interface between the negative and positive limbs of the cycle.

    “Among these genes, Period2 (Per2) plays a critical role in the regulation of this 24 h rhythm by serving as the interface between the negative and positive limbs of the cycle (Chen et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chen et al., 2009

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Rats were randomly assigned to an experimental condition.

    “Rats were left in their home cages for at least 10 d to entrain to the LD cycle before the start of each experiment and were randomly assigned to an experimental condition.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The rhythms of PER2 expression were consistent across medial and lateral regions of the striatum, and the effects of each experimental manipulation on their expression did not vary within the striatum.

    “We found that the rhythms of PER2 expression were consistent across these regions and that the effects of each experimental manipulation on their expression did not vary within the striatum.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In mammals, the master circadian clock resides in the SCN, and the phase of rhythmic clock gene expression in this region is entrained by environmental light.

    “In mammals, the master circadian clock resides in the suprachiasmatic nucleus (SCN), and the phase of rhythmic clock gene expression in this region is entrained by environmental light (Lowrey and Takahashi, 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lowrey and Takahashi, 2000

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Rhythmic clock gene expression is not limited to the SCN and has been characterized in several other regions of the brain and in peripheral tissues.

    “Rhythmic clock gene expression is not limited to the SCN, however, and has been characterized in several other regions of the brain and in peripheral tissues (Abe et al., 2002;Shieh, 2003;Amir et al., 2004;Lamont et al., 2005;Guilding and Piggins, 2007).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Abe et al., 2002 source

      Not checked in the free run.

    • cites Shieh, 2003

      Not checked in the free run.

    • cites Amir et al., 2004

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Data were analyzed only from those rats with complete unilateral lesions, as confirmed by an absence of DAT staining in the dorsal striatum ipsilateral to the 6-OHDA injection.

    “In the experiments involving unilateral injections of 6-OHDA toxin into the MFB, data were analyzed only from those rats with complete unilateral lesions, as confirmed by an absence of DAT staining in the dorsal striatum ipsilateral to the 6-OHDA injection.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Activation of D2 receptors modulates the circadian effects of light on locomotor activity in mice and regulates expression of clock genes in the retina and striatum.

    “In particular, activation of D 2 receptors has been demonstrated to modulate the circadian effects of light on locomotor activity in mice (Doi et al., 2006) and to regulate expression of clock genes in the retina (Besharse et al., 2004;Yujnovsky et al., 2006) and striatum (Imbesi et al., 2009;Sahar et al., 2010), a region important for motor control, learning, cognition, and reward.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Doi et al., 2006

      Not checked in the free run.

    • cites Besharse et al., 2004;Yujnovsky et al., 2006

      Not checked in the free run.

    • cites Imbesi et al., 2009;Sahar et al., 2010

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The doses of SCH 23390 and raclopride were chosen to occupy ~80% of striatal D1 or D2 DA receptors and did not impede motor function.

    “The doses of SCH 23390 and raclopride were chosen on the basis of previous studies indicating dose ranges that were effective in occupying ϳ80% of striatal D 1 or D 2 DA receptors and that did not impede motor function”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Creese and Chen, 1985

      Not checked in the free run.

    • cites Neisewander et al., 1998

      Not checked in the free run.

    • cites Wadenberg et al., 2001; Kapur et al., 2003

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    A unilateral lesion of dopaminergic projections and subsequent depletion of DA in the dorsal striatum significantly blunts the normal rhythm of PER2 expression in this region without affecting the rhythm in the SCN.

    “The results of our 6-OHDA experiments indicate that a unilateral lesion of dopaminergic projections and subsequent depletion of DA in the dorsal striatum significantly blunts the normal rhythm of PER2 expression in this region without affecting the rhythm in the SCN.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The drug doses used were in the range shown previously to enhance expression of immediate-early genes, striatal peptides, and electrophysiological responses of striatal neurons in 6-OHDA-lesioned rats.

    “Drug doses were in the range shown previously to enhance expression of immediate-early genes, striatal peptides, and electrophysiological responses of striatal neurons in 6OHDA-lesioned rats”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Gerfen et al., 1990, 1995

      Not checked in the free run.

    • cites Hu et al., 1992

      Not checked in the free run.

    • cites Zhang et al., 2007; Ballion et al., 2009

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Changes in the expression of peptides and receptors in striatal medium spiny neurons that develop after a unilateral 6-OHDA lesion can be reversed with intermittent or chronic DA receptor agonist treatment.

    “changes in the expression of peptides and receptors in striatal medium spiny neurons that develop after a unilateral 6-OHDA lesion can be reversed with intermittent or chronic DA receptor agonist treatment”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gerfen et al., 1990

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The normal PER2 rhythm in the dorsal striatum depends on the availability of D2, but not D1, DA receptors.

    “These results suggest that the normal PER2 rhythm in the dorsal striatum depends on the availability of D 2 , but not D 1 DA receptors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Extracellular DA levels peak in the middle of the dark (active) phase and fall during the light (inactive) phase of the daily cycle.

    “extracellular DA levels peak in the middle of the dark (active) phase and fall during the light (inactive) phase of the daily cycle”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Paulson and Robinson, 1994

      Not checked in the free run.

    • cites Castan ˜eda et al., 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PER2 expression peaks at the beginning of the light phase and reaches its trough near the beginning of the dark phase.

    “PER2 expression peaks at the beginning of the light phase and reaches its trough near the beginning of the dark phase”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Amir et al., 2006

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Daily stimulation of D2, but not D1, DA receptors restores and entrains the PER2 rhythm in the DA-depleted striatum.

    “daily stimulation of D 2 , but not D 1 DA receptors, restores and entrains the PER2 rhythm in the DA-depleted striatum.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    After a 6-OHDA lesion, the expression of D2 DA receptors on cell bodies is lost through destruction of DA fibers, whereas postsynaptic expression of D2 DA receptors in medium spiny neurons is upregulated.

    “After a 6-OHDA lesion, however, the expression of D 2 DA receptors on cell bodies is lost through destruction of DA fibers, whereas postsynaptic expression of D 2 DA receptors in medium spiny neurons is upregulated”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gerfen et al., 1990

      Not checked in the free run.

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

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Striatal dopamine levels exhibit daily rhythms with nocturnal peaks in mice and rats.

    “We have recently reported that striatal dopamine levels exhibit daily rhythms with nocturnal peaks in mice (Agostino et al., 2011a), as had been previously demonstrated in rats (Castaneda et al., 2004, Hood et al., 2010).”

    From Circadian dysregulation in Parkinson's disease (2017) · cites this paper as Hood et al., 2010

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • PER1 sample sizes conflict with ANOVA degrees of freedom

    Minor

    The Figure 7 caption reports 5-6 rats at each of four time points, or at least 20 rats. The reported F(3,12) tests imply 16 rats across four time-point groups.

  • AMPT striatal PER2 sample size conflicts with reported tests

    Minor

    The Figure 8 caption reports four rats per treatment group at each time point, implying 16 rats total and six degrees of freedom for each two-group t test. The reported ZT13 t test has five degrees of freedom, and the overall ANOVA has 11 residual degrees of freedom; both indicate one fewer rat.

2 of 2

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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
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2010-10-20
Volume
30
Issue
42
Pages
14046-14058
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.2128-10.2010
PMC
PMC6634752
OpenAlex
W1994354389
Semantic Scholar
1e97e34ebe3618b16bc6ac1f8b26c1ab8625ec3b
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
Licence
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 › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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