Involvement of dopamine signaling in the circadian modulation of interval timing

Eur J Neurosci. 2014 Jul;40(1):2299-310. doi: 10.1111/ejn.12569. Epub 2014 Apr 1.


Duration discrimination within the seconds-to-minutes range, known as interval timing, involves the interaction of cortico-striatal circuits via dopaminergic-glutamatergic pathways. Besides interval timing, most (if not all) organisms exhibit circadian rhythms in physiological, metabolic and behavioral functions with periods close to 24 h. We have previously reported that both circadian disruption and desynchronization impaired interval timing in mice. In this work we studied the involvement of dopamine (DA) signaling in the interaction between circadian and interval timing. We report that daily injections of levodopa improved timing performance in the peak-interval procedure in C57BL/6 mice with circadian disruptions, suggesting that a daily increase of DA is necessary for an accurate performance in the timing task. Moreover, striatal DA levels measured by reverse-phase high-pressure liquid chromatography indicated a daily rhythm under light/dark conditions. This daily variation was affected by inducing circadian disruption under constant light (LL). We also demonstrated a daily oscillation in tyrosine hydroxylase levels, DA turnover (3,4-dihydroxyphenylacetic acid/DA levels), and both mRNA and protein levels of the circadian component Period2 (Per2) in the striatum and substantia nigra, two brain areas relevant for interval timing. None of these oscillations persisted under LL conditions. We suggest that the lack of DA rhythmicity in the striatum under LL - probably regulated by Per2 - could be responsible for impaired performance in the timing task. Our findings add further support to the notion that circadian and interval timing share some common processes, interacting at the level of the dopaminergic system.

Keywords: circadian system; cortico-striatal circuits; dopamine; levodopa; timing and time perception.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • Animals
  • Circadian Rhythm / drug effects
  • Circadian Rhythm / physiology*
  • Corpus Striatum / drug effects
  • Corpus Striatum / physiology*
  • Discrimination, Psychological / drug effects
  • Discrimination, Psychological / physiology
  • Dopamine / metabolism*
  • Dopamine Agents / pharmacology
  • Levodopa / pharmacology
  • Male
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Period Circadian Proteins / metabolism*
  • Photic Stimulation
  • RNA, Messenger / metabolism
  • Random Allocation
  • Signal Transduction
  • Substantia Nigra / drug effects
  • Substantia Nigra / physiology*
  • Time Perception / drug effects
  • Time Perception / physiology*
  • Tyrosine 3-Monooxygenase / metabolism


  • Dopamine Agents
  • Per2 protein, mouse
  • Period Circadian Proteins
  • RNA, Messenger
  • 3,4-Dihydroxyphenylacetic Acid
  • Levodopa
  • Tyrosine 3-Monooxygenase
  • Dopamine