The circadian system is a target and modulator of prenatal cocaine effects

Shang, E.H., and Zhdanova, I.V.
PLoS One   2(1): e587 (Journal)
Registered Authors
Zhdanova, Irina
MeSH Terms
  • Animals
  • Animals, Genetically Modified/embryology
  • Circadian Rhythm/drug effects
  • Circadian Rhythm/genetics
  • Circadian Rhythm/physiology*
  • Cocaine/pharmacology*
  • Cocaine-Related Disorders/complications
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/physiology
  • Female
  • Fetal Death/epidemiology
  • Genes, Reporter
  • Green Fluorescent Proteins/genetics
  • Humans
  • Melatonin/pharmacology
  • Models, Animal
  • Pregnancy
  • Prenatal Exposure Delayed Effects/chemically induced
  • Prenatal Exposure Delayed Effects/physiopathology*
  • Synaptic Transmission/genetics
  • Zebrafish/embryology*
17622340 Full text @ PLoS One
BACKGROUND: Prenatal exposure to cocaine can be deleterious to embryonic brain development, but the results in humans remain controversial, the mechanisms involved are not well understood and effective therapies are yet to be designed. We hypothesize that some of the prenatal effects of cocaine might be related to dysregulation of physiological rhythms due to alterations in the integrating circadian clock function. METHODOLOGY AND PRINCIPLE FINDINGS: Here we introduce a new high-throughput genetically well-characterized diurnal vertebrate model for studying the mechanisms of prenatal cocaine effects by demonstrating reduced viability and alterations in the pattern of neuronal development following repeated cocaine exposure in zebrafish embryos. This effect is associated with acute cocaine-induced changes in the expression of genes affecting growth (growth hormone, zGH) and neurotransmission (dopamine transporter, zDAT). Analysis of circadian gene expression, using quantitative real-time RT-PCR (QPCR), demonstrates that cocaine acutely and dose-dependently changes the expression of the circadian genes (zPer-3, zBmal-1) and genes encoding melatonin receptors (zMelR) that mediate the circadian message to the entire organism. Moreover, the effects of prenatal cocaine depend on the time of treatment, being more robust during the day, independent of whether the embryos are raised under the light-dark cycle or in constant light. The latter suggests involvement of the inherited circadian factors. The principal circadian hormone, melatonin, counteracts the effects of cocaine on neuronal development and gene expression, acting via specific melatonin receptors. CONCLUSIONS/SIGNIFICANCE: These findings demonstrate that, in a diurnal vertebrate, prenatal cocaine can acutely dysregulate the expression of circadian genes and those affecting melatonin signaling, growth and neurotransmission, while repeated cocaine exposure can alter neuronal development. Daily variation in these effects of cocaine and their attenuation by melatonin suggest a potential prophylactic or therapeutic role for circadian factors in prenatal cocaine exposure.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes