Cannabidiol affects circadian clock core complex and its regulation in microglia cells

Addict Biol. 2019 Sep;24(5):921-934. doi: 10.1111/adb.12660. Epub 2018 Oct 11.

Abstract

Cannabis is often used by consumers for sleep disorders. Studies show that circadian rhythm could be affected by a misuse of cannabis. Recent research has connected the role of microglial cells with psychiatric disorders such as substance abuse. The aim was to show the effect of two major components of cannabis on circadian genes regulation in microglial cells. In BV-2 microglial cells, cannabidiol (CBD) induces a deregulation of circadian genes with (P-value = 0.039) or without (P-value = 0.0015) lipopolisaccharides stimulation. CBD up regulated Arntl (P = 9.72E-5) and down regulated Clock (P = 0.0034) in BV-2 cells. Temporal expression of Arntl (light and dark P = 0.0054) and Clock (light and dark P = 0.047) was confirmed to have 24 hours light and dark rhythmic regulation in dissected suprachiasmatic nucleus as well as of Cb1 cannabinoid receptor (light and dark P = 0.019). In BV-2 microglia cells, CBD also up regulated CRY2 (P = 0.0473) and PER1 (P = 0.0131). Other nuclear molecules show a deregulation of circadian rhythm in microglial cells by CBD, such as RORA, RevErbα, RORB, CREBBP, AFT4, AFT5 and NFIL3. Our study suggests that circadian rhythm in microglial cells is deregulated by CBD but not by THC. It is consistent with clinical observations of the use of therapeutic cannabis to treat insomnia.

Keywords: THC; cannabidiol; circadian genes; microglial cells.

MeSH terms

  • ARNTL Transcription Factors / drug effects
  • ARNTL Transcription Factors / genetics
  • Animals
  • CLOCK Proteins / drug effects
  • CLOCK Proteins / genetics
  • Cannabidiol / pharmacology*
  • Cannabinoid Receptor Agonists / pharmacology*
  • Circadian Clocks / drug effects*
  • Circadian Clocks / genetics
  • Cryptochromes / drug effects
  • Cryptochromes / genetics
  • Dronabinol / pharmacology*
  • Gene Expression / drug effects
  • Gene Expression Profiling
  • Mice
  • Microglia / drug effects*
  • Microglia / metabolism
  • Period Circadian Proteins / drug effects*
  • Period Circadian Proteins / genetics
  • RNA-Seq
  • Receptor, Cannabinoid, CB1 / drug effects
  • Receptor, Cannabinoid, CB1 / genetics
  • Suprachiasmatic Nucleus / drug effects
  • Suprachiasmatic Nucleus / metabolism

Substances

  • ARNTL Transcription Factors
  • Bmal1 protein, mouse
  • Cannabinoid Receptor Agonists
  • Cry2 protein, mouse
  • Cryptochromes
  • Period Circadian Proteins
  • Receptor, Cannabinoid, CB1
  • Cannabidiol
  • Dronabinol
  • CLOCK Proteins
  • Clock protein, mouse