Regulation of PI3K/Akt/GSK-3 pathway by cannabinoids in the brain

J Neurochem. 2007 Aug;102(4):1105-14. doi: 10.1111/j.1471-4159.2007.04642.x. Epub 2007 May 4.


Delta9-tetrahydrocannabinol (THC), the main psychoactive component in Cannabis sativa preparations, exerts its central effects mainly through the G-protein coupled receptor CB1, a component of the endocannabinoid system. Several in vitro and in vivo studies have reported neuroprotective effects of cannabinoids in excitotoxicity and neurodegeneration models. However, the intraneuronal signaling pathways activated in vivo by THC underlying its central effects remain poorly understood. We report that THC acute administration (10 mg/kg, i.p.) increases the phosphorylation of Akt in mouse hippocampus, striatum, and cerebellum. This phosphorylation was mediated by CB1 receptors as it was blocked by the selective CB1 antagonist rimonabant. Moreover, PI3K inhibition by wortmannin abrogated THC-induced phosphorylation of Akt, but blockade of extracellular signal-regulated protein kinases by SL327 did not modify this activation/phosphorylation of Akt. Moreover, administration of the dopaminergic D1 (SCH 23390) and D2 (raclopride) receptor antagonists did not block the activation of PI3K/Akt pathway induced in the striatum by cannabinoid receptor stimulation, suggesting that this effect is independent of the dopaminergic system. In addition, THC increased the phosphorylation of glycogen synthase kinase 3 beta. Therefore, activation of the PI3K/Akt/GSK-3 signaling pathway may be related to the in vivo neuroprotective properties attributed to cannabinoids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism*
  • Cannabinoids / pharmacology*
  • Dose-Response Relationship, Drug
  • Dronabinol / pharmacology
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology
  • Glycogen Synthase Kinase 3 / metabolism*
  • Male
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Psychotropic Drugs / pharmacology
  • Signal Transduction / drug effects*


  • Cannabinoids
  • Enzyme Inhibitors
  • Psychotropic Drugs
  • Dronabinol
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3