Anxiety, Stress, and Fear Response in Mice With Reduced Endocannabinoid Levels

Biol Psychiatry. 2016 May 15;79(10):858-868. doi: 10.1016/j.biopsych.2015.03.033. Epub 2015 Apr 14.


Background: Disruption of the endocannabinoid system through pharmacological or genetic invalidation of cannabinoid CB1 receptors has been linked to depression in humans and depression-like behaviors in mice. The two main endogenous cannabinoids, anandamide and 2-arachidonoyl glycerol (2-AG), are produced on demand from phospholipids. The pathways and enzymes involved in endocannabinoid biosynthesis thus play a major role in regulating the activity of this system. This study investigates the role of the main 2-AG producing enzyme diacylglycerol lipase α (DAGL-α).

Methods: We generated and used knockout mice lacking DAGL-α (Dagla(-/-)) to assess the behavioral consequences of reduced endocannabinoid levels in the brain. We performed different behavior tests to determine anxiety- and depression-related behavioral changes in Dagla(-/-) mice. We also analyzed expression of genes related to the endocannabinoid system via real-time polymerase chain reaction and used the mitotic marker 5-bromo-2'-deoxyuridine to analyze adult neurogenesis.

Results: Dagla(-/-) animals show an 80% reduction of brain 2-AG levels but also a reduction in cortical and amygdalar anandamide. The behavioral changes induced by Dagla deletion include a reduced exploration of the central area of the open field, a maternal neglect behavior, a fear extinction deficit, increased behavioral despair, increased anxiety-related behaviors in the light/dark box, and reduced hippocampal neurogenesis. Some of these behavioral changes resemble those observed in animals lacking the CB1 receptor.

Conclusions: Our findings demonstrate that the deletion of Dagla adversely affects the emotional state of animals and results in enhanced anxiety, stress, and fear responses.

Keywords: Anxiety; Cannabinoids; Dagla; Depression; Fear extinction; Stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / metabolism*
  • Brain / metabolism
  • Cohort Studies
  • Endocannabinoids / metabolism*
  • Exploratory Behavior / physiology
  • Extinction, Psychological / physiology
  • Fear / physiology*
  • Female
  • Lipoprotein Lipase / deficiency*
  • Lipoprotein Lipase / genetics
  • Male
  • Maternal Behavior / physiology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / physiology
  • Neurogenesis / physiology
  • Social Behavior
  • Stress, Psychological / metabolism*


  • Endocannabinoids
  • Lipoprotein Lipase