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

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 de...

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Vydáno v:Biological psychiatry (1969) Ročník 79; číslo 10; s. 858 - 868
Hlavní autoři: Jenniches, Imke, Ternes, Svenja, Albayram, Onder, Otte, David M., Bach, Karsten, Bindila, Laura, Michel, Kerstin, Lutz, Beat, Bilkei-Gorzo, Andras, Zimmer, Andreas
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Elsevier Inc 15.05.2016
Témata:
Animals
Anxiety
Anxiety - metabolism
Brain - metabolism
Cannabinoids
Cohort Studies
Dagla
Depression
Endocannabinoids - metabolism
Exploratory Behavior - physiology
Extinction, Psychological - physiology
Fear - physiology
Fear extinction
Female
Lipoprotein Lipase - deficiency
Lipoprotein Lipase - genetics
Male
Maternal Behavior - physiology
Mice, Inbred C57BL
Mice, Knockout
Motor Activity - physiology
Neurogenesis - physiology
Psychiatric/Mental Health
Social Behavior
Stress
Stress, Psychological - metabolism
Fear extinction
Depression
Cannabinoids
Anxiety
Dagla
Stress
ISSN:0006-3223, 1873-2402
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Shrnutí: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). 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. 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. Our findings demonstrate that the deletion of Dagla adversely affects the emotional state of animals and results in enhanced anxiety, stress, and fear responses.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0006-3223
1873-2402
DOI:10.1016/j.biopsych.2015.03.033