Endocannabinoid (eCB) signaling has been heavily implicated in the modulation of anxiety and depressive behaviors and emotional learning. However, the role of the most-abundant endocannabinoid 2-arachidonoylglycerol (2-AG) in the physiological regulationof affective behaviors is not well understood. Here,we show that genetic deletion of the 2-AG syntheticenzyme diacylglycerol lipase α (DAGLα) inmice reduces brain, but not circulating, 2-AG levels.DAGLα deletion also results in anxiety-like and sex-specific anhedonic phenotypes associated withimpaired activity-dependent eCB retrograde signaling at amygdala glutamatergic synapses. Importantly, acute pharmacological normalization of 2-AG levels reverses both phenotypes of DAGLα-deficient mice. These data suggest 2-AG deficiency could contribute to the pathogenesis of affective disorders and that pharmacological normalization of 2-AG signaling could represent an approach for the treatment of mood and anxiety disorders. The role of the primary endogenous cannabinoid 2-AG in mood and anxiety regulation is not well understood. Shonesy etal. show that deletion of a primary 2-AG synthetic enzyme, DAGLα, results in anxiety and sex-specific depressive phenotypes, which can be rapidly reversed by pharmacological normalization of endocannabinoid levels.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)