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

Abstract

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

Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition

“…In support of this premise, the enzymes that produce several classes of lipid transmitters, including lysophospholipids (6), eicosanoids (7), and endocannabinoids (8,9), are highly expressed in the nervous system and play important roles in brain development, synaptic plasticity, and the modulation of complex behaviors. For example, the diacylglycerol (DAG) lipase enzymes DAGLα and DAGLβ (10) produce the endocannabinoid 2-arachidonoylglycerol (2-AG) (11,12), and the constitutive genetic disruption of DAGLα lowers brain 2-AG and arachidonic acid (AA) content (13,14), resulting in impaired synaptic plasticity (13,14), hypophagia (15), enhanced anxiety and fear responses (16,17), and propensity for spontaneous seizures (15).…”

The Anxiolytic Actions of 2-Arachidonoylglycerol: Converging Evidence From Two Recent Genetic Endocannabinoid Deficiency Models

“…However, whether 2-AG deficiency states could contribute to the pathologic expression of anxiety and depressive behaviors is unknown. In the past 6 months, two studies, by Shonesy et al (Table 1), although Jenniches et al (4) additionally found that conditioned fear extinction was impaired in Dagla 2/2 mice ( Table 1). The remarkable concordance of the findings from different mouse lines and different laboratories provides strong support for the hypothesis that 2-AG signaling plays a key role in the regulation of emotional behavior and stress responsivity.…”

“…Second, Jenniches et al (4) generated Dagla 2/2 mice from homozygote breeders, yet showed that maternal behavior was impaired in Dagla 2/2 female mice, which could potentially confound interpretation of behavioral differences between genotypes in adulthood. Lastly, Jenniches et al (4) reported reductions in the levels of anandamide in addition to 2-AG in several brain regions, whereas Shonesy et al (4) did not observe changes in forebrain anandamide levels. Although the reasons for the differences are unknown at the present time, resolution of these discrepancies should be a high priority for future studies.…”

“…(4) showed that JZL-184 abrogated the genotype difference in immobility in the forced swim test, JZL-184 did not reduce immobility time of Dagla 2/2 mice per se and caused only a slight restoration of 2-AG levels in Dagla 2/2 mice. One possible explanation for this discrepancy in the reversibility of 2-AG deficiency the Dagla 2/2 behavioral phenotypes is differential bioavailability of JZL-184, as Jenniches et al (4) administered 20 mg/kg JZL-184 in an aqueous-based vehicle, which resulted in only an 33% increase in 2-AG levels in wild-type mice, whereas Shonesy et al(3)detected an 250% increase in wild-type mice using this same dose…”

“…First, Jenniches et al (4) found only a trend toward anhedonia in the sucrose preference test using a cohort of male and female mice. However, Shonesy et al (3) showed that only female Dagla 2/2 mice exhibited anhedonia in this assay.…”