Opposite control of frontocortical 2‐arachidonoylglycerol turnover rate by cannabinoid type‐1 receptors located on glutamatergic neurons and on astrocytes

This study examined the respective influences of cannabinoid type‐1 (CB₁) receptors expressed either in forebrain GABAergic neurons, in cortical glutamatergic neurons, or in astrocytes on the turnover rates of the endocannabinoids N‐arachidonoylethanolamide (AEA) and 2‐arachidonoylglycerol (2‐AG), and the non‐cannabinoid N‐acylethanolamides, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA), in mouse forebrain regions. To this end, conditional mutant mice lacking CB₁ receptors from either of these cell types were pre‐treated systemically with JZL195, a dual inhibitor of fatty acid amide hydrolase, the enzyme degrading AEA, PEA, and OEA, and of monoacylglycerol lipase, the main 2‐AG‐degrading enzyme. The analyses of frontocortical, hippocampal, and striatal AEA, 2‐AG, PEA, and OEA concentrations revealed that their respective baseline concentrations were not influenced by the mouse genotype. On the other hand, the accumulation of frontocortical and/or hippocampal 2‐AG levels in JZL195‐pre‐treated mice was dependent on the mouse genotype. Thus, JZL195‐induced 2‐AG accumulation rates were diminished in the frontal cortex of mice lacking CB₁ receptors in glutamatergic neurons while their respective values were increased in the frontal cortex and hippocampus of mice lacking these receptors in astrocytes. These genotypic differences occurred with parallel and proportionate changes in the fractional rate constants for degradation of 2‐AG, thus providing a mechanism whereby the baseline levels of 2‐AG remained constant between genotypes. Besides suggesting a cell‐type‐specific control of frontocortical and/or hippocampal 2‐AG synthesis and degradation rates by CB₁ receptors, this study highlights the interest of assessing endocannabinoid turnover rates when questioning the status of the endocannabinoid system.