Abstract
Animal studies point to an implication of the endocannabinoid system on executive functions. In humans, several studies have suggested an association between acute or chronic use of exogenous cannabinoids (Δ9-tetrahydrocannabinol) and executive impairments. However, to date, no published reports establish the relationship between endocannabinoids, as biomarkers of the cannabinoid neurotransmission system, and executive functioning in humans. The aim of the present study was to explore the association between circulating levels of plasma endocannabinoids N-arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG) and executive functions (decision making, response inhibition and cognitive flexibility) in healthy subjects. One hundred and fifty seven subjects were included and assessed with the Wisconsin Card Sorting Test; Stroop Color and Word Test; and Iowa Gambling Task. All participants were female, aged between 18 and 60 years and spoke Spanish as their first language. Results showed a negative correlation between 2-AG and cognitive flexibility performance (r = −.37; p<.05). A positive correlation was found between AEA concentrations and both cognitive flexibility (r = .59; p<.05) and decision making performance (r = .23; P<.05). There was no significant correlation between either 2-AG (r = −.17) or AEA (r = −.08) concentrations and inhibition response. These results show, in humans, a relevant modulation of the endocannabinoid system on prefrontal-dependent cognitive functioning. The present study might have significant implications for the underlying executive alterations described in some psychiatric disorders currently associated with endocannabinoids deregulation (namely drug abuse/dependence, depression, obesity and eating disorders). Understanding the neurobiology of their dysexecutive profile might certainly contribute to the development of new treatments and pharmacological approaches.
Highlights
Cannabis has been used for thousands of years and has long been associated with effects on cognitive and emotional processes
We explored the relationship between circulating levels of plasma endocannabinoids (AEA and 2-AG) and executive functions in healthy subjects in order to determine the plausible role of the endocannabinoid system on prefrontal-depended cognitive functioning
A negative correlation was found between 2AG and cognitive flexibility performance
Summary
Cannabis has been used for thousands of years and has long been associated with effects on cognitive and emotional processes. Several possible biosynthetic routes for the formation of AEA have been suggested with multiple enzymes implicated: the N-acylphosphatidylethanolamine specific phospholipase D (NAPE-PLD), the a,b-Hydrolase-4 (ABHD4), the glycerophosphodiesterase-1 (GDE1), a soluble phospholipase A2, an unidentified phospholipase C, and phosphatases. These biosynthetic pathways may be able to substitute one another as mice lacking NAPE-PLD do not show decreased AEA [6]. The biosynthetic precursors for 2-AG, the sn-1-acyl-2-arachidonoylglycerols (AArG) are mostly produced by phospholipase Cb (PLCb) acting on membrane phosphatidylinositols, and converted to 2-AG by the action of either of two isoforms of the same enzyme, the sn-1-diacylglycerol lipases a and b (DAGLa and DAGLb) [9]. The biosynthetic precursors for 2-AG, the sn-1-acyl-2-arachidonoylglycerols (AArG) are mostly produced by phospholipase Cb (PLCb) acting on membrane phosphatidylinositols, and converted to 2-AG by the action of either of two isoforms of the same enzyme, the sn-1-diacylglycerol lipases a and b (DAGLa and DAGLb) [9]. 2-AG is largely degraded by the monoacylglycerol lipase (MAGL) [7]
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