The N-acylethanolamines (NAEs) exert important behavioral, physiological, and immunological effects through actions at cannabinoid and other receptors. We measured concentrations of three NAEs, the Km and Vmax for fatty acid amide hydrolysis (FAAH), FAAH protein and FAAH mRNA in prefrontal cortex, hippocampus, hypothalamus, amygdala, striatum, and cerebellum at 4 h intervals, starting at 03:00. Significant differences in N-arachidonylethanolamine contents among the times examined occur in the prefrontal cortex (PFC), hippocampus, hypothalamus, and striatum. N-Oleoylethanolamine concentrations exhibit large fluctuations over the day in the cerebellum, including a threefold decrease between 19:00 and 23:00. N-Palmitoylethanolamine and N-oleoylethanolamine were significantly, positively correlated in all regions examined except the hypothalamus. FAAH Km values are significantly affected by time of day in PFC, hippocampus and amygdala and FAAH Vmax values are significantly affected in PFC, hippocampus and cerebellum. However, correlational data indicate that FAAH does not play a primary role in the circadian regulation of the NAE concentrations. FAAH protein expression is not significantly different among the harvest times in any brain region examined. Concentrations of 2-arachidonoylglycerol are significantly affected by time of harvest in the striatum and cerebellum, but not in other brain regions. Together, these data indicate that the NAEs exhibit diverse patterns of change with time of day that are likely the result of alterations in biosynthesis, and support the hypothesis that N-arachidonylethanolamine is a tonic activator of cannabinoid receptor signaling.
Concentrations of the endocannabinoid, anandamide (AEA) exhibit significant variability over the day that is brain region specific. It is our hypothesis that AEA is a tonic regulator of cannabinoid receptor activity in brain and that the changes in AEA content over the day reflect differences in AEA regulation of basal tone. The hypothesized patterns of tonic CB1 receptor activity in four brain regions are shown in this figure.