Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis.

The endocannabinoid system comprises receptors (CB1 and CB2 cannabinoid receptors), enzymes (Fatty Acid Amide Hydrolase [FAAH], which synthesizes the endocannabinoid anandamide), as well as the anandamide membrane transporter (AMT). Importantly, previous experiments have demonstrated that the endocannabinoid system modulates multiple neurobiological functions, including sleep. For instance, SR141716A (the CB1 cannabinoid receptor antagonist) as well as URB597 (the FAAH inhibitor) increase waking in rats whereas VDM-11 (the blocker of the AMT) enhances sleep in rodents. However, no further evidence is available regarding the neurobiological role of the endocannabinoid system in the homeostatic control of sleep. Therefore, the aim of the current experiment was to test if SR141716A, URB597 or VDM-11 would modulate the sleep rebound after sleep deprivation. Thus, these compounds were systemically injected (5, 10, 20mg/kg; ip; separately each one) into rats after prolonged waking. We found that SR141716A and URB597 blocked in dose-dependent fashion the sleep rebound whereas animals treated with VDM-11 displayed sleep rebound during the recovery period. Complementary, injection after sleep deprivation of either SR141716A or URB597 enhanced dose-dependently the extracellular levels of dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT), as well as adenosine (AD) while VDM-11 caused a decline in contents of these molecules. These findings suggest that SR141716A or URB597 behave as a potent stimulants since they suppressed the sleep recovery period after prolonged waking. It can be concluded that elements of the endocannabinoid system, such as the CB1 cannabinoid receptor, FAAH and AMT, modulate the sleep homeostasis after prolonged waking.