Activation of PAR1 in the lateral hypothalamus of rats enhances food intake and REMS through CB1R

Abstract

The activation of protease-activated receptor 1 (PAR1) in cultured rat hippocampal neurons triggers synaptic retrograde signaling through the endocannabinoid 2-arachidonoylglycerol, thereby activating the cannabinoid receptor 1 (CB1R). CB1R is a metabotropic receptor activated by marihuana and endocannabinoids that suppresses neurotransmitter release. Also, activation of the CB1R increases rapid eye movement sleep (REMS) and food intake. The lateral hypothalamus is a crucial structure to modulate both feeding and waking. To evaluate the effect of PAR1 stimulation in the lateral hypothalamus on food intake and on the sleep-waking cycle, we implanted rats with electrodes, for recording sleep, and cannulae, to administer S1820, a selective PAR1 agonist peptide, bilaterally into the lateral hypothalamus. To determine whether the effects induced by PAR1 stimulation were mediated by CB1R activation, we administered AM251, a CB1R inverse agonist, to block S1820 effects. Our results show that the stimulation of PAR1 into the lateral hypothalamus increases both food intake and REMS and such effects were prevented by AM251, indicating that PAR1 modulates both food intake and the sleep-waking cycle, in the lateral hypothalamus, through CB1R activation. This study shows novel behavioral changes induced by PAR1 activation and further supports the notion that endocannabinoids are food intake and REMS promoters.

Endocannabinoid Signaling Regulates Sleep Stability

“…However, studies with constitutive knockout mice are always subject to confounds arising from developmental adaptations, and this has been confirmed for the CB1 knockout mice used in these studies [ 26 , 27 ]. On the other hand, studies with CB1 antagonists in rodents have had conflicting results with some reporting a weak reduction in NREM sleep [ 15 , 19 , 28 – 30 ] and others finding no effects on sleep [ 13 , 31 , 32 ]. Of note, all of these studies were performed over short time windows (< 8 Hr recordings), and eCB levels are known to fluctuate over the circadian cycle [ 33 , 34 ].…”

Cannabinoids and Sleep: Exploring Biological Mechanisms and Therapeutic Potentials

“…For instance, Perez-Morales and colleagues (2013, 2014) found that direct administration of 2-AG into the lateral hypothalamus of mice increased the duration of REM sleep, while the administration of a CB1 receptor antagonist elicited opposing effects, indicating that CB1 receptor activation by 2-AG induces sleepiness [28,29]. Moreover, Perez-Morales et al (2012) discovered that tetrahydrolipstatin, an inhibitor of the 2-AG-synthesizing enzyme DAGL, reduces the activity of melanin-concentrating hormone (MCH)-releasing neurons in the hypothalamus, resulting in decreased REM sleep and food intake [30,31]. This suggests that CB1 receptors may regulate sleep by modulating the activity of MCH neurons, predominantly located in the lateral hypothalamus, which is active during the REM stage of sleep.…”

ENP11, a potential CB1R antagonist, induces anorexia in rats

“…Due to the fact that extensive scientific literature has supported the endocannabinoid system (eCBs) as a food ingestion modulator, the phyto and synthetic cannabinoids seem to be useful to affect such a function (Koch, 2001;Martínez-González et al, 2004;Méndez-Díaz et al, 2012;Merroun et al, 2009;Pérez-Morales et al, 2012;Soria-Gómez et al, 2010). In this context, it is now known that CB1R antagonists reduce food intake thereby promoting weight loss.…”