CANNABIS PRODUCES WELL-RECOGNIZED BEHAV- IORAL EFFECTS AND TWO TYPES OF G PROTEIN-COU- PLED RECEPTORS (CB1 AND CB2) HAVE BEEN CHARAC- TERIZED WHICH BIND THE ACTIVE COMPONENTS OF CANNABIS.1 Still, the functional roles of endogenous ligands

CANNABIS PRODUCES WELL-RECOGNIZED BEHAVIORAL EFFECTS AND TWO TYPES OF G PROTEIN-COUPLED RECEPTORS (CB1 AND CB2) HAVE BEEN CHARACTERIZED WHICH BIND THE ACTIVE COMPONENTS OF CANNABIS.1 Still, the functional roles of endogenous ligands for CB1 and CB2 receptors remain poorly defined.2 Early observations suggest a potent neuromodulatory role for these endocannabinoids, including alterations in sleep/wake behaviors3-5 and cardiovascular control.6,7 Cannabinoid receptors interact with opiate, GABA, dopamine, glutamate, and serotonin systems,8 all of which influence level of arousal and autonomic regulation. Of particular interest to us was the fact that activation of serotonin (5-HT) receptors within the peripheral nervous system can lead to significant autonomic perturbations, especially during sleep. For example, stimulating peripheral 5-HT subtype 3 (5HT3) receptors exacerbates apnea expression in sleeping rats,9 whereas blockade of 5-HT3 receptors suppresses sleep apnea in rats10,11 and bulldogs.12 By altering serotonin receptor function, endocannabinoids also may impact sleep/wake and autonomic behaviors. In this respect, the published findings are not fully consistent because the serotonin/cannabinoid interaction appears to be receptor subtype specific. For example, some investigators report that serotonin-related behaviors are enhanced by cannabinoids,13 while others find that serotonin-mediated responses are attenuated in a dose-dependent manner.14,15 The availability of specific cannabinoid receptor agonists and endogenous fatty acid amide ligands allowed us to examine the role of cannabinoids in determining autonomic stability during sleep. We used the rat model of sleep related breathing disorder to monitor the impact of CB1 receptor agonist ∆9-tetrahydrocannabinol (∆9THC) and endogenous fatty acid amide cis-9octadecenoamide (oleamide) on respiratory stability during sleep. Involvement of serotonin receptor systems in the cannabinoid effects was examined by testing the ability of ∆9THC and oleamide to block serotonin-induced exacerbation of sleep-related apnea.9