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Cardiorespiratory anomalies in mice lacking CB1 cannabinoid receptors.

ABSTRACT: Cannabinoid type 1 (CB1) receptors are expressed in the nervous and cardiovascular systems. In mice, CB1 receptor deficiency protects from metabolic consequences of a high-fat diet (HFD), increases sympathetic activity to brown fat, and entails sleep anomalies. We investigated whether sleep-wake and diet-dependent cardiorespiratory control is altered in mice lacking CB1 receptors. CB1 receptor knock-out (KO) and intact wild-type (WT) mice were fed standard diet or a HFD for 3 months, and implanted with a telemetric arterial pressure transducer and electrodes for sleep scoring. Sleep state was assessed together with arterial pressure and heart rate (home cage), or breathing (whole-body plethysmograph). Increases in arterial pressure and heart rate on passing from the light (rest) to the dark (activity) period in the KO were significantly enhanced compared with the WT. These increases were unaffected by cardiac (?1) or vascular (?1) adrenergic blockade. The breathing rhythm of the KO during sleep was also more irregular than that of the WT. A HFD increased heart rate, impaired cardiac vagal modulation, and blunted the central autonomic cardiac control during sleep. A HFD also decreased cardiac baroreflex sensitivity in the KO but not in the WT. In conclusion, we performed the first systematic study of cardiovascular function in CB1 receptor deficient mice during spontaneous wake-sleep behavior, and demonstrated that CB1 receptor KO alters cardiorespiratory control particularly in the presence of a HFD. The CB1 receptor signaling may thus play a role in physiological cardiorespiratory regulation and protect from some adverse cardiovascular consequences of a HFD.

SUBMITTER: Silvani A

PROVIDER: S-EPMC4065065 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Cardiorespiratory anomalies in mice lacking CB1 cannabinoid receptors.

Silvani Alessandro A Berteotti Chiara C Bastianini Stefano S Cohen Gary G Lo Martire Viviana V Mazza Roberta R Pagotto Uberto U Quarta Carmelo C Zoccoli Giovanna G

PloS one 20140620 6

Cannabinoid type 1 (CB1) receptors are expressed in the nervous and cardiovascular systems. In mice, CB1 receptor deficiency protects from metabolic consequences of a high-fat diet (HFD), increases sympathetic activity to brown fat, and entails sleep anomalies. We investigated whether sleep-wake and diet-dependent cardiorespiratory control is altered in mice lacking CB1 receptors. CB1 receptor knock-out (KO) and intact wild-type (WT) mice were fed standard diet or a HFD for 3 months, and implant ...[more]

PMID: 24950219

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Project description:Saliva serves multiple important functions within the body that we typically take for granted, such as helping prepare food for swallowing and defense against oral pathogens. Dry mouth is a primary symptom of Sjӧgren’s syndrome and is a side effect of many drug treatments. Cannabis users frequently report dry mouth, but the basis for this is still unknown. If the effects occur via the endogenous cannabinoid signaling system, then this may represent a novel mechanism for the regulation of salivation. We examined expression of cannabinoid CB1 receptors in submandibular salivary gland using immunohistochemistry and tested regulation of salivation by THC and cannabinoid-related ligands. We now report that CB1 receptors are expressed in the axons of cholinergic neurons innervating the submandibular gland. No staining is seen in submandibular gland epithelial cells (acinar and ductal), or myoepithelial cells (MECs). Treatment with THC (4 mg/kg, IP) or the cannabinoid receptor agonist CP55940 (0.5 mg/kg) reduced salivation in both male and female mice 1 h after treatment. CBD had no effect on its own but reversed the effect of THC in a concentration-dependent manner. Neither the CB1 receptor antagonist SR141716 (4 mg/kg) nor the CB2-selective agonist JWH133 (4 mg/kg) had an effect on salivation. We also found that fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide and related lipids, regulates salivation. Salivation was reduced in FAAH knockout mice as well as mice treated with the FAAH blocker URB597 (4 mg/kg). URB597 had no effect in CB1 knockout mice. FAAH protein is detected intracellularly in acinar but not ductal epithelial cells. In lipidomics experiments, we found that FAAH knockout mice chiefly had elevated levels of acylethanolamines, including anandamide, and reduced levels of acyglycines. Our results are consistent with a model wherein endocannabinoids activate CB1 receptors on cholinergic axons innervating the submandibular gland. THC likely acts by plugging into this system, activating CB1 receptors to reduce salivation, thus offering a mechanism underlying the dry mouth reported by cannabis users.

Dataset Information

Cardiorespiratory anomalies in mice lacking CB1 cannabinoid receptors.

Publications

Cardiorespiratory anomalies in mice lacking CB1 cannabinoid receptors.

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