Baglot, S. | Search bioRxiv

bioRxiv2023

Sex differences in pharmacokinetics, central accumulation, and behavioural effects of oral cannabis consumption in male and female C57BL/6 mice.

BackgroundCannabis edibles are an increasingly popular form of cannabis consumption. Oral consumption of cannabis has distinct physiological and behavioural effects than injection or inhalation. An animal model is needed to understand the pharmacokinetics and physiological effects of oral cannabis consumption in rodents as a model for human cannabis edible use. MethodsAdult male and female C57BL/6 mice received a single dose of commercially available cannabis oil (5 mg/kg THC) by oral gavage. At 0.5-, 1-, 2-, 3-, and 6-hours post-exposure, plasma, hippocampus, and adipose tissue was collected for THC, 11-OH-THC, and THC-COOH measures. ResultsWe report delayed time to peak THC and 11-OH-THC concentrations in plasma, brain and adipose tissue, which is consistent with human pharmacokinetics studies. We also found sex differences in the cannabis tetrad: (1) female mice had a delayed hypothermic effect 6 hours post-consumption, which was not present in males; (2) females had stronger catalepsy than males; (3) males were less mobile following cannabis exposure, whereas female mice showed no difference in locomotion but an anxiogenic effect at 3h post exposure; and (4) male mice displayed a longer lasting antinociceptive effect of oral cannabis. ConclusionsOral cannabis consumption is a translationally relevant form of administration that produces similar physiological effects as injection or vaping administration and thus should be considered as a viable approach for examining the physiological effects of cannabis moving forward. Furthermore, given the strong sex differences in metabolism of oral cannabis, these factors should be carefully considered when designing animal studies on the effects of cannabis. Significance statementOral delivery of cannabis oil in mice is a translational model that increases plasma, hippocampal, and adipose cannabinoids. Furthermore, oral cannabis and produces lasting psychoactive effects including sex dependent effects on hypothermia, cataplexy, locomotor activity and nociception.

pharmacology and toxicology↗

bioRxiv2020

Colonization with the commensal fungus Candida albicans perturbs the gut-brain axis through dysregulation of endocannabinoid signaling

Anxiety disorders are the most prevalent mental health disorder worldwide, with a lifetime prevalence of 5-7% of the human population. Although the etiology of anxiety disorders is incompletely understood, one aspect of host health that affects anxiety disorders is the gut-brain axis. We used a mouse model of gastrointestinal (GI) colonization to demonstrate that the commensal fungus Candida albicans affects host health via the gut-brain axis. In mice, bacterial members of the gut microbiota can influence the host gut-brain axis, affecting anxiety-like behavior and the hypothalamus-pituitary-adrenal (HPA) axis which produces the stress hormone corticosterone (CORT). Here we showed that mice colonized with C. albicans demonstrated increased anxiety-like behavior and increased basal production of CORT as well as dysregulation of CORT production following acute stress. The HPA axis and anxiety-like behavior are negatively regulated by the endocannabinoid anandamide (AEA). C. albicans-colonized mice exhibited systemic changes in the endocannabinoidome, within the GI tract and the brain, and showed a negative correlation between brain AEA levels and serum CORT. Further, increasing AEA levels using the well-characterized fatty acid amide hydrolase (FAAH) inhibitor URB597 was sufficient to reverse both neuroendocrine phenotypes in C. albicans-colonized mice. Thus, a commensal fungus that is a common colonizer of humans had widespread effects on the physiology of its host. To our knowledge, this is the first report of microbial manipulation of the endocannabinoid (eCB) system that resulted in neuroendocrine changes contributing to anxiety-like behavior.

microbiology↗