Impact of the mouse estrus cycle on cannabinoid receptor agonist‐induced molecular and behavioral outcomes

Abstract

Sexual dimorphisms are observed in cannabinoid pharmacology. It is widely reported that female animals are more sensitive to the cataleptic, hypothermic, antinociceptive, and anti‐locomotive effects of cannabinoid receptor agonists such as CP55,940. Despite awareness of these sex differences, there is little consideration for the pharmacodynamic differences within females. The mouse estrus cycle spans 4–5 days and consists of four sex hormone‐mediated phases: proestrus, estrus, metestrus, and diestrus. The endocannabinoid system interacts with female sex hormones including β‐estradiol, which may influence receptor expression throughout the estrus cycle. In the current study, sexually mature female C57BL/6 mice in either proestrus or metestrus were administered either 1 mg/kg i.p. of the cannabinoid receptor agonist CP55,940 or vehicle. Mice then underwent the tetrad battery of behavioral assays measuring catalepsy, internal body temperature, thermal nociception, and locomotion. Compared with female mice in metestrus, those in proestrus were more sensitive to the anti‐nociceptive effects of CP55,940. A similar trend was observed in CP55,940‐induced catalepsy; however, this difference was not significant. As for cannabinoid receptor expression in brain regions underlying antinociception, the spine tissue of proestrus mice that received CP55,940 exhibited increased expression of cannabinoid receptor type 1 relative to treatment‐matched mice in metestrus. These results affirm the importance of testing cannabinoid effects in the context of the female estrus cycle.

Resveratrol ameliorates maternal separation-induced anxiety- and depression-like behaviors and reduces Sirt1-NF-kB signaling-mediated neuroinflammation

“…First, studies have shown that the effects of maternal separation on offspring emotions can differ between sexes ( Francis-Oliveira et al, 2021 ). However, we only assessed the effect of resveratrol on maternal separation-induced anxiety- and depression-like behaviors in the male offspring, as fluctuating hormone levels in female mice may affect the results of behavioral experiments ( Wei et al, 2018 ; Kim et al, 2022 ). Secondly, we only examined the changes in the expression of inflammatory factors and the Sirt1/NF-κB signaling pathway in hippocampal regions and did not evaluate the changes in these indicators in other anxiety- and depression-related brain regions, such as the amygdala.…”

“…In the present study, it was considered that hormone level fluctuations during the estrous cycle of female mice may interfere with the results of behavioral experiments ( Wei et al, 2018 ; Zhou et al, 2020 ; Kim et al, 2022 ), the male C57BL/6J mice were used to investigate whether resveratrol can ameliorate maternal separation-induced anxiety- and depression-like behaviors in adulthood, and, if so, whether the mechanism involves the inhibition of inflammation response through the modulation of the Sirt1/NF-κB signaling pathway.…”

Modulation of type 1 cannabinoid receptor activity by cannabinoid by-products from Cannabis sativa and non-cannabis phytomolecules

“…Importantly, this study also focused only on male mice. Planned future studies will incorporate female mice as we and others have observed cannabinoid-dependent sex differences in vivo (Craft and Leitl, 2008;Wakley et al, 2014;Kim et al, 2022). Although caution should be exercised when extrapolating in vitro cell culture data into the whole animal in vivo systems, three observations from our dataset warrant further consideration with regard to effecting cannabis pharmacology.…”

Characterization of the effects of cannabinoid receptor deletion on energy metabolism in female C57BL mice

“…Yet, the breeding scheme was limited to less than 10 generations and results from our study were consistent, regardless of the generation of the mice. Also, we did not control for estrus cycle phase in our study, which can introduce variability as mouse estrus cycle was found to influence CB1R in the brain ( 35 ). Future directions include understanding the effects of diet composition and sex hormones on the activity of the endocannabinoid system and its role in energy regulation.…”