Plasma and Liver Lipids are Differentially Regulated After Cannabinoid Treatments in Male and Female Mice

Abstract

Cannabinoids (CBs) have sex-dependent behavioral and physiological effects and modulate lipids across the body. To understand how some of these sex differences may be due to differences how both phyto- and endocannabinoids are regulated in the liver and plasma, male and female CD1 mice were administered 10 mg/kg i.p. of cannabidiol (CBD), ∆9-tetrahydrocannabinol (THC), or THC+CBD then core blood and liver tissue were collected after 2 hours. Lipids were extracted from both liver and plasma, and samples were screened via HPLC/MS/MS for ∆9-tetrahydrocannabinol (THC), metabolites 11-OH-THC and 11-COOH-THC, cannabidiol (CBD), metabolites 7-OH-CBD and 7-COOH-CBD, ~70 endolipids including the endocannabinoids, N-arachidonoyl ethanolamine (Anandamide; AEA) and 2-sn-arachidonoyl glycerol (2-AG). Structural analogs to AEA (e.g. lipoamino acids, lipoamines) and 2-acyl glycerols) as well as free fatty acids and prostaglandins were also evaluated. Results show that at 2 hours post injection levels of CBs demonstrate key differences between males and females in both plasma and liver, and that these differences vary when co-administered as opposed to administered alone. Illustrating a link between liver and plasma, directionality of CB differences are similar between the two tissue types as a function of both sex and CB treatment. By contrast, endolipids had very different profiles as a function of sex, CB administration, and tissue type. Importantly, there are baseline differences between male and female mice in endocannabinoids and related lipids, which likely impact how CB administration modulates these endolipids. These data illustrate the complexity of outcomes of CB treatment between males and females on circulating CBs and endolipids and highlight the need to consider these factors when evaluating efficacy of CB drug treatments or usage.