Broad and Region-Specific Impacts of the Synthetic Cannabinoid CP 55,940 in Adolescent and Adult Female Mouse Brains.

Emma Leishman,Ken Mackie,Michelle N. Murphy,Michelle I. Murphy,Heather B. Bradshaw

doi:10.3389/fnmol.2018.00436

Emma Leishman, Ken Mackie + Show 3 more

Open Access

https://doi.org/10.3389/fnmol.2018.00436

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Abstract

Relative to Δ9-tetrahydrocannabinol (THC), the synthetic cannabinoid CP 55,940 (CP) is significantly more potent and efficacious at cannabinoid receptors, the primary targets for endogenous cannabinoids (eCBs). eCBs belong to a large, interconnected lipidome of bioactive signaling molecules with a myriad of effects in optimal and pathological function. Recreational use of highly potent and efficacious synthetic cannabinoids is common amongst adolescents, potentially impacting brain development. Knowledge of the molecular outcomes of synthetic cannabinoid use will be important to develop more targeted therapies for synthetic cannabinoid intoxication and to prevent long-term disruption to the CNS. Here, we test the hypothesis that CP has age and region-dependent effects on the brain lipidome. Adolescent [post-natal day (PND) 35 and PND 50] and young adult female mice were given either an acute dose of CP or vehicle and brains were collected 2 h later. Eight brain regions were dissected and levels of ∼80 lipids were screened from each region using HPLC/MS/MS. CP had widespread effects on the brain lipidome in all age groups. Interestingly, more changes were observed in the PND 35 mice and more were reductions in a lipid’s concentration, including region-dependent lowering of eCB levels. CP levels were highest in the cortex at PND 35, the hippocampus at PND 50, and in the cerebellum in the adult. These data provide novel insights into how high-potency, synthetic cannabinoids drive different, age-dependent, cellular signaling effects in the brain.

Highlights

The cannabis plant’s primary psychoactive component, THC activates the cannabinoid receptors CB1 (Devane et al, 1988) and CB2 (Munro et al, 1993), which are targets for endogenous cannabinoid (eCB)
Each of the N-acyl ethanolamine (NAE), free fatty acid, and 2-acyl glycerol species analyzed were detected in all brain regions
There were 656 total discrete measures in endogenous lipids that could have been detected in each group (82 lipids in eight brain regions). 529 were detected in the post-natal day (PND) 35 brain, 450 were detected in the PND 50 brain, and 406 were detected in the adult brain

Summary

Introduction

The cannabis plant’s primary psychoactive component, THC activates the cannabinoid receptors CB1 (Devane et al, 1988) and CB2 (Munro et al, 1993), which are targets for eCBs. In addition to endogenous and plant-derived cannabinoids, there are synthetic cannabinoids that are typically more potent and efficacious at cannabinoid receptors (Castaneto et al, 2014; Kemp et al, 2016). One of the first synthetic cannabinoids synthesized was CP 55,940 (CP) (Uchiyama et al, 2009a). CP stimulated G-protein binding at CB1 with an EC50 of 3.4 nM, whereas THC had an EC50 of 167.4 nM (Brents et al, 2011). In another assay measuring functional inhibition of cAMP accumulation, CP was a more effective agonist at CB1 and CB2 receptors than THC. CP inhibited adenylate cyclase with an IC50 of 1.83 nM at CB1 and an IC50 of 2.89 nM at CB2, whereas THC had an IC50 of 16.5 nM at CB1 and 41.8 nM at CB2 (Felder et al, 1995)

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