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

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.

Reduced fetal cerebral blood flow predicts perinatal mortality in a mouse model of prenatal alcohol and cannabinoid exposure

“…5 ]. In contrast, non-pregnant dams who underwent CB and ALC + CB exposures ( n = 6, data not shown) did not experience subsequent mortality over a 7-month observational period, consistent with prior research showing that CP-55,940 is not toxic or lethal to non-pregnant mice at concentrations equal to or greater than those included in our experimental design [ 43 – 45 ].…”

“…Synthetic cannabinoids are particularly favorable among young adults as a less expensive alternative to THC that is often undetectable through urine tests [ 68 ]. Notably, the vast majority of synthetic cannabinoid users are previous cannabis users, and use synthetic cannabinoids at levels comparable to [ 45 ] or exceeding cannabis, contributing to accidental overdose and synthetic cannabinoid toxicity [ 69 , 70 ]. Thus, the potency and binding preference demonstrated by CP-55,940 serves as a viable model of synthetic cannabinoid use [ 45 ].…”

Reduced fetal cerebral blood flow following prenatal drug exposure predicts perinatal mortality

“…4]. In contrast, non-pregnant dams who underwent Cannabinoid and Alcohol+Cannabinoid exposures ( n =6, data not shown) did not experience subsequent mortality over a 7-month observational period, consistent with prior research showing that CP-55940 is not toxic or lethal to non-pregnant mice at concentrations equal to or greater than those included in our experimental design 38–40 .…”

The systems medicine of cannabinoids in pediatrics: the case for more pediatric studies

“…2D) is a nonclassical, bicyclic lipophilic cyclohexylphenol sCB and is a full agonist for CB1R and CB2R. CP is more potent than delta-9-THC and recent work in an animal model suggests this sCB may selectively disrupt lipids in young brains compared to adult brains [64].…”