Developmental cannabidiol exposure increases anxiety and modifies genome-wide brain DNA methylation in adult female mice

Nicole M Wanner,Mathia Colwell,Chelsea Drown,Christopher Faulk

doi:10.1186/s13148-020-00993-4

Abstract

BackgroundUse of cannabidiol (CBD), the primary non-psychoactive compound found in cannabis, has recently risen dramatically, while relatively little is known about the underlying molecular mechanisms of its effects. Previous work indicates that direct CBD exposure strongly impacts the brain, with anxiolytic, antidepressant, antipsychotic, and other effects being observed in animal and human studies. The epigenome, particularly DNA methylation, is responsive to environmental input and can direct persistent patterns of gene regulation impacting phenotype. Epigenetic perturbation is particularly impactful during embryogenesis, when exogenous exposures can disrupt critical resetting of epigenetic marks and impart phenotypic effects lasting into adulthood. The impact of prenatal CBD exposure has not been evaluated; however, studies using the psychomimetic cannabinoid Δ9-tetrahydrocannabinol (THC) have identified detrimental effects on psychological outcomes in developmentally exposed adult offspring. We hypothesized that developmental CBD exposure would have similar negative effects on behavior mediated in part by the epigenome. Nulliparous female wild-type Agouti viable yellow (Avy) mice were exposed to 20 mg/kg CBD or vehicle daily from two weeks prior to mating through gestation and lactation. Coat color shifts, a readout of DNA methylation at the Agouti locus in this strain, were measured in F1 Avy/a offspring. Young adult F1 a/a offspring were then subjected to tests of working spatial memory and anxiety/compulsive behavior. Reduced-representation bisulfite sequencing was performed on both F0 and F1 cerebral cortex and F1 hippocampus to identify genome-wide changes in DNA methylation for direct and developmental exposure, respectively.ResultsF1 offspring exposed to CBD during development exhibited increased anxiety and improved memory behavior in a sex-specific manner. Further, while no significant coat color shift was observed in Avy/a offspring, thousands of differentially methylated loci (DMLs) were identified in both brain regions with functional enrichment for neurogenesis, substance use phenotypes, and other psychologically relevant terms.ConclusionsThese findings demonstrate for the first time that despite positive effects of direct exposure, developmental CBD is associated with mixed behavioral outcomes and perturbation of the brain epigenome.

Highlights

Use of cannabidiol (CBD), the primary non-psychoactive compound found in cannabis, has recently risen dramatically, while relatively little is known about the underlying molecular mechanisms of its effects
Cantacorps, and Valverde demonstrated that the protective effects of CBD on voluntary cocaine intake were ameliorated by pharmacological inhibition of hippocampal neurogenesis, and Campos et al determined that CBD’s anxiolytic effects were driven by facilitating endocannabinoid-mediated neurogenesis using a mouse model of chronic unpredictable stress [16, 20]
Mice were obtained from an Agouti viable yellow (Avy) colony maintained for over 220 generations with the Avy allele passed through the male line, resulting in forced heterozygosity on a genetically invariant background with 93% identity to C57BL/6 [62, 63]

Summary

Introduction

Use of cannabidiol (CBD), the primary non-psychoactive compound found in cannabis, has recently risen dramatically, while relatively little is known about the underlying molecular mechanisms of its effects. The impact of prenatal CBD exposure has not been evaluated; studies using the psychomimetic cannabinoid Δ9-tetrahydrocannabinol (THC) have identified detrimental effects on psychological outcomes in developmentally exposed adult offspring. Cannabidiol (CBD) is the primary non-psychomimetic compound found in cannabis (Cannabis sativa) and an FDA-approved treatment for childhood epilepsy that shows therapeutic potential for several neuropsychiatric disorders. CBD reduces psychotic symptoms in schizophrenia [9, 10] and lowers subjective measures of anxiety [11, 12] These findings contrast with previous research on the psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC), which report anxiogenic and other adverse psychological effects that concurrent CBD administration may counteract [13,14,15]. Cantacorps, and Valverde demonstrated that the protective effects of CBD on voluntary cocaine intake were ameliorated by pharmacological inhibition of hippocampal neurogenesis, and Campos et al determined that CBD’s anxiolytic effects were driven by facilitating endocannabinoid-mediated neurogenesis using a mouse model of chronic unpredictable stress [16, 20]

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