A Single δ9-Tetrahydrocannabinol (THC) Dose During Brain Development Affects Markers of Neurotrophy, Oxidative Stress, and Apoptosis.

Gaëtan Philippot,Caroline Tahan,Erica Forsberg,Henrik Viberg,Robert Fredriksson

doi:10.3389/fphar.2019.01156

Abstract

δ9-tetrahydrocannabinol (THC) is one of the most used drugs during pregnancy and lactation and efficiently crosses the placental and blood–brain barriers. Despite the recent legalization initiatives worldwide, the adverse outcome pathway (AOP) of THC following exposure during brain development is incompletely understood. We have previously reported that a single injection of THC on postnatal day (PND) 10 altered adult spontaneous behavior and habituation rates in adult mice. Similar behavioral alterations have been reported following PND 10 exposure to the commonly used over-the-counter analgesic acetaminophen (AAP; also known as paracetamol); as both THC and AAP interact with the endocannabinoid system, we hypothesize that this system might be involved in the AOP of both these pharmaceuticals/drugs. Here, we report that a single THC dose on PND 10 decreased transcript levels of tropomyosin receptor kinase b (Trkb) 24 h after exposure in both the frontal and parietal cortex, and in the hippocampus in mice. An increase in the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) ratio were also found in both the parietal cortex and hippocampus following neonatal exposure to THC. In addition, THC exposure increased transcript levels of cannabinoid receptor type 1 (Cb1r) in the parietal cortex and increased the apoptosis regulator BAX in the frontal cortex. This study is important for mainly 3 reasons: 1) we are starting to get information on the developmental neurotoxic AOP of PND 10 exposure to THC, where we suggest that transcriptional changes of the neurotrophic receptor Trkb are central, 2) our PND 10 exposure model provides information relevant to human exposure and 3) since PND 10 exposure to AAP also decreased Trkb transcript levels, we suggest THC and AAP may share key events in their respective AOP through endocannabinoid-mediated alterations of the brain-derived neurotrophic factor (BDNF)-TRKB signaling pathway.

Highlights

There is an urgent need for scientific data regarding both the harm and benefit of cannabis use, because the use of this drug — both therapeutically and recreationally — is growing dramatically
Post hoc analyses using Tukey’s multiple comparisons test revealed a decrease in Trkb gene transcript levels in mice neonatally exposed to 50 mg/kg compared to controls in both frontal cortex (p = 0.015) and parietal cortex (p = 0.016) (Figures 1A, B)
There was no significant effect on Syp or Psd95 transcript levels in either the frontal cortex, the parietal cortex or in the hippocampus 24h after exposure (p > 0.05) (Figure 3A–C)

Summary

Introduction

There is an urgent need for scientific data regarding both the harm and benefit of cannabis use, because the use of this drug — both therapeutically and recreationally — is growing dramatically. During the peak of the BGS, many fundamental processes occur in the brain: dendritic and axonal outgrowth, synaptogenesis, establishment of neuronal connections, proliferation of glia cells, and myelination (Davison and Dobbing, 1968; Kolb and Whishaw, 1989) In mice, it has been demonstrated in numerous studies that single-day exposures to xenobiotics during the peak of the BGS can have long lasting effects on memory, learning, and locomotor activity (Eriksson, 1997; Viberg et al, 2008; Pontén et al, 2011; Viberg et al, 2013; Viberg et al, 2014)

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