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A Single delta(9)-Tetrahydrocannabinol (THC) Dose During Brain Development Affects Markers of Neurotrophy, Oxidative Stress, and Apoptosis
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.ORCID iD: 0000-0003-2024-1824
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molekylär Neurofarmakologi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molekylär Neurofarmakologi)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
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2019 (English)In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 10, article id 1156Article in journal (Refereed) Published
Abstract [en]

delta(9)-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.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA , 2019. Vol. 10, article id 1156
Keywords [en]
delta(9)-tetrahydrocannabinol, developmental toxicology and neurotoxicology, acetaminophen (paracetamol), Trkb, oxidative stress, brain growth spurt, critical window development, neurotrophic
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-398418DOI: 10.3389/fphar.2019.01156ISI: 000497513300001PubMedID: 31636565OAI: oai:DiVA.org:uu-398418DiVA, id: diva2:1377091
Available from: 2019-12-11 Created: 2019-12-11 Last updated: 2019-12-11Bibliographically approved

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Philippot, GaetanForsberg, EricaViberg, HenrikFredriksson, Robert
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