title: Short-term exposure and long-term consequences of neonatal exposure to Δ(9)-tetrahydrocannabinol (THC) and ibuprofen in mice.
abstract: Both Δ(9)-tetrahydrocannabinol (THC) and ibuprofen have analgesic properties by interacting with the cannabinoid receptor type 1 (CB1R) and the cyclooxygenase (COX) systems, respectively. Evaluation of these analgesics is important not only clinically, since they are commonly used during pregnancy and lactation, but also to compare them with acetaminophen, with a known interaction with both CB1R and the COX systems. Short-term exposure of neonatal rodents to acetaminophen during the first weeks of postnatal life, which is comparable with a period from the third trimester of pregnancy to the first years of postnatal life in humans, induces long-term behavioral disturbances. This period, called the brain growth spurt (BGS) and is characterized by series of rapid and fundamental changes and increased vulnerability, peaks around postnatal day (PND) 10 in mice. We therefore exposed male NMRI mice to either THC or ibuprofen on PND 10. At 2 months of age, the mice were subjected to a spontaneous behavior test, consisting of a 60min recording of the variables locomotion, rearing and total activity. Mice exposed to THC, but not ibuprofen, exhibited altered adult spontaneous behavior and habituation capability in a dose-dependent manner. This highlights the potency of THC as a developmental neurotoxicant, since a single neonatal dose of THC was enough to affect adult cognitive function. The lack of effect from ibuprofen also indicates that the previously seen developmental neurotoxicity of acetaminophen is non-COX-mediated. These results might be of importance in future research as well as in the ongoing risk/benefit assessment of THC.
authors.affiliation: Department of Environmental Toxicology, Uppsala University, Sweden.
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Philippot
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Sweden.
authors.forename: Fred
authors.initials: F
authors.lastname: Nyberg
authors.affiliation: Department of Surgical Sciences, Uppsala University, Sweden.
authors.forename: Torsten
authors.initials: T
authors.lastname: Gordh
authors.affiliation: Department of Neuroscience, Psychiatry, Uppsala University, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Fredriksson
authors.affiliation: Department of Environmental Toxicology, Uppsala University, Sweden. Electronic address: henrik.viberg@ebc.uu.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Viberg
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002658:Developmental Disabilities / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D005260:Female; D007052:Ibuprofen / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D011247:Pregnancy; D013997:Time Factors
chemical_list: D018712:Analgesics, Non-Narcotic; D013759:Dronabinol; D007052:Ibuprofen
keywords: Analgesics; Cognitive function; Developmental neurotoxicity; Ibuprofen; Δ(9)-Tetrahydrocannabinol