Nasal accumulation and metabolism of Δ9-tetrahydrocannabinol following aerosol (‘vaping’) administration in an adolescent rat model

Torrens, Alexa; Ruiz, Christina M.; Martinez, Maricela X.; Tagne, Alex Mabou; Roy, Pritam; Grimes, Dakota; Ahmed, Faizy; Lallai, Valeria; Inshishian, Victoria; Bautista, Malia; Chen, Yen-Chu; Huestis, Marilyn A.; Das, Aditi; Fowler, Christie D.; Mahler, Stephen V.; Piomelli, Daniele

doi:10.1016/j.phrs.2022.106600

Cited by 9 publications

(4 citation statements)

References 42 publications

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“…While smoking and, to a lesser extent, "vaping" are the most common means of cannabis consumption in people, animal studies generally rely on IP injection, which is practical and reproducible and elicits in rodents pharmacokinetic and pharmacodynamic responses that are comparable to those seen in cannabis smokers. For example, previous studies have shown that IP injection results in substantial and reproducible tissue concentrations of D 9 -THC in adolescent and adult mice and rats of both sexes and produces peaks in plasma concentrations that are quantitatively comparable to those observed in adult nonmedical cannabis smokers (Huestis, 2007;Torrens et al, 2020Torrens et al, , 2023. Specifically, 5 mg/kg IP resulted in plasma peak THC concentrations in adult male mice (198 6 20 ng/ml) very similar to peak plasma concentrations in adult men (162 6 34 ng/ml) after smoking one cannabis cigarette containing about 34 mg of THC (Huestis and Cone, 2004;Torrens et al, 2020).…”

Section: Thc Administrationmentioning

confidence: 84%

Adolescent exposure to low-dose Δ9-tetrahydrocannabinol depletes the ovarian reserve in female mice

Lim

Lee

Nguyen

et al. 2023

Toxicological Sciences

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Cannabis use by adolescents is widespread, but its effects on the ovaries remain largely unknown. Δ9-tetrahydrocannabinol (THC) exerts its pharmacological effects by activating, and in some conditions hijacking, cannabinoid receptors (CBRs). We hypothesized that adolescent exposure to THC affects ovarian function in adulthood. Peripubertal female C57BL/6N mice were given THC (5 mg/kg) or its vehicle, once daily by intraperitoneal injection. Mice either received THC from postnatal day (PND) 30-33 and ovaries were harvested PND34 or mice received THC from PND30-43, and ovaries were harvested PND70. Adolescent treatment with THC depleted ovarian primordial follicle numbers by 50% at PND70, 4 weeks after the last dose. The treatment produced primordial follicle activation which persisted until PND70. THC administration also caused DNA damage in primary follicles and increased PUMA protein expression in oocytes of primordial and primary follicles. Both CB1R and CB2R were expressed in oocytes and theca cells of ovarian follicles. Enzymes involved in the formation (N-acylphosphatidylethanolamine phospholipase D) or deactivation (fatty acid amide hydrolase) of the endocannabinoid anandamide were expressed in granulosa cells of ovarian follicles and interstitial cells. Levels of mRNA for CBR1 were significantly increased in ovaries after adolescent THC exposure, and upregulation persisted for at least 4 weeks. Our results support that adolescent exposure to THC may cause aberrant activation of the ovarian endocannabinoid system in female mice, resulting in substantial loss of ovarian reserve in adulthood. Relevance of these findings to women who frequently used cannabis during adolescence warrants investigation.

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Section: Thc Administrationmentioning

confidence: 84%

Adolescent exposure to low-dose Δ9-tetrahydrocannabinol depletes the ovarian reserve in female mice

Lim

Lee

Nguyen

et al. 2023

Toxicological Sciences

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“…Adolescent isolation stress can interact with other anxiety- and reward-related behaviors (Chappell et al, 2013; Caruso et al, 2018; Walker et al, 2019; Hong et al, 2012) that may interact with adulthood alcohol consumption in differing models. In addition, human adolescent consumption of alcohol rarely occurs in isolation, with adolescents often consuming both prescribed (Crowley et al, 2014) and illicit (Torrens et al, 2023) substances that have the potential to interact with alcohol. Importantly, human adolescents are often co-abusing these substances with alcohol (Claus et al, 2022), driving a greater necessity to understand their individual and synergistic effects on brain development.…”

Section: Discussionmentioning

confidence: 99%

“…Adolescent isolation stress can interact with other anxiety-and reward-related behaviors (Chappell et al, 2013;Caruso et al, 2018;Walker et al, 2019;Hong et al, 2012) that may interact with adulthood alcohol consumption in differing models. In addition, human adolescent consumption of alcohol often occurs in combination with other substances, including both prescribed (Crowley et al, 2014) and illicit (Torrens et al, 2023) substances that have the potential to interact with alcohol.…”

Section: Discussionmentioning

confidence: 99%

Voluntary adolescent alcohol exposure does not robustly increase adulthood consumption of alcohol in multiple mouse and rat models

Sicher,

Liss,

Vozella

et al. 2024

Preprint

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Adolescence is a period of increased risk taking, including increased alcohol and drug use. Multiple clinical studies report a positive relationship between adolescent alcohol consumption and risk of developing an alcohol use disorder (AUD) in adulthood. However, few preclinical studies have attempted to tease apart the biological contributions of adolescent alcohol exposure, independent of other social, environmental, and stress factors, and studies that have been conducted show mixed results. Here we use several adolescent voluntary consumption of alcohol models, conducted across three institutes and with two rodent species, to investigate the ramifications of adolescent alcohol consumption on adulthood alcohol consumption in controlled, preclinical environments. We consistently demonstrate a lack of increase in adulthood alcohol consumption. This work highlights that risks seen in both human datasets and other murine drinking models may be due to unique social and environmental factors, some of which may be unique to humans.

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“…A total of twenty tadpoles per experimental condition, either at stage 38-39 or at stage 45, were treated as above with either URB597 (2.5 µM in 0.1% DMSO in rearing solution; Cayman Chemicals, Ann Arbor, MI, USA), JZL184 (2.5 µM in 0.1% DMSO in rearing solution; Cayman Chemicals), or vehicle solution (0.1% DMSO) for 1 h. Tadpoles were then transferred to fresh rearing solution without the drug, anesthetized in 0.05% Finquel, quickly rinsed to remove most of the rearing solution containing the drug, and immediately frozen until further processing for fatty acid analysis. Frozen tadpole samples were homogenized, extracted and processed for liquid chromatography-mass spectrometry (LC/MS-MS) analyses as in Torrens et al (2023). Triplicate experiments were used for the statistical analysis of data.…”

Section: Fatty Acid Analysis Of Tadpole Samplesmentioning

confidence: 99%

Cell-autonomous and differential endocannabinoid signaling impacts the development of presynaptic retinal ganglion cell axon connectivity in vivo

Río

Serrano

Gomez

et al. 2023

Front. Synaptic Neurosci.

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Cannabis exposure during gestation evokes significant molecular modifications to neurodevelopmental programs leading to neurophysiological and behavioral abnormalities in humans. The main neuronal receptor for Δ9-tetrahydrocannabinol (THC) is the type-1 cannabinoid receptor CB1R, one of the most abundant G-protein-coupled receptors in the nervous system. While THC is the major psychoactive phytocannabinoid, endocannabinoids (eCBs) are the endogenous ligands of CB1R and are known to act as retrograde messengers to modulate synaptic plasticity at different time scales in the adult brain. Accumulating evidence indicates that eCB signaling through activation of CB1R plays a central role in neural development. During development, most CB1R localized to axons of projection neurons, and in mice eCB signaling impacts axon fasciculation. Understanding of eCB-mediated structural plasticity during development, however, requires the identification of the precise spatial and temporal dynamics of CB1R-mediated modifications at the level of individual neurons in the intact brain. Here, the cell-autonomous role of CB1R and the effects of CB1R-mediated eCB signaling were investigated using targeted single-cell knockdown and pharmacologic treatments in Xenopus. We imaged axonal arbors of retinal ganglion cells (RGCs) in real time following downregulation of CB1R via morpholino (MO) knockdown. We also analyzed RGC axons with altered eCB signaling following treatment with URB597, a selective inhibitor of the enzyme that degrades Anandamide (AEA), or JZL184, an inhibitor of the enzyme that blocks 2-Arachidonoylglycerol (2-AG) hydrolysis, at two distinct stages of retinotectal development. Our results demonstrate that CB1R knockdown impacts RGC axon branching at their target and that differential 2-AG and AEA-mediated eCB signaling contributes to presynaptic structural connectivity at the time that axons terminate and when retinotectal synaptic connections are made. Altering CB1R levels through CB1R MO knockdown similarly impacted dendritic morphology of tectal neurons, thus supporting both pre- and postsynaptic cell-autonomous roles for CB1R-mediated eCB signaling.

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Nasal accumulation and metabolism of Δ9-tetrahydrocannabinol following aerosol (‘vaping’) administration in an adolescent rat model

Cited by 9 publications

References 42 publications

Adolescent exposure to low-dose Δ9-tetrahydrocannabinol depletes the ovarian reserve in female mice

Adolescent exposure to low-dose Δ9-tetrahydrocannabinol depletes the ovarian reserve in female mice

Voluntary adolescent alcohol exposure does not robustly increase adulthood consumption of alcohol in multiple mouse and rat models

Cell-autonomous and differential endocannabinoid signaling impacts the development of presynaptic retinal ganglion cell axon connectivity in vivo

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