bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2020.07.24.220103

COMBINED VAPOR EXPOSURE TO THC AND ALCOHOL IN PREGNANT RATS: MATERNAL OUTCOMES AND PHARMACOKINETIC EFFECTS

Breit, K. R.·Rodriguez, C. G.·Lei, A.·Thomas, J. D.
View original source ↗Export metadata ↓

Abstract

Cannabis is the most frequently used illicit drug among pregnant women, yet the potential consequences of prenatal cannabis exposure on development are not well understood. Electronic cigarettes have become an increasingly popular route of administration among pregnant women, in part to users perception that e-cigarettes are a safer route for consuming cannabis products. Importantly, half of pregnant women who consume cannabis also report consuming alcohol, but research investigating co-consumption of these drugs is limited, particularly with current routes of administration. The purpose of this study was to establish a co-exposure vapor inhalation model of alcohol and THC in pregnant rats, to ultimately determine the effects on fetal development. Pregnant Sprague-Dawley rats were exposed to moderate doses of THC via e-cigarettes, alcohol, the combination, or vehicle daily from gestational days 5-20. Importantly, pharmacokinetic interactions of alcohol and THC were observed during pregnancy. Combined exposure consistently increased blood alcohol concentrations, indicating that THC alters alcohol metabolism. In addition, THC levels also increased over the course of pregnancy and THC metabolism was altered by alcohol. Alcohol, but not THC, exposure during pregnancy reduced maternal weight gain, despite no group differences in food intake. Neither prenatal alcohol nor THC exposure altered gestational length, litter size, sex ratio or birth weight. However, prenatal alcohol exposure delayed eye opening, and prenatal THC exposure decreased body weights during adolescence among offspring. These individual and synergistic effects suggest that this novel co-exposure vapor inhalation paradigm can effectively be used to expose pregnant dams, exerting some effects on fetal development, while avoiding nutritional confounds, birth complications, or changes in litter size. With this model, we have demonstrated that combining THC and alcohol alters drug metabolism, which could have important consequences on prenatal development.

Source connections

Explore related subjects

pharmacology and toxicologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Breit, K. R., Rodriguez, C. G., Lei, A., Thomas, J. D.. 2020-07-26. COMBINED VAPOR EXPOSURE TO THC AND ALCOHOL IN PREGNANT RATS: MATERNAL OUTCOMES AND PHARMACOKINETIC EFFECTS. https://doi.org/10.1101/2020.07.24.220103

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Lipid-ASO therapeutics exhibit differential tissue targeted delivery upon systemic or local CNS administration

Antisense oligonucleotides (ASOs) are a powerful therapeutic modality, but their full potential is hindered by pharmacokinetic properties that affect tissue and cellular delivery. Lipid conjugation is increasingly used to modulate ASO's biodistribution and promote extrahepatic activity, yet lipid dependent effects on in vivo functional delivery, particularly in the central nervous system (CNS), remain less explored. Here, we performed a side by side in vivo comparison of cholesterol, palmitic acid (C16:0), docosanoic acid (C22:0), and eicosapentaenoic acid (C20:5) conjugated to a fully phosphorothioated 3 10 3 LNA gapmer ASO targeting the Malat1 long non coding RNA. Lipid-ASO conjugates were administered systemically or locally in the brain of mice and evaluated for tissue level and cellular level distribution by imaging, qPCR and single-cell RNA sequencing, simultaneously annotating cell origin and global transcriptional changes within the cell. Following systemic administration in mice, lipid conjugation improved overall multi organ efficacy compared to unconjugated ASO, but with pronounced tissue specific differences. Single cell sequencing of liver and heart transcriptomes revealed lipid dependent cellular uptake patterns and transcriptional responses distinct from administration of unconjugated ASO. After intracerebroventricular administration, selected fatty acid conjugates enhanced silencing in deep brain regions such as the striatum, whereas cholesterol conjugation impaired functional delivery despite increased CNS retention. Light-sheet microscopy showed restricted parenchymal penetration of cholesterol ASOs compared with broader but heterogeneous distribution of palmitic acid conjugate. Together, these findings demonstrate that lipid identity critically determines ASO efficacy, productive cellular uptake, and regional CNS engagement, emphasizing the need for context specific lipid design in ASO therapeutic development.

pharmacology and toxicology↗
bioRxiv2026

Novel Dissymmetric Ionizable Lipid-Assembled Lipid Nanoparticles for Delivery of Ferroptosis-Related siRNA in Diabetic Treatment

Small interfering RNA (siRNA) enables precise post-transcriptional gene silencing for refractory diseases, yet its clinical translation remains limited by the lack of safe and efficient delivery vectors. Inspired by the dissymmetric alkyl chain architecture of natural membrane phospholipids, we designed and synthesized 34 novel ionizable lipids with dissymmetric hydrophobic tails and formulated them into lipid nanoparticles (LNPs). Through systematic physicochemical and biological assessments, we established clear structure-activity relationships and identified two lead LNPs (O14-LNP, H18a-LNP) with superior endosomal escape capacity, enhanced in vivo gene silencing potency, and favorable biosafety relative to the clinical benchmark MC3-LNP. In both streptozotocin-induced and spontaneous db/db type 2 diabetes (T2D) mouse models, lead LNPs delivering ferroptosis-related siRNAs effectively ameliorated glucose and lipid metabolic disorders, restored islet function, and alleviated hepatic steatosis. This study not only lays a theoretical foundation for the rational design of novel ionizable lipids, but also validates the therapeutic potential of siRNA therapy targeting ferroptosis, providing a versatile delivery platform and targeted therapeutic strategy for the treatment of T2D.

pharmacology and toxicology↗
bioRxiv2021

Antidepressant and antipsychotic drugs reduce viral infection by SARS-CoV-2 and fluoxetine show antiviral activity against the novel variants in vitro

Background and PurposeRepurposing of currently available drugs is a valuable strategy to tackle the consequences of COVID-19. Recently, several studies have investigated the effect of psychoactive drugs on SARS-CoV-2 in cell culture models as well as in clinical practice. Our aim was to expand these studies and test some of these compounds against newly emerged variants. Experimental ApproachSeveral antidepressant drugs and antipsychotic drugs with different primary mechanisms of action were tested in ACE2/TMPRSS2-expressing human embryonic kidney cells against the infection by SARS-CoV-2 spike protein-dependent pseudoviruses. Some of these compounds were also tested in human lung epithelial cell line, Calu-1, against the first wave (B.1) lineage of SARS-CoV-2 and the variants of concern, B.1.1.7 and B.1.351. Key ResultsSeveral clinically used antidepressants, including fluoxetine, citalopram, reboxetine, imipramine, as well as antipsychotic compounds chlorpromazine, flupenthixol, and pimozide inhibited the infection by pseudotyped viruses with minimal effects on cell viability. The antiviral action of several of these drugs was verified in Calu-1 cells against the (B.1) lineage of SARS-CoV-2. By contrast, the anticonvulsant carbamazepine, and novel antidepressants ketamine and its derivatives as well as MAO and phosphodiesterase inhibitors phenelzine and rolipram, respectively, showed no activity in the pseudovirus model. Furthermore, fluoxetine remained effective against pseudo viruses with N501Y, K417N, and E484K spike mutations, and the VoC-1 (B.1.1.7) and VoC-2 (B.1.351) variants of SARS-CoV-2. Conclusion and ImplicationsOur study confirms previous data and extends information on the repurposing of these drugs to counteract SARS-CoV-2 infection including different variants of concern.

pharmacology and toxicology↗