Pham Aidan L, Marquardt Ashley E, Montgomery Kristen R, Sobota Karina N, McCarthy Margaret M, VanRyzin Jonathan W
Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA.
Department of Pharmacology and Physiology, University of Maryland Medicine - Institute for Neuroscience Discovery (UM-MIND), University of Maryland School of Medicine, Baltimore, MD, USA.
Neuropsychopharmacology. 2025 Jul 23. doi: 10.1038/s41386-025-02173-5.
Cannabis is the most frequently used illicit drug during pregnancy, with use steadily increasing in the United States as legalization and decriminalization expand to more states. Many pregnant individuals use cannabis to reduce adverse symptoms of pregnancy, considering it to be less harmful than other pharmaceuticals or alcohol. The primary psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), is a partial agonist of the candidate receptors of the endocannabinoid (eCB) system cannabinoid receptor 1 (CB1R) and 2 (CB2R). However, whether it perturbs neural development of the fetus is poorly understood. Previously we have shown that androgen mediated eCB tone in the developing amygdala promotes microglial phagocytosis of newborn astrocytes which has enduring consequences on the neural circuits regulating sex differences in social behavior. Microglia are the resident immune cells of the brain and express both CB1R and CB2R, making them likely targets of modulation by THC. It is also plausible that exposure to THC at differing gestational timepoints can result in distinct outcomes, as is the case with alcohol exposure. To model human cannabis use during either late or early pregnancy, we exposed rodents to THC either directly during the early postnatal period via intraperitoneal (IP) injection or in utero during the prenatal period via dam subcutaneous (SC) injection respectively. Here we show that postnatal THC exposure results in sex specific changes in microglial phagocytosis during development as well as social behavior during the juvenile period. Interestingly prenatal exposure to THC resulted in inverse changes to phagocytosis and social behavior. These findings highlight the differential effects of THC exposure across gestation.
大麻是孕期最常使用的非法药物，在美国，随着合法化和非刑事化扩展到更多州，其使用量稳步上升。许多孕妇使用大麻来减轻孕期的不良症状，认为它比其他药物或酒精危害更小。大麻的主要精神活性成分Δ9-四氢大麻酚（THC）是内源性大麻素（eCB）系统大麻素受体1（CB1R）和2（CB2R）的候选受体的部分激动剂。然而，它是否会干扰胎儿的神经发育尚不清楚。此前我们已经表明，雄激素介导的发育中的杏仁核中的eCB张力促进新生星形胶质细胞的小胶质细胞吞噬作用，这对调节社会行为性别差异的神经回路有持久影响。小胶质细胞是大脑中的常驻免疫细胞，同时表达CB1R和CB2R，这使得它们可能成为THC调节的目标。同样合理的是，在不同的妊娠时间点接触THC可能会导致不同的结果，就像接触酒精一样。为了模拟人类在妊娠晚期或早期使用大麻的情况，我们分别在出生后早期通过腹腔注射（IP）或在产前通过母鼠皮下注射（SC）将啮齿动物直接暴露于THC。在这里，我们表明出生后接触THC会导致发育过程中小胶质细胞吞噬作用以及幼年期社会行为的性别特异性变化。有趣的是，产前接触THC会导致吞噬作用和社会行为的相反变化。这些发现突出了孕期接触THC的不同影响。
