The Linda and Jack Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana, USA.
Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, USA.
Cannabis Cannabinoid Res. 2022 Jun;7(3):318-327. doi: 10.1089/can.2021.0015. Epub 2021 Jun 28.
There is widespread acceptance of cannabis for medical or recreational use across the society, including pregnant women. Concerningly, numerous studies find that the developing central nervous system (CNS) is vulnerable to the detrimental effects of Δ-tetrahydrocannabinol (THC). In contrast, almost nothing on the consequences of perinatal cannabidiol (CBD) exposure. In this study, we used mice to investigate the adult impact of perinatal cannabinoid exposure (PCE) with THC, CBD, or a 1:1 ratio of THC and CBD on behaviors. Furthermore, the lasting impact of PCE on fluoxetine sensitivity in the forced swim test (FST) was evaluated to probe neurochemical pathways interacting with the endocannabinoid system (ECS). Pregnant CD1 dams were injected subcutaneously daily with vehicle, 3 mg/kg THC, 3 mg/kg CBD, or 3 mg/kg THC +3 mg/kg CBD from gestational day 5 to postnatal day 10. Mass spectroscopic (MS) analyses were conducted to measure the THC and CBD brain levels in dams and their embryonic progenies. PCE adults were subjected to a battery of behavioral tests: open field arena, sucrose preference test, marble burying test, nestlet shredding test, and FST. MS analysis found substantial levels of THC and CBD in embryonic brains. Our behavioral testing found that PCE females receiving THC or CBD buried significantly more marbles than control mice. Interestingly, PCE males receiving CBD or THC+CBD had significantly increased sucrose preference. While PCE with THC or CBD did not affect FST immobility, PCE with THC or CBD prevented fluoxetine from decreasing immobility in both males and females. Excitingly, fatty acid amide hydrolase (FAAH) inhibition with a dose of URB597 that was behaviorally inactive in the FST rescued fluoxetine efficacy in PCE mice of both sexes. Our data suggest that PCE with either THC, CBD, or THC+CBD alters repetitive and hedonic behaviors in a phytocannabinoid and sex-dependent manner. In addition, PCE with THC or CBD prevents fluoxetine from enhancing coping behavior. The restoration of fluoxetine responsiveness in THC or CBD PCE adults by inhibition of FAAH suggests that PCE causes a lasting reduction of the ECS and that enhancement of anandamide signaling represents a potential treatment for behavioral deficits following PCE.
社会上普遍接受大麻用于医疗或娱乐目的，包括孕妇。令人担忧的是，许多研究发现，发育中的中枢神经系统（CNS）易受Δ-四氢大麻酚（THC）的有害影响。相比之下，几乎没有关于围产期大麻二酚（CBD）暴露后果的研究。在这项研究中，我们使用小鼠研究了围产期大麻素暴露（PCE）对行为的成年影响，包括 THC、CBD 或 THC 和 CBD 1:1 比例的影响。此外，还评估了 PCE 对强迫游泳试验（FST）中氟西汀敏感性的持久影响，以探究与内源性大麻素系统（ECS）相互作用的神经化学途径。怀孕的 CD1 母鼠从妊娠第 5 天到产后第 10 天每天皮下注射溶剂、3mg/kg THC、3mg/kg CBD 或 3mg/kg THC+3mg/kg CBD。进行质谱（MS）分析以测量母鼠及其胚胎后代的 THC 和 CBD 脑水平。PCE 成年小鼠接受了一系列行为测试：旷场试验、蔗糖偏好试验、埋珠试验、巢丝撕碎试验和 FST。MS 分析发现胚胎大脑中有大量的 THC 和 CBD。我们的行为测试发现，接受 THC 或 CBD 的 PCE 雌性比对照小鼠埋的珠子明显多。有趣的是，接受 CBD 或 THC+CBD 的 PCE 雄性对蔗糖的偏好明显增加。虽然 PCE 用 THC 或 CBD 不影响 FST 不动性，但 PCE 用 THC 或 CBD 阻止氟西汀降低雌雄两性的不动性。令人兴奋的是，用 URB597 抑制脂肪酸酰胺水解酶（FAAH），其在 FST 中行为上不活跃，可恢复 PCE 雌雄小鼠的氟西汀疗效。我们的数据表明，用 THC、CBD 或 THC+CBD 进行 PCE 以植物大麻素和性别依赖的方式改变重复性和享乐性行为。此外，PCE 用 THC 或 CBD 阻止氟西汀增强应对行为。用 FAAH 抑制恢复 THC 或 CBD PCE 成年动物对氟西汀的反应性表明，PCE 导致 ECS 的持续减少，增强大麻素信号传递代表 PCE 后行为缺陷的潜在治疗方法。
