Gómez María, Hernández Mariluz, Johansson Björn, de Miguel Rosario, Ramos José Antonio, Fernández-Ruiz Javier
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Compultense de Madrid, Spain.
Brain Res Dev Brain Res. 2003 Dec 30;147(1-2):201-7. doi: 10.1016/j.devbrainres.2003.10.016.
The consumption by women of cannabis derivatives during pregnancy and/or lactation affects the development of their offspring because like other psychoactive drugs, cannabinoids, the psychoactive ingredients of marijuana, can cross the placental barrier and be secreted into the maternal milk. Through this way, cannabinoids are able to affect the expression of key genes for neural developmental leading to neurotransmitter and behavioral disturbances. In this present study, we wanted to explore the influence of prenatal cannabinoid exposure on the gene expression of a key protein for brain development, the neural adhesion molecule L1, which plays an important role in processes of cell proliferation and migration, neuritic elongation and guidance, and synaptogenesis. To this end, pregnant rats were daily treated with delta9-tetrahydrocannabinol (delta9-THC) since the 5th day of gestation up to the day before birth (GD21), day at which rats were killed and their pups removed for analysis of L1-mRNA levels in different brain structures. Our results confirmed that the levels of L1 transcripts were significantly increased after prenatal delta9-THC exposure in several regions such as the fimbria, stria terminalis, stria medullaris and corpus callosum, which share the properties of being white matter regions and containing, exclusively during development, an abundant population of cannabinoid CB1 receptors, the major targets for the action of plant-derived cannabinoids. L1-mRNA levels were also increased in grey matter structures such as the septum nuclei and the habenula, but remained unchanged in most of the grey matter structures analyzed (cerebral cortex, basolateral amygdaloid nucleus, hippocampus, thalamic and hypothalamic nuclei, basal ganglia and subventricular zones) and also in a few white matter structures (fornix and fasciculus retroflexus). An important aspect of these observations is that the increase in L1-mRNA levels reached statistical significance only in the case of delta9-THC-exposed males but not in the case of delta9-THC-exposed females where only trends or no effects were detected, this supporting previous evidence on a sexual dimorphism, with greater effects in male fetuses, for the action of cannabinoids in the developing brain. In summary, cannabinoids seem to influence the expression of L1 in specific brain structures during the prenatal period, which, considering the role played by this protein in different events related to neural development, might explain the neurotransmitter and behavioral disturbances reported after prenatal consumption of marijuana.
女性在孕期和/或哺乳期摄入大麻衍生物会影响其后代的发育，因为与其他精神活性药物一样，大麻中的精神活性成分大麻素能够穿过胎盘屏障并分泌到母乳中。通过这种方式，大麻素能够影响神经发育关键基因的表达，从而导致神经递质和行为紊乱。在本研究中，我们想要探究产前暴露于大麻素对大脑发育关键蛋白神经黏附分子L1基因表达的影响，该蛋白在细胞增殖与迁移、神经突伸长与导向以及突触形成过程中发挥着重要作用。为此，从妊娠第5天至出生前一天（妊娠第21天），每天给怀孕大鼠注射δ9-四氢大麻酚（δ9-THC），在这一天将大鼠处死，并取出其幼崽以分析不同脑区的L1-mRNA水平。我们的结果证实，产前暴露于δ9-THC后，在如穹窿、终纹、髓纹和胼胝体等几个区域，L1转录本水平显著升高，这些区域均为白质区域，且在发育过程中仅含有大量大麻素CB1受体，而CB1受体是植物源大麻素作用的主要靶点。在灰质结构如隔核和缰核中，L1-mRNA水平也有所升高，但在分析的大多数灰质结构（大脑皮层、基底外侧杏仁核、海马体、丘脑和下丘脑核、基底神经节和脑室下区）以及一些白质结构（穹窿和后屈束）中保持不变。这些观察结果的一个重要方面是，L1-mRNA水平的升高仅在暴露于δ9-THC的雄性大鼠中具有统计学意义，而在暴露于δ9-THC的雌性大鼠中未检测到显著影响，仅发现有趋势或无影响，这支持了先前关于大麻素对发育中大脑的作用存在性别差异且对雄性胎儿影响更大的证据。总之，大麻素似乎在产前会影响特定脑结构中L1的表达，考虑到该蛋白在与神经发育相关的不同事件中所起的作用，这可能解释了产前摄入大麻后所报告的神经递质和行为紊乱现象。
