Effects of perinatal exposure to Delta(9)-tetrahydrocannabinol on the fetal and early postnatal development of tyrosine hydroxylase-containing neurons in rat brain
Effects of perinatal exposure to Delta(9)-tetrahydrocannabinol on the fetal and early postnatal development of tyrosine hydroxylase-containing neurons in rat brain
复制标题
DOI：
10.1007/bf02737066
复制
发表时间：
1996-12-01
影响因子：
3.1
通讯作者：
FernandezRuiz, JJ
中科院分区：
文献类型：
--
作者：
Bonnin, A;deMiguel, R;FernandezRuiz, JJ
在围产期，怀孕大鼠暴露于大麻的主要精神活性成分Δ⁽⁹⁾ - 四氢大麻酚（Δ⁽⁹⁾ - THC）会影响其后代在青春期前后及成年期大脑中酪氨酸羟化酶（TH）的基因表达和活性。在本研究中，我们探讨了在胎儿期和新生儿早期（此时TH表达在神经发育中起重要作用）是否也会出现这些影响。为此，我们分析了不同妊娠天数（GD）的胎儿以及两个产后年龄的新生儿大脑中TH的mRNA量、该酶的量和活性以及儿茶酚胺（CA）含量，这些胎儿和新生儿从妊娠第5天起每天暴露于Δ⁽⁹⁾ - THC或对照物。结果如下。暴露于Δ⁽⁹⁾ - THC显著影响了GD14胎儿大脑中TH基因的表达。因此，在这个年龄，暴露于Δ⁽⁹⁾ - THC的胎儿其mRNA量高于对照组。这与该年龄TH蛋白量和该酶活性的显著增加相对应。在GD16时这些参数恢复正常。然而，从GD18开始，TH基因对大麻素暴露的反应出现明显的性别差异，在GD21时尤为明显，此时暴露于Δ⁽⁹⁾ - THC的发育中的雌性大脑中TH - mRNA量增加，而在发育中的雄性大脑中则减少，这些影响大多延续到产后早期。然而，这些变化并不总是与TH的量和活性以及CA含量的平行变化相对应，就像在GD14时那样，这表明Δ⁽⁹⁾ - THC不会影响含TH神经元合成CAs的基础能力，但会影响TH基因的反应性。我们发现，暴露于Δ⁽⁹⁾ - THC的雌性新生儿中，主要的神经元内多巴胺代谢产物L - 3,4 - 二羟基苯乙酸的产生仅显著增加。总体而言，我们的结果支持这样一种观点，即围产期暴露于Δ⁽⁹⁾ - THC会在胎儿和新生儿早期大脑发育的某些关键时期影响TH基因的表达，有时还会影响大脑儿茶酚胺能神经元中该酶的活性。这些结果支持这样一种观点，即大麻素能够影响儿茶酚胺能发育的特定关键蛋白的基因表达，并且这些改变可能是围产期大麻素暴露在青春期前后及成年期导致的重要长期神经行为影响的根源。
The exposure of pregnant rats to Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the main psychoactive constituent of Cannabis sativa, during the perinatal period affects the gene expression and the activity of tyrosine hydroxylase (TH) in the brains of their offspring at peripubertal and adult ages. In the present work we explored whether these effects also appear during fetal and early neonatal periods, when TH expression plays an important role in neural development. To this end, the mRNA amounts for TH and the amounts and activity of this enzyme, in addition to catecholamine (CA) contents, were analyzed in the brain of fetuses at different gestational days (GD) and of newborns at two postnatal ages, which had been daily exposed to Delta(9)-THC or vehicle from d 5 of gestation. Results were as follows. The exposure to Delta(9)-THC markedly affected the expression of the TH gene in the brain of fetuses at GD 14. Thus, the amounts of its mRNA at this age were higher in Delta(9)-THC-exposed fetuses than in controls. This corresponded with a marked rise in the amounts of TH protein and in the activity of this enzyme at this age. Normalization was found in these parameters at GD16. However, a marked sexual dimorphism in the response of TH gene to cannabinoid exposure appeared from GD18 and was particularly evident at GD21, when TH-mRNA amounts increased in developing female brains, but decreased in developing male brains exposed to Delta(3)-THC, effects that were mostly prolonged to early postnatal ages. However, these changes did not correspond always with parallel changes in the amounts and activity of TH and in CA contents, as occurred in GD14, suggesting that Delta(9)-THC would not be affecting the basal capability to synthesize CAs in TH-containing neurons, but would affect the responsiveness of TH gene. We found only a marked increase in the production of L-3,4-dihydroxyphenylacetic acid, the main intraneuronal dopamine metabolite, in female newborns exposed to Delta(9)-THC. Collectively, our results support the belief that the perinatal exposure to Delta(9)-THC affects the expression of the TH gene and, sometimes, the activity of this enzyme in brain catecholaminergic neurons in certain critical periods of fetal and early neonatal brain development. These results support the notion that cannabinoids are able to affect the gene expression of specific key proteins for catecholaminergic development, and that these alterations might be the origin of important long-term neurobehavioral effects caused by perinatal cannabinoid exposure at peripubertal and adult ages.