Effects of perinatal exposure to delta 9-tetrahydrocannabinol on the fetal and early postnatal development of tyrosine hydroxylase-containing neurons in rat brain.

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 9-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.