delta 9-Tetrahydrocannabinol increases activity of tyrosine hydroxylase in cultured fetal mesencephalic neurons.

The exposure of pregnant rats to delta 9-tetrahydrocannabinol (delta 9-THC), the main psychoactive constituent of Cannabis sativa, during gestation and lactation, affects the gene expression and the activity of tyrosine hydroxylase (TH) in the brain of their offspring, measured at fetal and early postnatal ages, when the expression of this enzyme plays an important role in neural development. In the present article, we have examined whether delta 9-THC is able to affect TH activity in cultured mesencephalic neurons obtained from fetuses at gestational d 14. Thus, TH activity increased approximately twofold in cells obtained from naive fetuses when exposed for 24 h to medium containing delta 9-THC. In addition, TH activity was also approx twofold higher in cells obtained from fetuses exposed daily to delta 9-THC from d 5 of gestation than in cells obtained from control fetuses, when both were exposed to basal media. This effect of delta 9-THC on TH activity seems to be produced via the activation to cannabinoid receptors, in particular the CB1 subtype, which would presumably be located in these cells. This is because the exposure to medium containing both delta 9-THC and SR141716A, a specific antagonist for CB1 receptors, abolished the effect observed with delta 9-THC alone. SR141716A alone was without effect on TH activity. Collectively, our results support the notion that delta 9-THC increased TH activity in cultured mesencephalic neurons, as previously observed in vivo, and that this effect was produced by activation of CB1 receptors, which seem to be operative at these early ages. All this points to a role for the endogenous cannabimimetic system in brain development.