Δ9-tetrahydrocannabinol increases activity of tyrosine hydroxylase in cultured fetal mesencephalic neurons

The exposure of pregnant rats to Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the main psychoactive constituent ofCannabis 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 Δ⁹-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 Δ⁹-THC. In addition, TH activity was also approx twofold higher in cells obtained from fetuses exposed daily to Δ⁹-THC from d 5 of gestation than in cells obtained from control fetuses, when both were exposed to basal media. This effect of Δ⁹-THC on TH activity seems to be produced via the activation of cannabinoid receptors, in particular the CB₁ subtype, which would presumably be located in these cells. This is because the exposure to medium containing both Δ⁹-THC and SR141716A, a specific antagonist for CB₁ receptors, abolished the effect observed with Δ⁹-THC alone. SR141716A alone was without effect on TH activity. Collectively, our results support the notion that Δ⁹-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. Part of this work has been previously presented in abstract form at the 24th Meeting of the Federation of European Biochemical Societies, Barcelona, Spain, July, 1996.