Effect of chlorpromazine on cell proliferation in the developing rat brain. A combined biochemical and morphological study

Abstract

Chlorpromazine, a widely used drug in current clinical practice, produced a severe reduction of the rate of [3H]thymidine incorporation into brain DNA of 11-day-old rats. The depression of in vivo synthesis rate was detectable by 6 h after chlorpromazine administration (50 mg/kg, s.c.) and the rate was less than 40% and 60% of controls during period 14-30 h in forebrain and 6-30 h in cerebellum respectively. The depression was dose-dependent and half maximal effect was produced with about 10 mg/kg chlorpromazine. The drug caused some retardation in the rate of conversion of [3H]thymidine to [3H]thymine nucleotides in the brain, but the severe depression in DNA labelling was also evident after correcting the values on the basis of [3H]thymine nucleotides concentration. Mitotic activity was significantly reduced in the cerebellar external granular layer. Increased numbers of cell degenerations, shown by Feulgen cytophotometry to be postmitotic, were seen in both layers 12 and 32 h after chlorpromazine. Analysis of cell cycle parameters showed no significant changes. However, the labelling index in subependymal cells was reduced, indicating an increase in turnover time of about 40%. The results are consistent with an action of chlorpromazine on cell proliferation, either by direct effects on the generation and survival of cells, or via its major pharmacological actions on neurotransmitter balance. These effects are potentially of functional and clinical significance.