Haloperidol, a widely used neuroleptic, produced a significant depression of the rate of [3H]thymidine incorporation into the DNA of 11-day-old rat brain. The reduction of in-vivo DNA synthesis rate was detectable by 4 h after subcutaneous injection of a single dose of haloperidol (20 mg/kg) and through the period 10-24 h after drug treatment the rate was less than 50% of that of controls in the forebrain. [3H]Thymidine incorporation returned to control values by 32 h. The effect on the cerebellum was similar but less pronounced. The depression was dose-dependent and a half-maximal effect was produced with haloperidol doses of 5-10 mg/kg. Parallel histological studies on treated rats suggested prolongation of the DNA synthesis phase of the cell cycle in the forebrain subependymal layer, associated with an increase in turnover time of about 15%.

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The role in the regulation of cell replication of the neurotransmitter compounds and the drugs which affect their balance was studied in vitro, using morphologically preserved brain slices. Compounds affecting noradrenergic, dopaminergic and serotoninergic neurotransmitter systems reduced the brain cell replication, measured in terms of the rate of [3H]thymidine incorporation into DNA. The reduction was dose dependent and half-maximal effects were obtained at about 1-5 x 10(-4) M concentrations. Although agonists and antagonists both showed similar inhibitory effect, the action of agonists was reversed by the appropriate antagonists. Also, the pharmacologically active isomers were several-fold more effective than the inactive isomers in forebrain slices, although with cerebellar slices the selectivity was less marked. Cyclic nucleotides and drugs affecting cholinergic neurotransmitter systems were apparently ineffective. These results indicate that monoamines may be involved in the regulation of cell replication in the developing brain. Furthermore, as some of the CNS acting drugs tested are suspected behavioural teratogens the present results suggest that the reported behavioural abnormalities in the offspring may be related, in part, to a chronologically determined interference with the formation of certain cell types.

Dissociated cell cultures derived from whole brains of foetal rats (17 days of gestation) were maintained for periods of up to 21 days in vitro for the purpose of studying the transmitter-releasing properties of the dopaminergic neuronal cells and glial cells. In the neuron-enriched cultures, after 3 days in vitro, [3H]dopamine was released in response to depolarizing stimuli. Both the potassium and veratrine-evoked release of dopamine was Ca2+ dependent. Veratrine-evoked release was reduced in the presence of the calcium channel blocker verapamil and was tetrodotoxin sensitive. Glial cultures, after 7 days in vitro, did not respond to any depolarizing stimuli, although they displayed a significant ability to take up [3H]dopamine. Comparison between static incubations and perfused cultures showed no difference in the patterns of release resulting from veratrine stimulation. Tyrosine hydroxylase activity increased progressively in neuron-enriched cultures but was not detectable in glial cultures. These results show that neuron-enriched cultures respond to depolarizing stimuli in a manner similar to excised adult basal ganglia tissue, with the appearance of functional ionic channels after 3 days in vitro.