Brain from chlorpromazine

The following year, Lehmann (1955) published his second article on chlorpromazine. With relatively small doses, he found the primary brain-disabling effect Many patients dislike the empty feeling resulting from the reduction of drive and spontaneity which is apparently one of the most characteristic effects of this substance. He also spoke of lassitude and compared the effects to lobotomy In the management... 

Rapid placental transfer was reported in goats and mice. In goats, the fetal plasma levels approached 50% of maternal values within 10 min of the mother receiving an intravenous dose, and the fetal/maternal plasma ratio remained at 0.5 for 1 h, whereas ratios in the liver, kidney, heart, and brain all approached 1 and showed a marked effect on fetal heart rate. In pregnant mice, radiolabeled chlorpromazine rapidly crossed the placenta and accumulated in the eyes of both fetuses and mothers. Marked radioactivity remained in tissues of the eye for 5 months after the drug had been eliminated from other tissues. 

There is some evidence from a study in animals that chronic administration of drugs such as chlorpromazine (an antipsychotic) results in increased levels of manganese in the brain, including the caudate nucleus (Weiner et al. 1977). Chronic chlorpromazine treatment sometimes results in tardive dyskinesia, and manganese deposition in the brain might contribute to this condition. It has not been determined whether excess manganese exposure increases the risk of chlorpromazine-induced dyskinesia. 

Chlorpromazine arrests cultured cells in mitosis and disorganises the organised microtubule structure produced by cyclic adenosine monophosphate (Poffenbarger and Fuller 1977). It causes a reduction in the number of microtubules in spinal ganglion cells (Edstrom et al. 1973, Thyberg et al. 1977) and neuroblastoma cells (EdstrOm et al. 1975) in vitro. The micellar form of chlorpromazine interacts preferentially with one site on brain tubulin (Gann et al. 1981). Ghlorpromazine has been shown to bind reversibly to tubulin prepared from mouse brain via two well-resolved processes (Hin-... 

Incubated tissue slices from different regions of the rat brain contained cGMP in the following descending order of content cerebellum > hypothalamus > striatum > thalamus-midbrain > brain stem > hippocampus > cerebral cortex (Palmer and Duszynski 1975). cGMP levels were increased in incubated tissue slices from rat cerebral cortex in response to added cholinomimetic agents (carba-chol and choline chloride) and neuroleptic compounds (chlorpromazine, 8-hydroxychlorpromazine, 7-hydroxychlorpromazine methiodide, haloperidol, thioridazine, chlorpromazine sulphoxide and promethazine) (Palmer et al. 1976). Calcium ions were required for this effect. 

Finally, the possible role of endogenous histamine in the CNS has been investigated. This histamine comes from the histidine which has been transformed in situ by cerebral histidine decarboxylase, since histamine cannot cross the blood-brain barrier. It is difficult to determine exactly how much histamine the CNS contains since assays are rendered imprecise by chemical interference, but it appears that histamine behaves at this level like the catecholamines and S-hydroxytryptamine under the influence of reserpine. The hypothalamus is rich in histidine decarboxylase and in histamine, but the way in which the histamine is distributed is altogether different from that of the other amines. This histamine is governed by the action of methyltransferase, which in turn is inhibited by chlorpromazine. The question of whether histamine is somehow related to schizophrenia is still being debated. 

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