Radioactive uptake of [14C]histamine by certain tissues in guinea-pigs treated and untreated with chlorpromazine

1. Oral administration of [14C]histamine induced the presence of small amounts of [14C]histamine in stomach and ileal tissues of control guinea-pigs. In contrast, much larger amounts were found after 8 h infusion. 2. Similar amounts of [14C]histamine were found in the tissues when [14C]histamine was given by intravenous infusion from 24-30 h after chlorpromazine injection.     

Dopamine neuronal transport kinetics and effects of amphetamine

The dopamine (DA) transporter (DAT) regulates DA neurotransmission by recycling DA back into neurons. Drugs that interfere with DAT function, e.g., cocaine and amphetamine, can have profound behavioral effects. The kinetics of DA transport by DAT in isolated synaptosomal or single cell preparations have been previously studied. To investigate how DA transport is regulated in intact tissue and to examine how amphetamine affects the DAT, the kinetics of DA uptake by the DAT were examined in tissue slices of the mouse caudate-putamen with fast-scan cyclic voltammetry. The data demonstrate that inward DA transport is saturable and sodium-dependent. Elevated levels of cytoplasmic DA resulting from disruption of vesicular storage by incubation with 10 microM Ro 4-1284 did not generate DA efflux or decrease its uptake rate. However, incubation with 10 microM amphetamine reduced the net DA uptake rate and increased extracellular DA levels due to DA efflux through the DAT. In addition, a new, elevated steady-state level of extracellular DA was established after electrically stimulated DA release in the presence of amphetamine, norepinephrine, and exogenous DA. These results from intact tissue are consistent with a kinetic model of the DAT established in more purified preparations in which amphetamine and other transported substances make the inwardly facing DAT available for outward transport of intracellular DA.     

Different effects of chlorpromazine on bleomycin-and epirubicin induced cytotoxicity

The effect of the antiemetic chlorpromazine on bleomycin- and epirubicin cytotoxicity was testedin vitro. Chlorpromazine (0.1 or 0.01 mg/l) enhanced epirubicin-induced toxicity to cultured Chinese fibroblasts whereas 0.01 mg/l chlorpromazine inhibited the cytotoxicity of bleomycin. The results encourage further studies on the effects of commonly used antiemetics on the cytotoxicity and antitumoral effects of anticancer chemotherapeutics.     

pH-dependent effects of chlorpromazine on liposomes and erythrocyte membranes

Chlorpromazine (CPZ) is an amphipathic antipsychotic drug that binds to erythrocytes reaching in this way the central nervous system. CPZ is a basic molecule with pK=8.6. This paper reports on CPZ-induced lysis of red blood cells and liposomes. Haemolysis was tested under hypotonic conditions, in the pH range 5.0-10.0. Cell sensitivity towards CPZ increased with increasing pH. Increasing pH caused also a decrease in the critical micellar concentrations of CPZ. These results are interpreted in terms of a competition between repulsive electrostatic forces and attractive hydrophobic forces, that would act both in pure CPZ and in mixed CPZ-phospholipid micelles. In order to eliminate possible pH effects mediated by red blood cell proteins, experiments were carried out in which CPZ induced release of a fluorescent dye from liposomes (large unilamellar vesicles). The latter observations confirmed that membrane sensitivity towards CPZ was increased at higher pH.     

Learning and cross drug effects: Thermic effects of pentobarbital and amphetamine

The effects of environmental cues explicitly paired or unpaired with pentobarbital on the thermic effects of pentobarbital and amphetamine were investigated. Rats received 19 injections of pentobarbital in a distinctive environment and were subsequently tested for the thermic effects of pentobarbital and amphetamine in the distinctive environment, another environment previously associated only with saline, or in the colony room not previously associated with injections. Rats tested in the context of the environmental cues previously associated with pentobarbital were tolerant to the hypothermic effect of pentobarbital, but rats tested in the environment previously associated only with saline or in the colony room were not tolerant. Pentobarbital-experienced rats administered amphetamine in the context of the usual pentobarbital cues exhibited an exaggerated hyperthermic reaction compared to previously drug-naive rats administered amphetamine. Pentobarbital-experienced rats injected with amphetamine in the homeroom exhibited a smaller hyperthermic response than previously drug-naive rats administered amphetamine in the home room. These results demonstrate that an animal's response to a drug can be affected by cues paired and unpaired with drug administration.     

Modulation of fluoropyrimidine metabolism by chlorpromazine

Chlorpromazine is a potent inhibitor of calmodulin and can alter the accumulation, metabolism, and incorporation into RNA of several fluoropyrimidine drugs. Using S-180 murine sarcoma cells, the accumulation of the base Fluorouracil and its metabolism to ribonucleotides is enhanced by chlorpromazine treatment, as measured by HPLC. In contrast, the accumulation and metabolism of the nucleoside Fluorouridine was suppressed by chlorpromazine. Cytotoxicity studies revealed that non-toxic concentrations of chlorpromazine were synergistic with Fluorouracil, but were antagonistic with Fluorouridine. These findings suggest that modulation by chlorpromazine of specific nucleoside kinase involved in Fluorouracil metabolism can result in increased therapeutic utility.