Action Of Chlorpromazine Research Articles

Bioenergetics of thermogenesis: Effects of some neurotropic drugs on heat production

1. 1. DDT is able to stimulate heat production in rats independently on central thermal receptors. 2. 2. Chlorpromazine and imipramine decreased the hyperthermic effect of DDT on intact as well as decapitated rats. 3. 3. DDOH blocked completely oxygen consumption by mitochondria pretreated with chlorpromazine or imipramine. 4. 4. DDOH reversed the passive swelling of mitochondria induced by chlorpromazine or imipramine in KCl and NaCl solutions. 5. 5. Dearrangement of mitochondrial membrane permeability to osmotically active cations as a mode of anti-hyperthermic action of chlorpromazine or imipramine on peripherial heat production stimulated by DDT is discussed.

Mechanism of chlorpromazine action on rat intestinal transport processes

In a previous study, it was observed that chlorpromazine (CPZ) inhibited the transport of l-methionine in the rat intestine. The present experiments were designed to delineate the possible mechanism of this effect. Pre-incubation studies with CPZ demonstrated that the tissue concentration of CPZ was much more important than the medium concentration in inhibiting l-methionine transport. This seemed to favor an ‘indirect’ or ‘within-cell’ effect (metabolic inhibition or inhibition of sodium and potassium ion-stimulated adenosine triphosphatase [(Na + + K +)-ATPase]) over a ‘direct’ or ‘surface’ effect (an effect on passive membrane permeability or at the carrier level). CPZ did not affect diffusional entry of l-methionine at the intestinal brush border. The inhibition of non-diffusional mucosal transport of l-methionine by CPZ was not competitive; CPZ inhibited d-galactose transport in the same time-dependent manner as it inhibited l-methionine transport. No CPZ effect on carrier-mediated diffusion of d-xylose was observed. Thus, CPZ effect on active transport processes in the intestine seems to be mediated predominantly within the cell; from the present study it is not clear whether this effect is through inhibition of metabolic energy or inhibition of (Na + + K +)-ATPase.

Adenylyl cyclase from a prolactin producing tumor cell: The effect of phenothiazines

An adenylyl cyclase stimulated by low concentrations of chlorpromazine was observed in homogenates of a clonal pituitary tumor cell line (GH 3/C14) which releases prolactin and growth hormone. A half-maximal increase in activity of the GH 3/C14 cyclase occurred in the presence of 0.5 × 10 −6M chlorpromazine and a significant increase in activity was observed with a concentration of chlorpromazine as low as 10 −7M. Several derivatives (7-methoxychlorpromazine, 7-hydroxychlorpromazine and 8-hydroxychlorpromazine) were found to mimic the stimulatory action of chlorpromazine on adenylyl cyclase, whereas chlorpromazine-5, N-dioxide was ineffective. Under the assay conditions used, sodium fluoride caused a four-fold increase in activity. However, dopamine at concentrations up to 2 × 10 −4M was ineffective in stimulating or inhibiting the enzyme whether present alone or in combination with chlorpromazine. The ergot alkaloids, ergotamine and ergocryptine, blocked the stimulation of cyclase activity observed in the presence of chlorpromazine (10 −5M). Homogenates of normal pituitaries showed no enhancement of adenylyl cyclase activity by chlorpromazine alone. However, when chlorpromazine was tested in the presence of 5′ guanylimidophosphate [GPP(NH)P], there was a significant increase in cyclase activity in the pituitary similar to that observed in the GH 3/C14 preparation. These results suggest that hyperprolactinemia resulting as a side effect of phenothiazine treatment may be attributable to a direct action of these drugs to increase adenylyl cyclase activity in prolactin-producing cells of the anterior pituitary.

Photodynamic action of chlorpromazine on adenovirus-5: repairable damage and single-strand breaks: R.S. Day, III and M. DiMattina, Chemistry Branch, DCCP, NCI, NIH, Bethesda, Maryland 20014, (U.S.A.)

Photodynamic action of chlorpromazine on adenovirus-5: repairable damage and single-strand breaks: R.S. Day, III and M. DiMattina, Chemistry Branch, DCCP, NCI, NIH, Bethesda, Maryland 20014, (U.S.A.)

Photodynamic action of chlorpromazine on adenovirus 5: Repairable damage and single strand breaks

Chlorpromazine, a substituted phenothiazine, commonly used as a sedative, has been found to photosensitize the inactivation of human adenovirus 5 to wavelengths of light between 330 and 390 nm. The slope of the inactivation curve is three fold greater when fibroblasts from people having xeroderma pigmentosum (XP) were used as viral hosts than when normal fibroblasts were used, showing that at least two-thirds of the damage produced in the virions is repairable by normal human fibroblasts. The phototreatment of chlorpromazine sensitized virions also results in the production of DNA strand breaks, which correlate fairly well with the production of lethal viral damage as measured in XP fibroblasts. These findings suggest that the photosensitization of the skin observed in patients treated with chlorpromazine might be due to DNA damage.

Hypothermic action of chlorpromazine in monkeys.

1 In the conscious monkey (Macaca cyclopis) intravenous administration of chlorpromazine 0.1-8.0 mg/kg produced a fall of rectal temperature of 0.3 to 3.5 degrees C after a latency of 3.5 to 10.8 minutes. The course of hypothermia lasted from 125 to 600 min or more. 2 Direct injection of chlorpromazine 100-800 mug into the lateral or fourth cerebral ventricle produced a similar fall of 0.3 to 2.0 degrees C but with shorter latency (2 to 3.5 min) and with a duration of 94 to 375 minutes. 3 Two distinct structures in the brain stem, namely, the preoptic anterior hypothalamus (POAH) and medulla oblongata, responded to direct injection of chlorpromazine 200 mug. The sensitivity was slightly higher in the POAH than in the medulla. Structures in between were not sensitive. 4 The results suggest that chlorpromazine works principally through the central nervous system, i.e. the POAH and medulla oblongata, to mediate its hypothermic effect.

The action of chlorpromazine on the electrodermal response in the cat

Chlorpromazine (0·02–2·50 mg/kg. i.v.) was found to have a dose-dependent depressant action on the electrodermal response evoked by either central brainstem or reflex stimulation in chloralose-anaesthetized cats. Responses elicited by reflex, midbrain. and pontine stimulation were significantly reduced at a lower dose of chlorpromazine (0·10 mg/kg) than were responses evoked by stimulation of either the hypothalamus or the medulla (0·50 mg/kg). Chlorpromazine did not inhibit the postganglionic peripherally evoked response in the doses administered.

202) - Comparative studies on the actions of chlorpromazine and diazepam in isolated rat heart

202) - Comparative studies on the actions of chlorpromazine and diazepam in isolated rat heart

Proposed mechanisms of stimulation and inhibition of guanylate cyclase with reference to the actions of chlorpromazine, phospholipases and triton X-100

Particulate guanylate cyclase activity in the homogenate of guinea pig tracheal muscle was activated prominently after treatment with phospholipase-A or C. Even after the stimulation by phospholipases or Triton X-100, most of the activity was still associated with the particulate fraction. Phenothiazine tranquilizers and imipramine strongly inhibited the activity, whereas haloperidol did not. These results suggest that (i) particulate guanylate cyclase is associated fimly with the membrane and perturbation of the membrane architecture rather than solubilization of the enzyme is accountable for the stimulation, and (ii) stabilization of membranes in such a way that it affects the function of mucarinic cholinergic receptors inhibits the activity.

PROPERTIES OF THIAMINE DI‐ AND TRIPHOSPHATASES IN RAT BRAIN MICROSOMES: EFFECTS OF CHLORPROMAZINE

Abstract— The mechanism of the action of chlorpromazine on rat brain thiamine phosphatases were studied to clarify the properties of these enzymes in the CNS. Chlorpromazine at concentrations of 0.25‐1.0 mm caused marked decrease of microsomal and soluble thiamine triphosphatase (TTPase) activities and marked increase of microsomal thiamine diphosphatase (TDPase) activity. Imipramine and desipramine also inhibited TTPase but did not cause any marked change in TDPase activities. Addition of chlorpromazine (0.5 mm) decreased the Vmax of microsomal TTPase by about one‐half, increased that of TDPase about 3‐fold, and lowered the Km value for TDP but not for TTP.Acetone treatment of the microsomal fraction lowered the TTPase activity and markedly enhanced the TDPase activity. In acetone‐treated microsomes, chlorpromazine also inhibited TTPase activity but did not activate TDPase. Deoxycholate had similar effects to chlorpromazine on these enzyme activities.

Protective effect of serotonin against the inhibitory action of chlorpromazine on membrane potential of two-blastomere mouse embryos in vitro

The action of chlorpromazine, serotonin and prostaglandin F2-alpha on the cellular membrane potential of 2-cell mouse embryos, as well as a protective effect of serotonin and prostaglandin F2-alpha against the inhibition of the membrane potential by chlorpromazine were studied. Chlorporomazine (1.10-5 g/ml) proved to induce a strong decrease of the membrane potential, but serotonin, prostaglandin F2-alpha were ineffective. Serotonin (1.10-4 g/ml) prevented the action of chlorpormazine (2.10-6 g/ml), whereas prostaglandin F2-alpha (4-8.10-6 g/ml) was ineffective in this respect.

Tierexperimenteller Beitrag zum Problem der irreversiblen Hirnschädigung bei der Neuroleptica-Langzeittherapie

Question: Reports in clinical literature about persistent terminal extrapyramidal hyperkinesis in neuroleptic long-term treated patients and speculation about demential brain decomposition in such cases give rise to suppose irreversible psychopharmacotoxical brain damage. Histopathological and animal experimental results in this question given up to this day are not in agreement with each other. Therefore an own chlorpromazine long-term experiment in rats is reported with special regard to biometric-statistical results. Materials and methods: Experiments were performed in 36 adult albino rats of either sex, weighing 300–400 g, fed by a standard diet, receiving food and water ad libitum. The animals were divided into 3 groups of 12 animals accidentally. Group I received 15 mg/kg/die chlorpromazine per os by means of a throat probe, group II 10 mg/kg/die, group III was left untreated (controls). The experiment was carried out for 6 months, the animals were killed by perfusion of Bonin's solution 6–8 weeks after interruption of chlorpromazine application. 8 μm paraffin sections were stained by kresylviolet. After histological examination the material was investigated statistically. In the ncl. N. XII, ncl. N. VII, ncl. orig et term. N. V., ncl. cochlearis ant., ncl. vestibularis princeps, Oliva sup., and ncl. dentatus the glia/neurons ratio was stated by counting 200 cells, and in the formation reticularis 400 cells in each animal. The calculated differences in the glia/neurons ratio between the groups were evaluated for statistical significance by the x 2-test. In the ncl. dentatus, oliva sup., ncl. cochlearis ventr., and ncl. vestibularis glia cells and neurons were counted in a plane of 1.2 mm 2 , in the formatio reticularis and in homologuous parts of cerebellar stratum moleculare in a plane of 2.4 mm 2. The differences between the mean values of the groups were verified for statistical significance by means of the t-test. Results: In histological examination only 50% of the animals of group I showed a slight loss of neurons and increase of glia cells. Statistically however, significant increase of glia cells was found in the glia/neurons ratio all over the investigated area (rhombencephalic brain stem and cerebellum) and for the ncl. dentatus, the oliva sup., and the ncl. cochlearis ventr. especially (table 1, fig. 3). This change in the glia/neurons ratio is caused by a tendency for decreasing of neurons and increasing of glia cells, too (table 2). In the nucleus dentatus the loss of neurons was found to be of high significance. These changes are supposed to be due to chlorpromazine action, and in this manner the experimental results speak for an irreversible psychopharmacotoxical brain damage.

Action of chlorpromazine on spore-forming Bacillus species.

The hypothesis that chlorpromazine inhibition of bacterial endospore germination acts at the level of hexose monophosphate shunt (HMP) dehydrogenases was tested and substantiated for Bacillus cereus T and Bacillus megaterium. However, this cannot be an exclusive mechanism of action in bacterial systems because inhibitory effects on growth and respiration are caused by the drug even when these HMP enzymes are not present in the organisms.

Involvement of brain cholinergic mechanisms in the action of chlorpromazine.

THE function of cholinergic neurones in ganglia1, striatum and other brain areas is normally regulated by dopamine (DA)2 which, applied microiontophoretically, reduces the increased activity of caudate neurones elicited by acetylcholine3. Moreover, DA iontophoresis on caudate neurones mimics the responses elicited by electrical stimulation of the substantia nigra4,5.

A new prolonged-acting type of chlorpromazine: behavioral effects and prolonged actions on nerve membranes.

A chlorethyl derivative of chlorpromazine was prepared (2-chlor-10-(3-(beta-chlor-ethyl)-methylammopropyl)-phenothiazine HCl). This drug stabilized human erythrocytes (from hypotonic hemolysis) in the micromolar concentration range and had prolonged nerve-blocking potency. By using a 14C-labelled form of this drug, it was found to adhere persistently to both erythrocyte and brain synaptosome membranes. In animal behavior tests, the drug (P-B 845 Cl) was about one-fourth the potency of chlorpromazine. There is a possibility that the drug may have some long-term action since the animals recovered more slowly from the antiamphetamine actions of P-B 845 Cl than from the anti-amphetamine actions of chlorpromazine.

Actions of atropine, hemicholinium-3, and physostigmine on chlorpromazine-induced changes in rat brain monoamines.

The influence of atropine, hemicholinium-3 (HC-3), and physostigmine on the accumulation of monoamines after monoamine oxidase inhibition with pargyline, and on their disappearance after synthesis inhibition with α-methyl-p-tyrosine (α-MT), was investigated in whole brain of normal and chlorpromazine (CPZ)-treated rats. The results disclosed that the accumulation of dopamine (DA) and serotonin (5-HT) is significantly inhibited by atropine and HC-3, as is the loss of DA. None of these drugs affected the noradrenaline (NA) accumulation except for HC-3, which produced a small but statistically significant potentiation. Both atropine and HC-3 increased while physostigmine inhibited the disappearance of NA. These drugs, however, had no effect on the normal cerebral concentrations of monoamines. CPZ substantially increased the accumulation of DA and 5-HT and the loss of DA and NA without affecting their normal concentrations. HC-3, and to some extent atropine, inhibited the action of CPZ on the accumulation of DA and 5-HT. These drugs also inhibited the CPZ-induced accentuation of DA loss but enhanced that of NA. Physostigmine produced the opposite effects. In both normal and CPZ-treated animals, choline, which by itself was ineffective, partly reversed the actions of HC-3 but not that of atropine. These results support the hypothesis of cholinergic–aminergic interaction at the cerebral level and demonstrate the usefulness of HC-3 as a tool in such investigations.

Effects of morphine on striatal dopamine metabolism: Possible mechanism of its opposite effect on locomotor activity in rats and mice

In rats, the catalepsy induced by analgesic doses of morphine was paralleled by a dose-dependent increase in the concentration of dopamine's (DA) metabolite, homovanillic acid (HVA) in the striatum. The effect of morphine on striatal HVA was supra-additive with the corresponding action of chlorpromazine (CPZ). It is concluded that in rats morphine induces catalepsy and a decrease in dopaminergic activity in the striatum by a mechanism different from that of other cataleptogenic agents, such as the neurologic CPZ. In mice, morphine induced an increased in locomotor activity (running); this effect was attenuated by bilateral lesions placed in the caudate nucleus. Pretreatment of mice with diethyldithiocarbamate (DDC), or d,l-α-methyl-p-tyrosine (αMT), inhibited the morphine-induced running activity. In αMT-treated mice 1-3,4-dihydroxyphenylalanine (l-dopa) restored the effectiveness of morphine whereas d,l-threo-3,4-dihydroxyphenylserine (dops) was ineffective. In contrast, in DDC-treated mice, dops and clonidine, but not 1-dopa, were effective in restoring morphine's effectiveness. Doses of morphine inducing running activity in mice produced a slight increase in striatal HVA level. It is concluded that in mice morphine produces locomotor hyperactivity by releasing DA from the presynaptic terminals in the striatum, thus increasing the dopaminergic activity in this structure. Norepinephrine has an important auxiliary function.

Effect of the activation of the kinin-forming system on the potency of chlorpromazine.

Studies were performed on the effects of the activation of the kinin-forming system on the action of chlorpromazine in rats and mice. It was found that in animals with CNS kinin enzymes previously activated with kallikrein, or in animals which had been given bradykinin, the psychodepressive activity of chlorpromazine became markedly higher. The administration of Trasylol® brought about a decrease of the postkallikrein activation of kinin-generating enzymes and abolished the potentiating kallikrein effect on the action of chlorpromazine. Under multiple pathological conditions which are followed by increased kinin levels, an altered potency of drugs acting on CNS should be taken into consideration.

Interaction between piperazine and chlorpromazine.

The interaction between piperazine and chlorpromazine has been studied in rats and mice. Piperazine administered a few hours previously potentiated the action of chlorpromazine on the central nervous system. No such interaction was found between piperazine and prochlorperazine.

Chlorpromazine and avoidance: a genetic analysis.

Chlorpromazine exerts a significantly higher impairment on the performance of C57BL/6By than on BALB/cBy inbred mice pretrained in an active avoidance task. The effects of the drug on this measure assessed in these two strains, their reciprocal F1 hybrids, their recombinant inbred strains, and two C57BL/6By congenic lines indicate that at least two genes modulate the action of chlorpromazine on avoidance behavior. It was possible to characterize one of the loci modulating the effect of chlorpromazine on avoidance performance. We assign the symbol Cpz. The locus is in chromosome 9, Linkage Group II.