Chronic Administration Of Chlorpromazine Research Articles

Maternal immune activation leads to age-related behavioral and immunological changes in male rat offspring - the effect of antipsychotic drugs

BackgroundPrenatal immune system disturbances have been postulated to play an important role in pathogenesis of schizophrenia and related disorders. In the present study, we sought to answer the question whether behavioral changes in the neurodevelopmental model of schizophrenia in rats are accompanied by alterations in proliferative activity of splenocytes and pro- and anti-inflammatory cytokine levels. Furthermore, the effects of two antipsychotic drugs on these parameters were determined. MethodsLipopolysaccharide (LPS) was administered subcutaneously to pregnant dams at a dose of 1mg/kg every second day from the 7th day of pregnancy till delivery. Age-dependent behavioral and immunological changes were studied when control and prenatally LPS-pretreated offspring male rats were 30 and 90 days old. Chlorpromazine (10mg/kg ip) or clozapine (10mg/kg ip) was administered chronically (21 days) after behavioral verification to 3 months old offspring males. Changes in sensorimotor gating (prepulse inhibition, PPI), mitogen-induced proliferative activity of splenocytes ([3H]-thymidine incorporation) and cytokine levels (ELISA) were measured. ResultsPrenatally LPS-pretreated rats showed PPI deficit only at 90 but not at 30 days of age, whereas an enhancement of mitogen-stimulated proliferative activity of splenocytes was observed in both time points. Additionally, the level of proinflammatory cytokines (IL-1β, IL-2, IL-6, TNF-α) in prenatally LPS-pretreated rats was enhanced when they were 30 days old and remained elevated in 90 days old offspring. No changes in IL-10 level were observed. Chronic administration of chlorpromazine or clozapine reduced the deficit in PPI deficit in prenatally LPS-treated rats. In the used model, chlorpromazine normalized both T and B lymphocyte proliferation, whereas clozapine B lymphocyte activity only. Moreover, both antipsychotics modulated the enhanced levels of IL-β, IL-2 and TNF-α in the offspring of LPS-treated mothers. ConclusionsThis study indicates that in LPS-evoked model of schizophrenia, peripheral immunological changes are long-lasting and precede behavioral deficit. The disturbances in T cell-mediated immunity as well as cytokine production were attenuated by antipsychotic drug administration.

Effect of Chronic Administration of Chlorpromazine on Electrical Parameters of Command Neurons in Edible Snail

Electrophysiological experiments showed that chronic administration of neuroleptic chlorpromazine depolarized plasma membrane and decreased the threshold of action potential generation in command neuron of defense behavior of edible snail and motoneurons of pneumostome closure reflex. The effects of chlorpromazine on electrical parameters of the identified neurons can be explained by its serotonin-depleting action.

Intense arousal of novel male mice in proximity to previously inseminated females: Inactivation of males via chlorpromazine does not diminish the capacity to disrupt pregnancy

In the course of investigating early pregnancy disruptions by novel males, intense behavioral interactions and chemical emissions were observed among males housed in proximity to inseminated females. These interactions were evident despite wire-mesh separations between males and females. Experiments were designed to examine whether such arousal plays a role in pregnancy disruption. During the first 5 days of pregnancy, inseminated CF-1 strain female mice were either left undisturbed or exposed to novel outbred males. Physical separations between males did not diminish the frequency of pregnancy disruption. Subsequently, we investigated whether heavy sedation of novel males via chronic chlorpromazine administration would diminish the capacity to disrupt pregnancy. Pregnancy was disrupted to the same degree in females exposed to drug-treated males and those exposed to alert competing males given vehicle injections. These data show an unprecedented degree of arousal and pheromonal emission among competing males but suggest that these factors are not critical for the capacity to disrupt pregnancy.

The effect of chronic chlorpromazine administration on monoamine levels in various regions of rat brain.

The neuroleptic drug, chlorpromazine (CPZ) has been shown to exert its antipsychotic effect by blocking post synaptic dopamine receptors. However, its effect on steady state levels of monoamines is still in discrepancy. In the present study, CPZ (4 mg/kg body weight) was administered intraperitoneally to adult Wistar rats chronically for 75 days and the levels of norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) were assayed in various brain regions by high performance liquid chromatography (HPLC). After the experimental period body and brain weights were not statistically different from controls. NE and 5-HT levels were increased only in hippocampus by 15% (p < 0.01) and 16% (p < 0.01) respectively. DA levels were consistently increased in cortex by 39% (p < 0.001), striatum-accumbens by 18% (p < 0.01), hippocampus by 27% (p < 0.01), hypothalamus by 34% (p < 0.001), cerebellum by 36% (p < 0.001) and brainstem by 40% (p < 0.001) in CPZ treated rats compared to controls. The results suggest that chronic CPZ administration increases DA levels in almost all regions of brain and reflect the ability of CPZ to preferentially interfere with synaptic transmission mediated by DA in brain. It also suggests that this increase in DA might be responsible for certain side effects seen in patients after chronic CPZ treatment.

Factors related to the presence of autoantibodies in patients with chronic mental disorders

Serum samples from 307 patients with various chronic mental disorders were examined for the presence of several autoantibodies. Autoantibodies detected included antinuclear antibodies (ANA) in 122 307 (39.7%), rheumatoid factor (RF) in 23 307 (7.5%), anticardiolipin antibodies (anti-CL) in 23 304 (7.6%, IgM in 12 patients, IgM in 13 patients). Isolated cases with IgG anti-dsDNA, anti-Ro(SSA), and anti-Ro(SSA)/anti-La(SSB) were also identified. The analysis of data revealed that the aging process in patients studied contributed significantly to the incidence of ANA (p < 0.0001) and RF (p < 0.01). In addition, the chronic administration of chlorpromazine (CPZ) was associated with the presence of ANA (p < 0.03) as well as with the presence of IgM and/or IgG anti-CL antibodies (p < 0.003). Finally, the diagnosis of schizophrenia correlated with the presence of ANA (p < 0.001). This study represents the autoantibody profile of patients with chronic mental disorders and emphasizes the multifactorial origin of autoantibody response in psychiatric patients.

The inhibition of glutamate dehydrogenase by some antipsychotic drugs

The phenothiazines chlorpromazine and perphenazine and the butyrophenone haloperidol were shown to be reversible inhibitors of glutamate dehydrogenase (GDH). Inhibition by chlorpromazine was found to be partial, whereas haloperidol and perphenazine would, apparently, give full inhibition at saturating concentrations. Double-reciprocal plots of the difference between activities in the absence and presence of the inhibitor against the inhibitor concentration were linear with chlorpromazine and perphenazine but parabolic when haloperidol was used as the inhibitor. Comparisons between the responses of commercially available preparations of ox liver GDH, which have been shown to have suffered limited proteolysis during purification, and the ox brain enzyme prepared by a procedure which does not result in such proteolysis, revealed the latter preparation to be more sensitive to inhibition because of a higher apparent affinity for these drugs. The apparent dissociation constants for enzyme-drug interactions were, however considerably higher than the concentrations that have been reported to occur in vivo following chronic administration of chlorpromazine and haloperidol. This casts doubt on earlier claims that inhibition of GDH may be involved in the antipsychotic actions of these drugs, although it might be a factor in the side effects associated with the use of such compounds.

Quantitative electron microscopic investigation on changes of mitochondria in long-term CPZ administration in rat brain, liver and heart.

The effect of chronic administration of chlorpromazine (CPZ) on mitochondria (MT) in the rat brain (striatum), liver and heart was quantitatively examined with both the electron microscope and computer-assisted PICTURE ANALYSIS OA-1. The specimens were taken from six female rats, three controls and three experimentals to which 20 mg/kg body weight of CPZ was administered orally for 15 months from 5 weeks after birth. Thus the quantitative electron microscopic study was made on the mitochondrial sizes (cross-sectional areas) and cristal densities and the following results were obtained: 1) The sizes of MT from the striatal nerve cells and axo-dendritic spine postsynapses and liver parenchymal cells were larger in the CPZ-administered rats than in the controls, whereas there were no statistically significant changes in the sizes of MT from the striatal axo-dendritic spine presynapses and heart papillary muscle cells to which the influence of long-term CPZ administration could be well expected. 2) In contrast, with the mitochondrial sizes, the cristal densities represented by the number of cristae per unit area (mu2) of MT have decreased in the striatal nerve cells and axo-dendritic spine pre- and postsynapses, liver parenchymal cells and heart papillary muscle cells of the CPZ-administered rats than in those of the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Chronic Administration of Antidepressants on Duration of Immobility in Rats Forced to Swim

Chronic administration of imipramine and desipramine significantly reduced the duration of immobility in rats forced to swim in comparison with acute administration. However, amitriptyline did not potentiate the reductive effect of chronic administration. Chlorimipramine, a selective serotonin uptake inhibitor, did not affect the duration of immobility in both the acute and chronic administration. On the other hand, the chronic administration of chlorpromazine, haloperidol and diazepam enhanced the duration of immobility, whereas their acute administration had no effect on it. Sulpiride reduced and enhanced the duration of immobility by the acute and chronic administration, respectively. The present results suggest that the chronic administration of drugs to rats in a forced swimming test can clarify the characteristics of the psychotropic drugs.

The residual effect of chronic neuroleptic treatment on the neuroleptic binding assay in rats

Chronic chlorpromazine administration to rats (25 mg/Kg/day) for 30 days followed by a washout period of 10 days resulted in an increase in both measured maximum number of binding sites, B max, and the apparent dissociation constant, K d, for the binding of 3H-spiroperidol to neural membranes of the brain. When membrane suspensions were progressively diluted before the binding assay, it was found that the apparent B max did not change with dilution, remaining higher in membranes of chlorpromazine-treated rats than in controls. The apparent increase in K d, on the other hand, was found to be an artifact of the assay. Thus extrapolation of the measured or apparent K d value to infinite dilution resulted in identical value for K d regardless of the treatment.

Chlorpromazine-induced lupus anticoagulant and associated immunologic abnormalities.

Chronic administration of chlorpromazine is associated with the development of a lupus-like circulating anticoagulant and a variety of immunological abnormalities. The prevalence of these findings was studied in 123 psychiatric patients. The anticoagulant was present in 11 of 30 patients receiving chlorpromazine (CPZ), in none of 17 patients who had been off phenothiazine therapy for over a year and in none of 53 controls. It was also seen in 5 of 13 patients who had been switched from CPZ to another phenothiazine even after several years being off CPZ. The anticoagulant was characterized by prolongation of the partial thromboplastin time, thromboplastin dilution test, and Russell's viper venom time. Washed frozen platelets partially corrected the abnormality induced by the anticoagulant. In all but one case the anticoagulant was associated with positive antinuclear antibody test and/or increased serum IgM. Six of 16 patients also had decreased complement levels, and two had a positive direct Coombs' test. None of these patients manifested bleeding, hemolysis, splenomegaly, or other clinical features of systemic lupus erythematosus.

Chronic chlorpromazine administration in rats: effects on ability to work in the heat.

To identify and quantitate the effects of chronic chlorpromazine (CPZ) administration on the ability to work in the heat, 2 mg CPZ were administered by intraperitoneal injection daily for 14 days to rats weighing between 250 and 350 g at the time of experimentation. When these animals exercised in the heat (35 degrees C) to hyperthermic exhaustion (Tre = 42.5-43 degrees C), it was demonstrated that their endurance capacity was significantly reduced (P less than 0.001) when compared with saline-treated controls. Increments in rectal temperature while on the treadmill were significantly (P less than 0.02) elevated among th CPZ-treated rats. Exercise on the treadmill to hyperthermic exhaustion resulted in significantly (P less than 0.001) increased circulating levels of lactate and potassium when these were compared in blood samples taken immediately before and after exercise in the heat for both groups, but creatine phosphokinase levels were unaffected. Additionally, lactate levels were significantly (P less than 0.05) increased in the postrun blood samples of CPZ-treated rats when compared with the appropriate saline-treated controls. We concluded from these studies that chronic administration of CPZ in rats reduces their ability to work in the heat. Further, their rate of heat gain while exercising in the heat is increased, and the combined effects of exercise in the heat and CPZ administration exacerbated the effects on the clinical chemical indices of heat-exercise injury.

Effects of chronic administration of antipsychotic drugs on GABA and other amino acids in the mesolimbic area of rat brain

Albino rats were injected once daily with chlorpromazine (20 mg/kg) or haloperidol (3 mg/kg) for 100 days, and were sacrificed 24 hours or 35 days after the last injection. Brains were frozen rapidly in liquid nitrogen, after which the mesolimbic area (containing nucleus accumbens and olfactory tubercle) and striatum were dissected from each frozen brain. Amino acids were quantitated in the mesolimbic area, and GAD enzyme activity was measured in the striatum. Chronic administration of chlorpromazine and haloperidol did not alter brain GABA content or GAD activity in the treated rats, as compared to saline-injected controls, either 1 or 35 days after injections ended. However, a significant elevation of aspartate content and reduction of glycine content was found after chronic administration of haloperidol. These data suggest that alterations which may be found in the GABA system in autopsied brain from psychotic patients do not result from previous antipsychotic drug therapy.

The effects of chronic chlorpromazine administration on the albino rat retina

Chlorpromazine, 2 to 35 mg/kg/day, was administered orally to male albino Wistar rats for 13 months. The retina appeared histologically normal and retinal cyclic adenosine monophosphate phosphodiesterase activity was unaltered.

Effect of chronic chlorpromazine administration of prior treatment with reserpine on brain apomorphine concentrations and apomorphine-induced sterotyped behaviour in the rat

Rats were pretreated with a single dose of reserpine (10 mg/kg i.p.) oe were gioven daily injections of chlorpromazine (15 mg/kg s.c.) for 3 weeks. Controls received distilled water. 72 h after reserphine and 1 week after withdrawal from chlorpromazine apomorphine was administered (10 mg/kg i.p.). Both the intensity and duration of apomorphine-induced stereotyped behavior (ASB) and the concentration of apomorphine in brain were measured. Further groups of rats pretreated with reserpine of chlorpromazine as well as corresponding controls, received 0.25 mg/kg apomorphine and the development of ASB was rated. 14 of 16 reserpine-pretreated rats and 4 of 16 control rats developed ASB after 0.25 mg/kg apomorphine ( p < 0.001). After withdrawal from chlorpromazine, apomorphine (0.25 mg/kg) induced ASB in 12 out of 14 experimental and 5 out of 14 control rats ( p < 0.05). Following 10 mg/kg of apomorphine there was a significant ebhancdement of motor activity associated with ASB in rats exposed to reserpine or withdrawn from chlorpromazine, compared to controls. This enhancement could notbe explained by differences in brain apomorphine concentrations. The results are not inconsistent with the concept of neuroleptic-induced supersensitivity of dopamine receptors.

Effect of chlorpromazine on central nervous system concentrations of manganese, iron, and copper

Chronic administration of chlorpromazine produced alterations in trace metal concentrations in caudate nucleus, frontal cortex, and cerebellar hemisphere of guinea pigs. Manganese concentration following chronic chlorpromazine rose significantly in the caudate nucleus and cerebellar hemisphere whereas iron concentration rose most significantly in the caudate nucleus. Copper content was decreased in all regions examined. The possible significance of increased manganese and iron in the caudate nucleus is discussed in relationship to the clinical problems of chlorpromazine-induced dyskinesias.

Striatal adenylate cyclase activity following reserpine and chronic chlorpromazine administration in rats

Adenylate cyclase activity was assayed in rat striatal homogenates. Dopamine and, to a lesser extent, 1-norepinephrine added in vitro produced a dose-dependent enhancement of adenylate cyclase activity. Fluphenazine did not alter basal enzyme activity, but prevented both dopamine- and 1-norepinephrine-elicited increases. No significant changes in basal- or dopamine-stimulated adenylate cyclase activity were found in homogenates from rats pretreated with chlorpromazine for 21 days or reserpine for 2 days. It is concluded that the behavioral and neurophysiologic postsynaptic supersensitivities that follow similar pretreatments are not mediated by alterations in the sensitivity of striatal adenylate cyclase to dopamine.

Retinal toxicity of chlorpromazine in the rat

The retinal toxicity of chlorpromazine was studied in both albino and pigmented rats. In albino rats, the chronic administration of chlorpromazine (10 mg/kg po during 4 months) induced a large decrease in the amplitude of the electroretinogram (ERG) without detectable histological lesions. In pigmented rats (10 or 25 mg/kg for 6 months), despite a high concentration in ocular tissues, chlorpromazine did not induce functional ERG or histologic lesions. These data indicate that the ocular toxicity of chlorpromazine is not due to its affinity for melanin.

Action of some centrally active drugs and heavy metals on in vitro oxidation of dopamine by rat brain tissue.

The effect of chlorpromazine, amitryptyline, amphetamine, diphenhydramine, and iproniazid on the in vitro oxidation of dopamine to melanin by rat brain mitochondrial preparation was investigated. Chlorpromazine and amitryptyline very markedly inhibited the oxidation (ED50 60 and 180 μM, respectively) while iproniazid was ineffective. Other drugs were moderately active. The reaction was enzyme catalyzed and could not be ascribed to the anionic component. Chronic administration of chlorpromazine and amitryptyline (19 and 9.5 mg/kg, i.p.) produced a biphasic response characterized by stimulation of melanogenesis during the first 2–3 weeks followed by inhibition. On the other hand, physostigmine and choline markedly stimulated the oxidation process. The chronic ingestion of heavy metals; mercury, lead, and cadmium, up to toxic levels had no effect on the in vitro oxidation of dopamine.

The effects of acute and chronic administration of chlorpromazine on the acquisition and extinction of positively reinforced operant responses

Chlorpromazine (CPZ) depressed the acquisition of positively reinforced conditioned responses in rats. The degree of depression depended on the dose level and the difficulty of the task. High doses blocked the learning process at an early stage, and had a greater depressant effect than did a lower dose at the same stage. Chronic treatment even if discontinued during training decreased performance of a previously learned task and facilitated extinction. Continued chronic treatment decreased motor activity and ability to acquire a discriminative response. It is proposed that CPZ affects learning not only by depressing motor activity, but also by impairing other processes that are involved in the acquisition of conditioned responses. It appears that chronic CPZ has little permanent effect on the ability to learn new tasks, but may affect the retention of previously learned responses.

Chronic chlorpromazine administration: Some pharmacological and psychological effects in man

This study was undertaken to determine whether there were changes in the pharmacological profile of chlorpromazine when it was given over a long period of time and in view of these findings to examine claims that chlorpromazine is clinically useful as an antidepressant. Fifteen patients with chronic mental illness were given infusions of epinephrine, norepinephrine, histamine, and yohimbine before and at 1, 10, 30, and 90 days during a course of chlorpromazine therapy. Psychological measurements by observers unaware of drugs given indicated that the anxiety‐arousing effects of epinephrine were reduced by chlorpromazine but that the anxiety‐like effects of yohimbine were potentiated. Histamine and norepinephrine had no significant psychological effect. Treatment with chlorpromazine reduced manifestations of mental illness. Base‐line blood pressure was reduced Significantly early in chlorpromazine therapy but only slightly later on. The systolic pressor effects of epinephrine were reduced by chlorpromazine but to a lesser extent late in the 90 day period. Norepinephrine systolic blood pressure effects were not Significantly altered by chlorpromazine. The cardiovascular effects of histamine were potentiated by chlorpromazine throughout as were the cardiovascular effects of yohimbine. In a parallel dog study chlorpromazine augmented norepinephrine pressor effects. It is concluded that, in view of its tendency to potentiate yohimbine and norepinephrine, chlorpromazine has some characteristics similar to those of the antidepressant drug imipramine. These results are discussed in relation to findings that chlorpromazine and imipramine alter storage and release of catecholamines