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At least 1,099 records · Page 61Linked to original sources
PubMed1990

Effects of haloperidol and clozapine on preprotachykinin-A messenger RNA, tachykinin tissue levels, release and neurokinin-1 receptors in the striato-nigral system.

The effects of haloperidol and clozapine on tachykinin tissue levels, preprotachykinin-A messenger RNA, spontaneous and potassium-evoked tachykinin release, dopamine D2 receptors, and [125I]Bolton-Hunter-substance P binding sites in the striato-nigral system were examined. Chronic administration (10 days) of the dopamine receptor antagonist haloperidol (2 mg/kg i.p.) significantly decreased tissue levels of substance P like-immunoreactivity and neurokinin A like-immunoreactivity in the striatum and the substantia nigra. The corresponding preprotachykinin-A mRNA was decreased in the striatum. Haloperidol did not affect the potassium-evoked tachykinin release in the substantia nigra but significantly increased the spontaneous release. Haloperidol increased the number of D2-receptors but left [125I]Bolton-Hunter-substance P binding sites, representing neurokinin 1 (NK-1) receptors, as determined by competition experiments with selective ligands, unchanged. Clozapine (30 mg/kg, i.m.) did not influence nigral and striatal tachykinin tissue levels, preprotachykinin-A mRNA and potassium-evoked release or spontaneous efflux in the substantia nigra, or D2-receptors and [125I]Bolton-Hunter-substance P binding sites. The present data indicate that neuroleptics influence the striato-nigral tachykinin system in different ways. Tachykinins may, therefore, contribute to the therapeutic and/or untoward effects of certain neuroleptic drugs.

Animals↗
PubMed1995

Haloperidol blocks the uptake of [18F]N-methylspiroperidol by extrastriatal dopamine receptors in schizophrenic patients.

We had previously demonstrated extrastriatal uptake of [18F]N-methylspiroperidol (18F-NMS) in the human brain. This study evaluates the effect of haloperidol on 18F-NMS binding in extrastriatal brain regions. Six schizophrenic patients on haloperidol underwent two PET scans with 18F-NMS at 12 h and at 6 days after haloperidol withdrawal. There was a significant increase in 18F-NMS uptake in striatal, thalamic, and temporal regions but not in frontal, occipital, or cerebellar regions, following drug withdrawal. Haloperidol's ability to block the uptake of 18F-NMS is an indication of the specificity of the radioligand's binding in these regions and supports the postmortem data demonstrating the presence of dopamine D2 receptors in the thalamus and temporal cortex of the human brain.

Adult↗
PubMed1987

Effect of dopamine and haloperidol on the c-wave and light peak of light-induced retinal responses in chick eye.

The relation between dopaminergic cells (and centrifugal fibers), the electroretinogram (ERG) c-wave, and the light peak were electrophysiologically investigated by observing the effects of a retrobulbar conduction block and intravitreal injection of either dopamine or haloperidol on these retinal responses. The retrobulbar conduction block (1% lidocaine) caused a decrease in the amplitude of the c-wave and the light peak in newly hatched chicks. Injections (2-20 microliters) containing dopamine (0.1-10 mM) or haloperidol (1.3-13 mM) were given intravitreously while the responses were recorded. Although intravitreous injection of saline for control resulted in no observable change in the responses, dopamine selectively augmented the c-wave of ERGs and the light peak, but not the a-, b-, and d-waves. Haloperidol decreased first the light peak and later the c-wave. The augmentation of the retinal responses by dopamine and their reduction by haloperidol was statistically significant. The estimated threshold concentration of dopamine in the vitreous cavity was 1-3.5 microM. Since in many species the interplexiform cells have been found to contain dopamine, we hypothesize that the modulatory effects on the c-wave and the light peak in this preparation may be due to a centrifugal feed-back loop which includes the interplexiform cells to the horizontal and bipolar cells and the horizontal cells to the cones.

Animals↗
PubMed1988

The effects of haloperidol on the partial reinforcement extinction effect (PREE): implications for neuroleptic drug action on reinforcement and nonreinforcement.

The effects of haloperidol 0.1 mg/kg on the partial reinforcement extinction effect (PREE) paradigm at one trial a day, were examined. Two groups of rats were trained to run in a straight alley. The continuously reinforced (CRF) group received food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasi-random 50% schedule. All animals were then tested in extinction. Haloperidol 0.1 mg/kg was administered in a 2 x 2 design, i.e., drug-no drug in acquisition and drug-no drug in extinction. The PREE, i.e., increased resistance to extinction of partially reinforced as compared to continuously reinforced animals, was obtained in all four drug conditions. The administration of haloperidol in acquisition increased markedly resistance to extinction in CRF animals. The administration of the drug in extinction decreased resistance to extinction in both CRF and PRF animals. The results are explained in terms of two independent actions of haloperidol: the well-known effect of reduction in the effectiveness of reinforcement as well as enhancement of the effectiveness of nonreinforcement.

Animals↗
PubMed1988

Chronic haloperidol administration increases the density of D2 dopamine receptors in the medial prefrontal cortex of the rat.

Rats received haloperidol (1.3-1.5 mg/kg/day) via their drinking water for 21 weeks. At the end of this period the density of D2 dopamine receptors and their affinity for [3H]-spiperone were measured in the striatum and medial prefrontal cortex. The chronic haloperidol treatment increased the density of D2 receptors in the striatum by 70% and in the medial prefrontal cortex by 50%. The chronic haloperidol did not significantly alter the apparent affinity of D2 receptors for [3H]-spiperone in either structure. These results indicate that the density of D2 receptors in the medial prefrontal cortex is influenced by chronic exposure to haloperidol in a manner that is very similar to the well-documented increase that occurs in the striatum.

Animals↗
PubMed1988

Effect of metergoline, fenfluramine, and 8-OHDPAT on catalepsy induced by haloperidol or morphine.

The influences of the indirect serotonin agonist fenfluramine (5; 10 mg/kg s.c.), the serotonin antagonist metergoline (5; 10 mg/kg s.c.) and the 5-HT1A agonist 8-OHDPAT (0.1; 0.2; 0.46 mg/kg s.c.) on haloperidol-induced catalepsy in rats or mice and on morphine-induced catalepsy in rats were studied. Morphine-induced catalepsy was enhanced by fenfluramine and attenuated by metergoline, whereas neither fenfluramine nor metergoline had any effect on haloperidol-induced catalepsy. 8-OHDPAT strongly antagonised catalepsy induced by morphine or haloperidol. We conclude that serotonergic transmission plays a major role in effectuating morphine catalepsy but not in effectuating haloperidol catalepsy. The antagonistic effect of 8-OHDPAT suggests a secondary, modulating role for 5-HT1A receptor mediated events in both types of catalepsy.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1988

Effects of chronic haloperidol treatment on amygdaloid seizure generation in cats.

We evaluated the effect of chronic haloperidol treatment (0.5-2 mg/kg/day, 21 day) on amygdala-generating seizures using a kindling procedure induced by low frequency electrical stimulations. The number of stimulating pulses required for triggering of epileptic afterdischarge (pulse-number threshold; PNT) is the indicator of the seizure generating threshold. A PNT decrease occurred, followed by a PNT increase toward the pre-treatment level during high-dose, chronic haloperidol treatment. A PNT increase occurred, followed by a PNT decrease toward the pre-treatment level during the withdrawal period after the high-dose treatment. A decrease of the triggered seizure duration occurred during the high-dose treatment. These results indicate that a transient decrease of seizure generating threshold occurs during chronic haloperidol treatment, and withdrawal of the drug is followed by what appears to be a rebound phenomenon. We suggest that this effect might be related to the antipsychotic potency and associated neurochemical changes known to be caused by chronic haloperidol treatment.

Amygdala↗
PubMed1987

Effects of haloperidol and d-amphetamine on perceived quantity of food and tones.

The hypothesis that dopamine (DA) receptor agonists and antagonists affect "hedonia" associated with natural rewards was tested, using a psychophysical procedure previously shown to be sensitive to both the sweetness of food and the motivational state of rats. Rats were first trained to discriminate between two different quantities of a rewarding stimulus by pressing one of two levers. Perceived quantity was subsequently derived from generalization trials of intermediate quantities. Haloperidol (0.03-0.083 mg/kg), a DA receptor antagonist, did not influence perceived food quantity, an indirect marker of hedonic value. On the other hand, d-amphetamine (0.25-1.0 mg/kg) affected perceived food quantity in a dose-dependent fashion, and in the same direction as occurs after increasing hunger or food sweetness. Both haloperidol and amphetamine influenced the perceived quantity of a stimulus without natural reinforcing properties (a tone), but the effect of amphetamine on the perceived quantity of this initially neutral stimulus was opposite in direction to that observed with food. These results suggest that whereas amphetamine affects hedonic processes, haloperidol does not. In addition, it seems that haloperidol probably produces its actions through effects on motor mechanisms or by interfering with the response-facilitating properties of rewards.

Animals↗
PubMed1987

The effect of haloperidol on cocaine self-administration is augmented with repeated administrations.

Administration of haloperidol (0.075 mg/kg) prior to a 4-h self-administration session increases cocaine intake by male rats. Animals pretreated daily with haloperidol showed a significant augmentation of this response, with cocaine intake climbing from 37% above baseline to 65% above baseline in 7 days. Control rats given two treatments of haloperidol 7 days apart showed no augmentation of the response. This increased drug effect is unusual, since most behavioral actions of haloperidol in laboratory animals show tolerance. In humans, the antipsychotic activity of neuroleptic drugs requires many days to develop. Cocaine self-administration behavior might therefore provide a model for antipsychotic drug action.

Animals↗
PubMed1996

Haloperidol-increased muscle tone in rats as a model of parkinsonian rigidity.

The aim of the present study was to find out whether haloperidol-induced rigidity was similar to that seen in parkinsonism. Simultaneous measurements of the muscle resistance (mechanomyogram, MMG) of the hind foot to passive flexion and extension in the ankle joint, as well as determination of the electromyographic (EMG) activity of the gastrocnemius and tibialis anterior muscles of rats were carried out. Haloperidol was injected in doses of 0.5-10 mg/kg 1 h before the start of measurements. Haloperidol increased, in a dose-dependent manner, the muscle resistance of the rat's hind leg to passive movements. Muscle rigidity was accompanied with an increase resting, as well as in the stretch-induced long-latency EMG activity (in which supraspinal reflexes are most probably involved) in both those muscles, whereas the short-latency EMG activity (first large bursts of EMG activity, beginning ca. 9 ms after the start of a movement, probably of a spinal origin) was significantly decreased. The obtained results suggest that the haloperidol-increased MMG/EMG activity might be a good model of parkinsonian rigidity.

Animals↗
PubMed1988

Catalepsy after microinjection of haloperidol into the rat medial prefrontal cortex.

To investigate the behavioural role of mesocortical dopamine innervation we performed bilateral microinjections of haloperidol into various parts of the rat frontal cortex and into adjacent subcortical forebrain structures. Haloperidol (2.5 micrograms/0.5 microliter) locally injected into the medial prefrontal cortex or into the rostral part of the neostriatum resulted in the development of catalepsy as measured in the bar test. In contrast, injections of haloperidol into the nucleus accumbens, more caudal parts of the neostriatum, anterior cingulate cortex, rostral and lateral parts of the prefrontal cortex and into the lateral ventricles failed to induce catalepsy. It is concluded that blockade of dopamine receptors located in the rostral neostriatum and in the medial prefrontal cortex contributes to the development of haloperidol induced catalepsy.

Animals↗
PubMed1984

Haloperidol plasma levels and clinical response in paranoid schizophrenics.

The relationship between haloperidol plasma levels, plasma prolactin, and therapeutic efficacy was evaluated in 20 paranoïd schizophrenics in a fixed-dose study for 6 weeks. We found a significant intrapatient cross-correlation of therapeutic efficacy, as measured by decrease in MSS and BPRS rating scales and time-dependent haloperidol and prolactin changes, which were tested at weekly intervals. However, no significant curvilinear relationship was present between steady-state haloperidol plasma levels and MSS and BPRS improvement scores. Our data do not furnish clear-cut evidence in favor of the existence of a therapeutic window for haloperidol plasma levels in paranoïd schizophrenia.

Adult↗
PubMed1975

A longitudinal therapeutic comparison between two prototypic neuroleptics (haloperidol and chlorpromazine) in matched groups of schizophrenics. Nontherapeutic interactions with trihexyphenidyl. Theoretical implications for potency differences.

The treatment process with two prototypic neuroleptics--haloperidol and chlorpromazine--and the nontherapeutic effects of trihexyphenidyl on this process were studied in carefully matched groups of ten schizophrenics each, using a "double-blind", repeated-measure, longitudinal research design. Measurements of various aspects of psychopathology, social participation and clinical indices of arousal were made periodically and objective test of cognition and attention were given. The two treatment groups were highly comparable in epidemiological and clinical terms and differed significantly during the baseline period in only one of the 39 parameters. Longitudinal nonparametric analyses showed that significant therepeutic changes tended to occur more quickly and involved a wider spectrum of schizophrenic phenomena with haloperidol than with chlorpromazine. Parametric analyses also indicated that at the completion of the study, haloperidol-treated patients had significant improvement in many more dimensions than the chlorpromazine-treated patients and that the changes with haloperidol were generally of greater magnitude. At the same time, chlorpromazine treatment seemed to be more susceptible to the antagonistic effects of trihexyphenidyl. No differential patterns of responses were noted for the two neuroleptics to provide any clinical validity to the distinction often made between "sedative" and "activating" neuroleptics. These data were in agreement with those from a previous comparative study which had a very different research design and a somewhat different type of schizophrenic population. The clinical and potency differences between the two neuroleptics were again explained on the basis of the fact that chlorpromazine has much stronger built-in anticholinergic properties, which may be acting in opposition to the antipsychotic activity. It was suggested that the degree of inherent anticholinergic activity may be an important determinant of potency differences among presently known neuroleptics. The possible role of cholinergic mechanisms in schizophrenia was discussed.

Adult↗
PubMed1975

Effects of clozapine, thioridazine, perlapine and haloperidol on the metabolism of the biogenic amines in the brain of the rat.

The effects of clozapine, thioridazine, perlapine and haloperidol on the metabolism of the biogenic amines in the brain of the rat have been investigated. Haloperidol, perlapine and thioridazine induce catalepsy and enhance the turnover of DA in the striatum as indicated by the dose-dependent increase in the DA-metabolites, HVA and DOPAC. These effects are due to blockade of dopaminergic transmission, haloperidol being far more potent than perlapine or thiridazine. Clozapine differs from these agents in that it elevates the concentration of striatal DA. The increase of the concentrations of HVA and DOPAC by clozapine is not accompanied by development of catalepsy. Therefore, clozapine seems to influence striatal DA by a mechanism other than DA-receptor blockade. All four drugs enhance the turnover of NA in the brain stem. This effect is probably secondary to the blockade of NA-receptors. There was no correlation between the effects on NA-metabolism and the EEG-arousal inhibitory activities of these agents or their clinical antipsychotic effects. Clozapine increase the concentration of 5-HT and 5-HIAA in the brain. This effect was not seen with the other drugs. Perlapine seems to enhance the turnover of 5-HT, whereas haloperidol reduced the 5-HT concentration. Thioridazine appears to have no effect on the metabolism of 5-HT.

Animals↗
PubMed1984

Modification of the behavioural effects of haloperidol and of dopamine receptor regulation by altered thyroid status.

Rats made hypothyroid by the chronic oral administration of 200 mg/kg propylthiouracil were less sensitive to the cataleptic effects of haloperidol (0.1 mg/kg) treatment than were euthyroid rats chronically treated with isotonic saline. However, rats made hyperthyroid by the chronic injection of 200 micrograms/kg thyroxine were not more sensitive to the cataleptic suppressant effects of haloperidol (0.1 mg/kg). Higher doses of haloperidol (1 and 5 mg/kg) produced significantly greater catalepsy in the hyperthyroid rats and significantly reduced catalepsy in the hypothyroid rats. Receptor binding studies carried out on the striata from rats sacrificed 48 h after a 6-day course of chronic haloperidol (0.1 mg/kg once daily) treatment revealed a significant upregulation (increase) of dopamine receptors in the hypothyroid rats only. These findings are consistent with the hypothesis that altered thyroid status can modify the sensitivity of dopamine receptors.

Animals↗
PubMed1976

Haloperidol-induced tardive dyskinesia in monkeys.

In three cebus monkeys the chronic daily administration of haloperidol (0.5 mg/kg/day orally) created sedation and parkinsonism during the first 5-7 weeks. Later the animals developed signs reminiscent of acute dystonia, as seen in the clinic during treatment with neuroleptics. These signs were dose-dependent and in extreme cases included widespread tonic and clonic seizures. After 3 and 12 months, respectively, two of the cebus monkeys developed buccolingual signs (grimacing and tongue protrusion), similar to tardive dyskinesia in the clinic. The tardive dyskinesia symptoms were reduced in a dose-dependent manner after each haloperidol administration, being most pronounced in the morning before haloperidol was given. Biperiden reduced acute dystonia but reinstated signs of tardive dyskinesia, which had been abolished by haloperidol. It is suggested that cebus monkeys may provide a useful animal model for the study of neurologic long-term complications from neuroleptic drugs.

Animals↗
PubMed1984

Lithium does not interact with haloperidol in the dopaminergic pathways of the rat brain.

Prophylactic treatment with lithium has been reported to prevent haloperidol-induced dopamine (DA) receptor supersensitivity. If such an effect exists, then lithium may be useful in the prevention of tardive dyskinesia, which is related to the neuroleptic-induced DA hyperfunction. In the experiments reported here chronic lithium administration had no effect on DA synthesis or utilization in the nigrostriatal, mesolimbic, or mesocortical DA pathways in the rat brain. Similarly, lithium had no effect on the increase in DA metabolism induced by the acute administration of haloperidol. Also, chronic lithium treatment failed to modify the biochemical tolerance which developed after prolonged administration of the neuroleptic drug. Supersensitivity of the presynaptic DA receptors, which was induced by prolonged exposure to haloperidol, likewise was unaffected by prophylactic lithium treatment. We conclude that lithium does not affect changes in DA metabolism or receptor supersensitivity induced by haloperidol. These results do not support the use of lithium in neurological disorders that may be related to neuroleptic-induced DA receptor supersensitivity.

Animals↗
PubMed1984

Prophylactic effect of neuroleptics in symptom-free schizophrenics: a comparative dose-response study of haloperidol and propericiazine.

Remitted schizophrenic outpatients were treated in order to prevent relapse with three doses of haloperidol or propericiazine for 1 year in a double-blind controlled study employing a randomized design. The drug's ability to prevent relapse was evaluated by counting the number of symptom-free days for each patient before any sign of relapse or over-dose appeared. Patients were randomly assigned to the following drugs orally administered once per day at night: placebo; haloperidol 1 mg, 3 mg, and 6 mg; propericiazine 10 mg, 30 mg, and 60 mg. Serum prolactin levels in each patient were estimated by radioimmunoassay. All patients treated with placebo relapsed within 1 year and the relapse rate with placebo was significantly higher than with any dose of the two neuroleptics. Haloperidol increased the number of symptom-free days in a dose-dependent manner. Propericiazine at 10 mg and 30 mg also increased the number of symptom-free days dose-dependently but at 60 mg, the number decreased. It appears that propericiazine shows an inverted U-shaped dose-response curve. Prolactin levels were elevated dose-dependently by both drugs but failed to show a significant correlation with the number of symptom-free days. The present results indicate that haloperidol is superior to propericiazine from the viewpoint of the wider "therapeutic window" in maintenance treatment and antidopaminergic properties of neuroleptics, wherein it is important to prevent relapse even in remitted schizophrenics.

Adult↗