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PubMed1995

Inhibition by haloperidol of adenosine 5'-triphosphate-evoked responses in rat pheochromocytoma cells.

The effects of haloperidol, a typical antipsychotic drug, on adenosine 5'-triphosphate (ATP)-induced increase in intracellular Ca2+ concentration ([Ca]i) and inward currents were investigated using rat pheochromocytoma PC12 cells. Haloperidol (10-100 microM) significantly attenuated the rise in [Ca]i evoked by 30 microM ATP. This inhibition was not mimicked by (-)-sulpiride, an antagonist to dopamine D2-receptor. Dopamine or other dopaminergic agents did not affect the [Ca]i rise evoked by ATP. Under whole-cell voltage-clamp, haloperidol inhibited the ATP-activated current in the cells. These results suggest that haloperidol inhibits the ATP-receptor/channel, leading to the attenuation of the ATP-evoked increase in [Ca]i. Mechanisms involving dopamine receptors may not contribute to the inhibition by haloperidol.

Adenosine Triphosphate↗

PubMed1996

Haloperidol prevents ketamine- and phencyclidine-induced HSP70 protein expression but not microglial activation.

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, inclu ding ketamine and phencyclidine (PCP), produce abnormal intracellular vacuoles in posterior cingulate and retrosplenial cortical neurons in the rat. Ketamine also induces 70-kDa heat shock protein (HSP70) expression in pyramidal neurons in the posterior cingulate and retrosplenial cortex and, as shown by this study, activates microglia in the retrosplenial cortex of the rat. Whereas HSP70 protein expression was induced with ketamine doses of 40 mg/kg (ip) and higher, doses of 80 mg/kg and higher were required to activate microglia. HSP70-positive neurons were observed in 30- to 90-day-old rats but not in younger, 10- to 20- day old animals following ketamine (80 mg/kg, ip). Pretreatment with the antipsychotic drug haloperidol at doses of 1.0 mg/kg and above abolished all HSP70 immunostaining produced by ketamine (80 mg/kg). However, a single dose of haloperidol (5 mg/kg, im) did not decrease the number of microglia activated in retrosplenial cortex by ketamine (80-140 mg/kg). Similarly, PCP (10 and 50 mg/kg, ip)-induced microglial activation in the posterior cingulate and retrosplenial cortex of adult rats was not blocked by haloperidol (10 mg/kg, im, 1 h prior to PCP). These results suggest that ketamine and PCP injure neurons in the posterior cingulate and retrosplenial cortex of adults rats. Though haloperidol may afford some protection against this injury since it inhibits induction of HSP70 expression, the failure to prevent microglial activation suggests that single doses of haloperidol do not completely protect neurons from NMDA antagonist toxicity.

Animals↗

PubMed1997

Haloperidol decreases hyperkinetic paw treading induced by globus pallidus lesions in the rat.

Systemic haloperidol injections decrease the severity of several hyperkinetic syndromes caused by damage to the basal ganglia in humans. A model of hyperkinesia in the rat, exaggerated paw treading triggered by oral sensory stimulation, has been reported previously to result from lesions of the globus pallidus or ventral pallidum/substantia innominata. This hyperkinesia appears as forepaw and forelimb extension and retraction, which can be emitted vigorously and repeatedly for up to minutes at a time. The present study aimed to discover whether this experimental hyperkinesia is pharmacologically similar to human hyperkinetic syndromes: can it be suppressed by neuroleptic administration? Systemic injections of haloperidol (2 mg/kg), diazepam (5 mg/kg, as a sedative comparison), or vehicle were given to rats that expressed the paw treading syndrome after pallidal lesions. Effects on hyperkinetic treading and on tests of sensorimotor function were compared. Results indicated that haloperidol was effective in ameliorating the hyperkinesia in rats with bilateral globus pallidus lesions but not in rats with ventral pallidum/substantia innominata lesions. By contrast, diazepam, which produced sedation and sensorimotor impairment, did not decrease the hyperkinesia induced by either lesion. Although only haloperidol decreased hyperkinetic treading after globus pallidus lesions, haloperidol produced less of a sensorimotor impairment than diazepam on climbing, hanging, and righting reflex tests. These results implicate a specific role for dopamine neurotransmission in the expression of triggered hyperkinetic treading induced by globus pallidus lesions.

Animals↗

PubMed1994

c-fos antisense oligonucleotide specifically attenuates haloperidol-induced increases in neurotensin/neuromedin N mRNA expression in rat dorsal striatum.

Acute administration of neuroleptic drugs such as haloperidol robustly increases transcription of the gene encoding the neuroactive peptide, neurotensin, in the dorsolateral striatum of the rat. This induction of neurotensin/neuromedin (NT/N) mRNA by haloperidol is preceded by increases in c-fos mRNA expression in the same region. Our recent studies demonstrate that a vast majority of haloperidol-sensitive NT/N mRNA expressing cells in the dorsolateral striatum coexpress c-fos mRNA. These data suggest that the transcription factor, Fos, may participate in NT/N gene induction by neuroleptics. Present studies investigated this possibility using an antisense c-fos oligodeoxynucleotide (which has been shown to block the expression of Fos protein in vivo) or its sense sequence oligomer injected into opposite caudate-putamen of awake, freely moving rats. Eight hours following the injection of the oligomers, the animals were challenged with a systemic injection of haloperidol (1 mg/kg) and were sacrificed 1 h later. Examination of NT/N mRNA by in situ hybridization histochemistry revealed approximately 50% attenuation in the NT/N mRNA expression in the dorsolateral striatum injected with the antisense oligomer compared to the contralateral side which received the sense oligomer. On the other hand, expression of proenkephalin mRNA in the dorsolateral striatal neurons or NT/N mRNA in the nucleus accumbens shell was not altered following the c-fos antisense oligomer injection. These data demonstrate a specific role of Fos in the regulation of the neurotensin/neuromedin N gene in the rat dorsolateral striatal neurons by acute haloperidol treatment.

Animals↗

PubMed1980

The influence of haloperidol pretreatment on the morphine toxicity.

The influence of dopaminergic modifiers on morphine-induced analgesia and lethality was studied comparing both the effect of a single pre-dose of haloperidol and and continuous pretreatment for three weeks with haloperidol. A single administration of haloperidol enhanced morphine-induced analgesia probably due to the receptor blocking action of haloperidol which supports the reduction of dopamine release produced by morphine. The daily haloperidol administration for 3 weeks however decreased the analgesic action of morphine in consequence of a dopamine receptor supersensitivity developed in this time. The lethality was increased under both conditions. These results suggest that the dopaminergic system, dependent upon its sensitivity, plays a modulating role in morphine-induced analgesia, but not in morphine-induced lethality.

Analgesics↗

PubMed1992

Pharmacological comparison of the sigma recognition site labelled by [3H]haloperidol in human and rat cerebellum.

The radioligand binding characteristics of [3H]haloperidol (in the presence of spiperone, 25 nmolL-1) were investigated in rat and human cerebellar membranes. In both rat and human cerebellar membrane preparations saturation studies with [3H]haloperidol (non-specific binding defined by pentazocine, 10 mumolsL-1) demonstrated high affinity saturable specific binding to a homogenous population of binding sites (rat, Bmax 6693 +/- 1242 fmol mg-1 protein, pKD 8.33 +/- 0.08; human, Bmax 2550 +/- 437 fmol mg-1 protein, pKD 8.59 +/- 0.11; mean +/- SEM, n = 3-6). Competition studies employing a wide range of structurally diverse competing compounds displayed that the [3H]haloperidol binding site was pharmacologically similar in both preparations and comparable to sigma recognition sites previously identified in various tissues originating from different species. In addition, with reference to the potential subtypes of sigma recognition sites, the labelling of these sites by low nanomolar concentrations of [3H]haloperidol provides evidence that they belong to the sigma-1 recognition site subtype. The present findings suggest that the pharmacology of the rat and human cerebellar sigma recognition site are directly comparable and provides further supporting evidence towards the use of [3H]haloperidol radioligand binding studies in the rat to detect sigma receptor ligands with potential therapeutic activity.

Animals↗

PubMed1996

Chronic clozapine versus chronic haloperidol treatment: differential effects on electrically evoked dopamine efflux in the rat caudate putamen, but not in the nucleus accumbens.

Fast cyclic voltammetry at carbon-fibre micro-electrodes was used to investigate the effects of chronic clozapine or haloperidol administration on electrically evoked dopamine efflux in the nucleus accumbens and caudate putamen of the anaesthetized rat. Stimulation trains were delivered to the median forebrain bundle (60 pulses, 350 microns duration) every 5 min, and the evoked dopamine efflux measured as a function of a) the applied stimulus intensity (range 0.2 mA-1.0 mA), and b) the applied stimulus frequency (range 10 Hz-250 Hz). Chronic administration of either clozapine (20 mg/kg x 21 days, p.o.) or haloperidol (1 mg/kg x 21 days, p.o.) significantly reduced electrically evoked dopamine efflux in the nucleus accumbens over the range of stimulus intensities and frequencies tested. The reduction in evoked dopamine efflux observed in the nucleus accumbens of clozapine- and haloperidol-treated rats showed no statistically significant difference. In contrast, only chronic haloperidol treatment significantly reduced evoked dopamine efflux in the caudate putamen. These findings demonstrate that chronic treatment with either the atypical neuroleptic, clozapine, or the typical neuroleptic, haloperidol, produce long-term changes in mesolimbic dopamine function; actions which may underlie their antipsychotic efficacy. They also provide further evidence that the sparing action of clozapine on nigrostriatal dopamine activity may underlie the lower incidence of extrapyramidal side effects associated with its long-term administration.

Animals↗

PubMedDate not supplied

Further evidence for the subsensitivity of striatal AMPA receptors, induced by chronic haloperidol administration: an autoradiographic study.

The aim of the present study was to investigate the influence of chronic treatment with haloperidol on the striatal N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxasole-propionic acid (AMPA) and dopamine D2 receptors using a quantitative autoradiography in rats. Haloperidol was given to animals in a dose of ca. 1 mg/kg/day in drinking water for 6 weeks or 3 months and was afterwards withdrawn for 5 days. Haloperidol increased by 20-50% the binding of [3H]spiperone in different regions of the caudate-putamen. Haloperidol decreased by ca. 30% the binding of [3H]AMPA in the ventrolateral region of intermediate part of the caudate-putamen, but did not influence the binding of [3H]MK-801. The present results suggest that, apart from supersensitivity to dopamine, chronic treatment with haloperidol also induces subsensitivity of striatal AMPA receptors.

Animals↗

PubMed1988

Differential effects of the new antipsychotic risperidone on large and small motor movements in rats: a comparison with haloperidol.

Risperidone, a new antipsychotic agent, was studied for its effects on spontaneous motor activity in rats in comparison with haloperidol. Motor activity was recorded via the optical scanning technique (horizontal and vertical activity) and via a recently developed technique based on the piezo-electric principle which, in contrast to optical scanning, is very sensitive to small, stationary movements (piezo activity). Risperidone and haloperidol at low doses depressed both vertical activity (ED50s: 0.062 and 0.038 mg/kg, respectively) and horizontal activity (0.18 and 0.060 mg/kg, respectively). With increase of dose, motor activity decline was significantly faster with haloperidol than with risperidone. Moreover, haloperidol also rapidly depressed piezo activity (ED50: 0.085 mg/kg) whereas risperidone depressed this component of motor behaviour at much higher doses only (ED50: 2.80 mg/kg). Visual inspection did not reveal abnormal behavioural movements following the test compounds. Risperidone, therefore, preserves normal small movements over a much larger dose interval than haloperidol; this effect may be related to its relatively low cataleptogenic activity and potentially also to a reduced EPS liability. The present results further confirm that the piezo technique may complement the optical scanning method, and thereby enhance the information on the extent that test compounds modify behaviour.

Animals↗

PubMed1988

Haloperidol- and apomorphine-induced changes in pup searching behaviour of house mice.

Maternal pup searching behaviour of lactating house mice treated with apomorphine, haloperidol or saline was examined on a running board with a central depression as a nest. Pup searching was elicited by artificial ultrasonic stimuli: a female moved out from the nest either towards a 50 kHz tone (key stimulus) which is adequate to activate species specific pup searching behaviour or towards a 20 kHz tone (neutral stimulus), thus showing her preference for one of these stimuli. Under apomorphine (0.00625; 0.0125; 0.025 mg/kg) the females preferred the key stimulus. Nevertheless apomorphine (0.00625-0.025 mg/kg) prolonged response latencies and shortened the duration of pup searching. At the highest dose (0.05 mg/kg), apomorphine induced stereotyped sniffing. Haloperidol (0.025; 0.05; 0.1 mg/kg) had opposite effects to apomorphine: it lowered the threshold for elicitation, shortened response latencies and prolonged the duration of pup searching. Females treated with haloperidol (0.025-0.1 mg/kg) did not prefer the key stimulus. Changes in response elicitation and in the performance of pup searching induced by apomorphine and haloperidol, respectively, were assumed to be due to i) a reduced and an increased responsiveness to external stimuli respectively, ii) an enhanced and a reduced tendency for response switching respectively, and iii) a preference for spontaneous behaviour in apomorphine-treated females, with an increased dependence on exteroceptive stimuli following haloperidol.

Acoustic Stimulation↗

PubMed1986

Disinhibitory effects of buspirone and low doses of sulpiride and haloperidol in two experimental anxiety models in rats: possible role of dopamine.

Low doses of buspirone, haloperidol and sulpiride were compared with diazepam in two experimental models of anxiety in rats. In a conflict test, 0.6 and 1.2 mg/kg buspirone, 0.05 and 0.10 mg/kg haloperidol and 0.5 mg/kg sulpiride significantly increased punished responding. Buspirone 1.2 and 2.5 mg/kg significantly reduced the number of unpunished responses while haloperidol and sulpiride at the doses tested had no effect. Effects on punished responding were seen in a narrow dose range and were less pronounced with these drugs than with diazepam. Similar results were obtained with rats', activity in the two-compartment exploratory test. At doses causing no change in the locomotion of rats in photocell activity cages, buspirone (0.1 mg/kg), haloperidol (0.025-0.100 mg/kg) and sulpiride (0.5-1.0 mg/kg) significantly increased the number of crossings between the two compartments. Again, the peak effects were small when compared with the effect of diazepam and the active dose range was very narrow. Apomorphine 0.2 mg/kg SC significantly counteracted the effect of 0.1 mg buspirone and 1.0 mg/kg sulpiride in the two-compartment exploratory test with no effect on 2.5 mg/kg diazepam. The data show that buspirone, in a narrow dose range, shows disinhibitory effects in experimental models of anxiety. Similar effects are shown by low doses of haloperidol and sulpiride. It is suggested that buspirone and sulpiride produce these disinhibitory effects by blocking particular dopamine receptors in the brain, possibly those located in the nerve terminals, but it is likely that other mechanisms, particularly serotonin, are involved in the effects of buspirone in anxious states.

Animals↗

PubMed1980

Reinterpretation of the effect of haloperidol and ethanol on insulin secretion.

We were unable to confirm the report of haloperidol induced dose-dependent inhibition of insulin and glucagon release from the isolated canine pancreas. The possibility that the inhibition was caused by ethanol, previously used as the solvent for haloperidol, was tested. Infusion of ethanol at increasing concentrations (15.8 to 252 mmol/l) caused a progressive inhibition of insulin (-17 +/- 1 to -69 +/- 2%) and glucagon (-13 +/- 3 to -67 +/- 3%) secretion, using a perfusate containing 200 mg/dl glucose and 2.65 mmol/l calcium. Haloperidol (5 to 20 mumol/l) dissolved in ethanol (252 mmol/l) did not augment the inhibitory effects of ethanol. At a low calcium concentration (1.3 mmol/l) ethanol further inhibited insulin secretion (-83 +/- 2%) with no additional inhibition by 20 mumol/l haloperidol (-80 +/- 3%). At a high calcium concentration (8.8 mmol/l) the inhibitory effect of ethanol on insulin or glucagon secretions was diminished and variable. This strongly suggests that the inhibition of insulin and glucagon secretion previously attributed to haloperidol was caused by the ethanol solvent.

Animals↗

PubMed1975

A comparative study of haloperidol and chlorpromazine in terms of clinical effects and therapeutic reversal with benztropine in schizophrenia. Theoretical implications for potency differences among neuroleptics.

In a double-blind, cross-over study, the comparative therapeutic effects of 6-week courses of two prototypic neuroleptics--haloperidol and chlorpromazine--and the reversal of those effects with benztropine were investigated in a group of 18 schizophrenics. Periodic measurements were made for 32 dimensions of psychopathology, social participation, span of attention, sleeplessness, pulse rate and neurological side effects. The results showed that haloperidol was generally a more effective drug over the period studied. This was particularly apparent in terms of social and emotional responsiveness, communicativeness and cognitive processes. The only superiority of chlorpromazine seemed to be that patients felt less dysphoric on it than they did on haloperidol. Haloperidol also proved to be more rapid in its action. The data failed to support the clinical validity of the distinction often made between "sedative" and "activating" neuroleptics. Consistent with previous reports, benztropine had the effect of diminishing therapeutic response to both neuroleptics. However, haloperidol again proved less susceptible to this effect. The slowness and lesser therapeutic efficiency of chlorpromazine and its greater susceptibility to benztropine reversal were all considered to be due to its built-in anti-cholinergic properties acting in opposition to its antipsychotic activity. The low potency of chlorpromazine-like drugs was attributed to their inherent anticholinergic characteristics. It was suggested that one of the factors determining potency difference among neuroleptics may be the degree of built-in anticholinergic activity.

Adult↗

PubMed1975

Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine, haloperidol, loxapine and chlorpromazine.

The present study has compared the abilities of clozapine, haloperidol, chlorpromazine and loxapine to induce dopamine (DA)-receptor hypersensitivity in rats, as measured by the apomorphine response after withdrawal of the antipsychotic drugs. Haloperidose during 1-2 weeks after withdrawal. Clozapine, given prior to apomorphine, reduced the responses of the haloperidol and loxapine groups to the control level. The effects of haloperidol and clozapine were quantified in rats with unilateral striatal lesions. Biochemical investigations showed that tolerance developed to the increase in striatal homovanillic acid (HVA) after chronic treatment with haloperidol, chlorpromazine and loxapine, whereas clozapine (20 mg/kg p.o.) failed to affect the HVA content, and no tolerance developed to the increase seen at 80 mg/kg. Cross-tolerance to the rise in HVA was seen with haloperidol, chlorpromazine and loxapine, but chronicc pretreatment with clozapine failed to affect the rise in HVA induced by a singel dose of the former compounds.

Animals↗

PubMed1978

A putative multipartite model of haloperidol interaction in apomorphine-disturbed behavior of the dog.

The interaction between various doses of apomorphine and haloperidol on intracranial self-stimulation in the dog was studied using a pradigm in which reinforcing brain-stimulation was controlled by a discriminative auditory stimulus. Reinforced lever-pressing was decreased by low doses of apomorphine and completely suppressed by stereotypogenic doses. At various doses of apomorphine, low doses of haloperidol either increased response inhibition by enhancing stereotypy, or increased lever pressing by reducing stereotypy while concomitantly increasing the number of nonreinforced responses. Intermediate to relatively high doses of haloperidol antagonized stereotypy and the response inhibition produced by apomorphine. High doses of haloperidol antagonized stereotypy but also suppressed self-stimulation. Thus, haloperidol is not only able to restore performance capability, but also disturbed reinforcing and discriminative stimulus control.

Animals↗

PubMed1985

Dopamine-sensitive alternation and collateral behaviour in a Y-maze: effects of d-amphetamine and haloperidol.

The degree of alternation of arm choice in a Y-maze was examined on 15-min tests over 4 days in rats treated (IP) with saline, amphetamine (0.5 or 2.0 mg/kg) or pretreated with haloperidol (0.08 mg/kg) in each condition prior to test. On day 1 amphetamine-treated animals chose arms at random, but from day 2-4 those receiving the higher dose perseverated their choice. Controls maintained alternation. These effects could be prevented by haloperidol pretreatment. Amphetamine treatment increased the frequency of rearing at the middle, choice-point of the maze more than at the end of an arm. The increase at the mid-point was suppressed by haloperidol pretreatment from day 1 and at the end of an arm from day 2. Amphetamine induced an increase in head-turning/"looking" that was suppressed by haloperidol from day 2. The effect of haloperidol in increasing the duration of an item of looking or rearing at the end of an arm also started later in testing. Two effects are postulated to have occurred: (i) a conflict on day 1 between novelty-controlled sensory or attentional effects that leads to an alternation of arm choice and amphetamine-induced dopaminergic activity that facilitates an alternation of behavioural responses. The result was random choice and increased rearing at the choice point. (ii) On days 2-4 the drug-induced effects on switching motor responses came to control behaviour.

Animals↗

PubMed1984

Treatment schedule as a determinant of the development of tolerance to haloperidol.

Three groups of rats received haloperidol 0.5 mg/kg IP twice daily for 20 days, twice daily for 10 days, or every other day for 40 days. The rats in control groups received saline injections according to the same schedules as the experimental groups. During the chronic treatments, spontaneous motor activity was measured as an indicator of behavioral tolerance, and at the completion of treatments, limbic and striatal homovanillic acid (HVA) levels were determined in order to provide a biochemical indication of tolerance. Both of the haloperidol groups on twice-daily injection schedules exhibited a trend towards recovery of spontaneous motor activity during treatment, indicative of behavioral tolerance, as well as reduced HVA levels indicative of near complete biochemical tolerance. The group receiving haloperidol every other day exhibited a trend toward behavioral intolerance to haloperidol, along with elevated HVA levels that indicated a complete absence of tolerance. The suggested importance of treatment schedule rather than cumulative drug dosage in the development of tolerance to haloperidol may have significance to long-term side effects of chronic neuroleptic treatment such as tardive dyskinesia and clinical issues such as drug holidays.

Animals↗

PubMed1983

Effect of haloperidol on glutamate decarboxylase activity in discrete brain areas of the rat.

Using freeze-dried samples of rat brain, the effect of haloperidol on glutamate decarboxylase (GAD) activity without exogenously added pyridoxal-5'-phosphate (PLP) was studied in discrete brain nuclei and areas. Repeated injections of haloperidol produced significant changes in GAD activity in the dorsal part of the caudate nucleus, entopeduncular nucleus, pars reticulata of the substantia nigra, lateral hypothalamic area, and dorsomedial hypothalamic nucleus. A reduction of GAD activity after haloperidol was observed in the entopeduncular nucleus and pars reticulata of the substantia nigra. This finding demonstrates biochemically that haloperidol-induced extrapyramidal behavior may be involved in the reduction of GABAergic transmission in the entopeduncular nucleus and pars reticulata of the substantia nigra. A decrease in GAD activity in the lateral hypothalamic area indicates that interaction between GABAergic neurons as well as dopaminergic neurons may be involved in the haloperidol-induced behavioral changes. In addition, close interaction between GABAergic and dopaminergic systems in the dorsomedial hypothalamic nucleus and dorsal part to the caudate nucleus was demonstrated.

Animals↗