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PubMed1985

Chronic haloperidol during development attenuates dopamine autoreceptor function in striatal and mesolimbic brain regions of young and older adult rats.

The effects of chronic haloperidol administration during the prenatal and preweanling periods on dopamine autoreceptor function were examined in striatum, olfactory tubercles, and nucleus accumbens of young (2-3 month) and older (12-13 month) adult rats. In striatum of young and older adult rats that had been chronically treated with haloperidol early in life, as well as in the nucleus accumbens of older adults receiving early chronic haloperidol, gamma-butyrolactone (GBL) did not induce significant increases in dopamine levels. In olfactory tubercles of young adults that had received early chronic treatment with haloperidol, apomorphine pretreatment failed to reverse the observed GBL-induced increase in dopamine levels. Thus, dopamine autoreceptor function appears to be attenuated in rats chronically treated with haloperidol during early development, in contrast to reports of autoreceptor supersensitivity following neuroleptic treatment in adulthood.

4-Butyrolactone↗

PubMed1981

Serum and CSF levels of haloperidol by radioimmunoassay and radioreceptor assay during high-dose therapy of resistant schizophrenic patients.

Serum and cerebrospinal fluid (CSF) levels of haloperidol were measured in 12 chronic neuroleptic-nonresponsive schizophrenic patients after 1 month on 60 mg haloperidol daily and then again after 1 month on 120 mg haloperidol daily. Serum haloperidol and CSF haloperidol rose with increasing dose. Serum and CSF levels were significantly correlated. No clinical improvement was achieved despite the high serum and CSF drug levels.

Drug Resistance↗

PubMed1979

Interaction of apomorphine and haloperidol: effects on locomotion and other behaviour in the marmoset.

The behavioural effects of increasing doses of apomorphine and haloperidol were observed in a group of six marmosets. Behaviour was classified quantitatively into categories: Locomotion, inactivity, checking (small head movements), social interaction and purposeful activities. Statistical analysis revealed that apomorphine had a stimulant effect on checking and locomotion which could be antagonized by haloperidol. Activities and social contact were severly reduced by both apomorphine and haloperidol. Inactivity was increased by the lowest dose of apomorphine in otherwise untreated animals. It is suggested that haloperidol antagonizes the stimulant effects of apomorphine but is synergistic to its suppressant effects, and that the low dose effect of apomorphine on inactivity is mediated by a mechanism which may be different from that acted upon by haloperidol.

Animals↗

PubMed1980

Spontaneous activity and apomorphine stereotypy during and after withdrawal from 3 1/2 months continuous administration of haloperidol: some methodological issues.

Rats were treated continuously with haloperidol (1.5 mg/kg/day in drinking water) for 3 1/2 months. Prior to withdrawal of neuroleptic both spontaneous activity and stereotypy responses to a low dose of apomorphine (0.15 mg/kg SC) were significantly reduced. Thus these indices of dopamine receptor blockade did not show tolerance or adaptation. When these measures were repeated shortly after haloperidol withdrawal stereotypy responses of the control group were indistinguishable from their responses on initial testing while haloperidol-withdrawn animals showed substantially more intense responsivity than on their initial assessment; the stereotypy responses of haloperidol-withdrawn animals were indistinguishable from parallel control values at 10--20 min after apomorphine challenge but were significantly above control values at 30--40 min after challenge. Control animals showed habituation of locomotor activity in the motility monitor when measures on the first and second assessments were compared while haloperidol animals showed indistinguishable activities on each assessment. Such methodological epiphenomena may influence the interpretation of studies on the functional sequelae of prolonged neuroleptic treatment and its subsequent withdrawal in the rat.

Animals↗

PubMed1989

Differential tolerance to cataleptic effects of SCH 23390 and haloperidol after repeated administration.

The development of tolerance to the cataleptic effect of the selective D-1 antagonist SCH 23390 (0.5 mg/kg/day SC or 0.1 mg/kg/day SC) and haloperidol (1 mg/kg/day SC) during repeated administration was investigated. Catalepsy in rats was measured using the horizontal bar method. SCH 23390 induced a dose-related cataleptic effect of short duration, whereas the cataleptic effect of haloperidol appeared more slowly and lasted longer. Marked tolerance to the cataleptic effect of haloperidol developed already 6 days from the beginning of the treatment. The cataleptic effect of the higher dose regimen of SCH 23390 was also significantly reduced after 6 days' treatment. However, unlike haloperidol, this subacute tolerance was gradually reversed and was no longer significant after 12 and 18 days. The cataleptic response to the lower dose of SCH 23390 (0.1 mg/kg/day) was not significantly altered during the treatment and no initial catalepsy tolerance was observed with this dose regimen. These results suggest that different mechanisms are involved in the expression of cataleptic behaviour during chronic treatment with SCH 23390 and classical antipsychotics, such as haloperidol.

Animals↗

PubMed1977

Catecholamine synthesis in rat brain after axotomy: interaction between apomorphine and haloperidol.

Axotomy of the ascending monoaminergic fibers by means of a complete cerebral hemitransection stimulated the formation of dopa during 30 min after inhibition of the aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCl, 100 mg/kg i.p., in c. striatum and the dopamine-rich part of the limbic system. Apomorphine, 0.5 mg/kg i.p., antagonized the accumulation of dopa not only on the intact but also on the lesioned side. Haloperidol, 2 mg/kg i.p., stimulated dopa accumulation on the intact side but could not further stimulate the increase in dopa caused by transection. When both drugs were given together, the inhibitory effect of apomorphine was fully counteracted by haloperidol on both sides. In the predominantly noradrenaline-innervated occipito-temporal cortex dopa formation was slightly higher on the lesioned than on the intact side and was not markedly influenced by apomorphine. In the rest of the hemispheres the apomorphine-induced decrease in dopa formation was more pronounced on the intact than on the lesioned side and was fully antagonized by haloperidol. The dopamine concentration was slightly higher in the lesioned c. striatum as compared to the intact side irrespective of the drugs administered. In c. striatum and the limbic system haloperidol caused a decrease in dopamine on the intact side which was not antagonized by additional treatment with apomorphine. Hemitransection caused a decrease in noradrenaline especially in the hemisphere portion. Neither apomorphine nor haloperidol or both drugs in combination changed the latter effect. In general, the tyrosine concentration tended to be higher on the lesioned than on the intact side in all brain structures investigated. The data support the view that a local receptor-mediated feedback mechanism exists which is controlling dopamine synthesis even in the absence of impulse flow.

Animals↗

PubMed1986

Diazepam attenuates the antagonism of haloperidol against apomorphine-induced stereotypic behavior after subchronic but not acute treatment in rats.

Apomorphine-induced stereotypic behavior was investigated in rats treated with diazepam or haloperidol and with the combination of both drugs in a one day trial or subchronically. The drugs were administered via the drinking water. Diazepam dose-dependently reduced apomorphine stereotypies after the subchronic (6 days) but not after the acute treatment. Haloperidol suppressed apomorphine-induced stereotypic behavior dose-dependently after acute as well as after subchronic administration apparently without the development of tolerance. This discrepancy to other studies may be explained by the concomitant increase in maximum number of D2-receptors in the striatum. The apomorphine antagonistic effect of haloperidol was attenuated when the neuroleptic was administered subchronically in combination with the benzodiazepine. This finding was unexpected since both drugs reduced apomorphine-induced stereotypic behavior when administered alone. The further increase in maximum number of D2-receptors due to combined treatment with low doses of diazepam, suggesting a sort of "over adaptation", possibly explains the haloperidol-antagonistic action of diazepam in the behavioral experiments. Binding studies on dopamine (D1), 5-hydroxytryptamine (5-HT2) and benzodiazepine receptors revealed that modification of the apomorphine-induced stereotypies by the combined treatment with haloperidol and diazepam cannot be explained by interactions of the drugs at the level of the D1, 5-HT2 or benzodiazepine-receptors.

Animals↗

PubMed1984

Dopamine and serotonin metabolites in rat cerebroventricular fluid following withdrawal of haloperidol or electroshock treatment.

Levels of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and of the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined in the CSF of rats at various times after repeated electroshock treatment (EST) or chronic administration of haloperidol. The acidic metabolites were analyzed in 25 microliter CSF using HPLC with an electrochemical detector. A significant decrease in the CSF levels of DOPAC and HVA was found 4 days after the last administration of chronic haloperidol, EST, or both. The decrease in the level of the dopamine metabolites indicated a slower dopamine turnover, which might have resulted from hypersensitivity of presynaptic dopamine receptors after these treatments. Rats treated with haloperidol also showed an increase in 5-HIAA levels, possibly due to enhanced serotonin turnover. The 5-HIAA increase following haloperidol was prevented by a concurrent administration of EST, suggesting attenuation by EST of the haloperidol-induced enhancement of serotonin turnover.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1989

Human scalp hair as evidence of individual dosage history of haloperidol: method and retrospective study.

Hair samples and morning pre-dose plasma were collected from 40 patients who had received fixed daily doses of haloperidol for more than four months and whose compliance was good. After washing, 1 to 2 cm-long portions nearest to the roots of 2 to 3 strands of hair were completely dissolved in 2.5N NaOH. Haloperidol in that sample or alkalinised plasma was extracted and measured by RIA. Haloperidol concentrations in hair correlated well both with the trough concentration in plasma at steady-state (r = 0.772, n = 39) and with the daily dose (r = 0.555, n = 40). Another keratinized tissue, nail, was also collected from 20 of the 40 patients and the haloperidol level was compared with that in hair. The former was only about 4.3% of the latter and was significantly correlated only with the daily dose (r = 0.525, n = 20). Hair from 10 other patients in whom the dosage of haloperidol had been changed within a few months prior to sampling the hair was cut into 0.5 or 1 cm-long portions from the roots and the drug concentration in each portion was measured. If hairs were assumed to grow at 1 cm/month, a history of individual dosage could be deduced in 9 of the 10 patients from the distribution of drug level along the length of the hair. The results suggest that human scalp hair could serve as a useful tool for monitoring individual dosage history over several months, or in demonstrating exposure or non-exposure of a patient to a drug.

Adult↗

PubMed1987

Haloperidol-induced emotional defecation: a possible model for neuroleptic anxiety syndrome.

The neuroleptic haloperidol was found to produce increased defecation in laboratory rats when tested in well habituated environments. It is well known that haloperidol induces catalepsy through antagonism of striatal dopaminergic receptor mechanisms. When another cataleptic agent, morphine, was tested, no significant increases in defectation were detected. Another study focused on the possible role of peripheral dopamine receptor sites within the gastrointestinal tract on neuroleptic-induced defecation. When the peripheral dopamine receptor antagonist domperidone was tested, no significant differences in fecal elimination were recorded. Thus, it appeared that the cataleptic state per se, or the peripheral effects of haloperidol did not seem to be responsible for the increased defecation. Defection is often used as an index of emotionality. The fact that this measure increased following administration of a major tranquilizer suggested the need to study more directly the relationship of this phenomenon of defecation with the affective state of the animal. In a control study it was found that the antianxiety agent benzodiazepam did not by itself influence defecation. However, those animals which were pre-injected with diazepam followed by haloperidol did not show increased defecation. Thus under certain circumstances, normal rats given haloperidol show "emotional defecation" which seems to reflect increased anxiety. This finding may serve as a basis for the development of an animal model for some of the atypical side effects of major tranquilizers, such as akathisia, dysphoria, and neuroleptic anxiety syndrome.

Animals↗

PubMed1976

Selective neuroendocrine effects of low-dose haloperidol in normal adult men.

The neuroendocrine effects of haloperidol, usually reported as side effects of this drug when given in antipsychotic doses, have not been systematically investigated. In the present study five normal adult men were administered saline and two doses of of haloperidol (0.25 mg, 0.5 mg) intramuscularly in a double-blind randomized block design. The anterior pituitary hormones GH, LH, FSH, and PRL were measured in blood samples taken every 20 min for several hours thereafter. The low doses of haloperidol used have been shown by others to alter the human EEG; in our subjects these doses produced no objective or subjective clinical effects. There were no drug related changes in GH, LH, or FSH. PRL, however, showed a prompt, statistically significant, dose-related increase in plasma levels, with a return to baseline with 5 h. Haloperidol has strong dopamine-blocking effects, and the hypothalamic inhibitory mechanism for PRL release is believed to be dopamine-mediated. The results of this study suggest that haloperidol may have utility in low doses primarily for its hypothalamic neuroendocrine effects, and that dose-related PRL release may be a useful paradigm for comparing dopamine-blocking antipsychotic agents in humans.

Adult↗

PubMed1991

Subchronic buspirone, mesulergine, and ICS 205-930 lack effects on D1 and D2 dopamine binding in the rat striatum during chronic haloperidol treatment.

We administered the serotonergic agents buspirone, mesulergine and ICS 205-930 during the last two weeks of a 4-week oral haloperidol chronic treatment regimen and determined dopamine receptor binding and apomorphine-induced stereotypic activity after a drug washout period. D1 receptor binding was not affected by any treatment. Chronic haloperidol treatment produced a significant increase in the density of D2 receptors for all groups, including the groups that were administered combination treatment of haloperidol and serotonergic compounds. Apomorphine-induced stereotypic activity measured 4 days after the last haloperidol treatment was elevated to the same extent for all haloperidol treated groups. Contrary to a previous report, subchronic treatment with buspirone did not significantly reverse neuroleptic-induced D2 receptor up-regulation.

Animals↗

PubMed1990

Changes in locomotion and dopamine neurotransmission following amphetamine, haloperidol, and exposure to novel environmental stimuli.

Locomotor behavior and dopamine (DA) neurotransmission were assessed in rats exposed to either a novel or familiar stimulus environment while under the influence of amphetamine, haloperidol or saline. The behavioral results indicated that, as expected, amphetamine increased horizontal locomotor activity in a dose-dependent manner. Exposure to novelty also increased horizontal activity, and this behavioral effect was disrupted by both amphetamine and haloperidol. Regardless of whether the animals were exposed to the novel or familiar stimulus environment, amphetamine increased DA synthesis in the nigrostriatal system, but not in the mesolimbic system, whereas haloperidol increased DA synthesis in both the nigrostriatal and mesolimbic systems. Amphetamine also decreased DA metabolism and haloperidol increased DA metabolism in both the nigrostriatal and mesolimbic systems. In contrast, exposure to novelty alone was without effect on DA synthesis or metabolism in any region examined, suggesting that novelty-induced hyperactivity and amphetamine-induced hyperactivity involve different neurochemical mechanisms. However, exposure to novelty while under the influence of haloperidol produced a significant increase in DA metabolism in both the nigrostriatal and mesolimbic systems. These latter results suggest that exposure to novelty may produce a measurable activation of DA systems when the autoreceptors involved in the negative feedback loop are blocked.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Effects of haloperidol on the multitrial partial reinforcement extinction effect (PREE): evidence for neuroleptic drug action on nonreinforcement but not on reinforcement.

Two experiments investigated the effects of haloperidol (0.1 mg/kg) on the partial reinforcement extinction effect (PREE). In experiment 1 two groups of rats were trained to run in a straight alley using six trials/day with an intertrial interval (ITI) of 5-8 min. 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 was administered in a 2 x 2 design, i.e., drug-no drug in acquisition and drug-no drug in extinction. In experiment 2 two groups of rats were trained to press a lever in an operant chamber using a discrete trial procedure of ten trials/day with an ITI of 60 s. The CRF group was rewarded on each trial and the PRF group was rewarded on a quasi-random 50% schedule. Haloperidol was administered for 22 days prior to the start of the PREE procedure as well as throughout acquisition and extinction. The PREE, i.e., increased resistance to extinction of PRF as compared to CRF animals, was obtained in both experiments in all drug conditions. In both experiments haloperidol increased the rate of extinction. Experiment 1 revealed that this effect was entirely due to the administration of the drug in extinction, independently of the drug condition in acquisition. In contrast to previous results in a one trial/day procedure, the administration of haloperidol to CRF animals did not increase resistance to extinction, failing to support the notion that neuroleptics attenuate the rewarding properties of reinforcement.

Animals↗

PubMed1992

Haloperidol reduces ethanol-induced motor activity stimulation but not conditioned place preference.

This experiment examined the impact of a dopamine receptor blocker on ethanol's rewarding effect in a place conditioning paradigm. DBA/2J mice received four pairings of a tactile stimulus with ethanol (2 g/kg, IP), haloperidol (0.1 mg/kg, IP)+ethanol, or haloperidol alone. A different stimulus was paired with saline. Ethanol produced increases in locomotor activity that were reduced by haloperidol. However, conditioned preference for the ethanol-paired stimulus was not affected by haloperidol. Haloperidol alone decreased locomotor activity during conditioning and produced a place aversion. These results indicate a dissociation of ethanol's activating and rewarding effects. Moreover, they suggest that ethanol's ability to induce conditioned place preference is mediated by nondopaminergic mechanisms.

Animals↗

PubMed1996

Behavioral effects of sertindole, risperidone, clozapine and haloperidol in Cebus monkeys.

Extrapyramidal side effects (EPS) are major limitations to neuroleptic treatment of psychoses. To evaluate further the behavioral characteristics of the novel antipsychotic agents, a wide range of single intramuscular doses of sertindole (0.1-2.5 mg/kg IM), risperidone (0.01-0.25 mg/kg IM), clozapine (1.0-25.0 mg/kg IM), and haloperidol (0.01-0.25 mg/kg IM) were blindly evaluated at weekly intervals in Cebus monkeys previously sensitized to neuroleptics. All drugs except clozapine produced dystonia and parkinsonian symptoms, but haloperidol and risperidone were 50-100 times more potent than sertindole in producing EPS. Sertindole, risperidone and haloperidol had no significant sedative effects, whereas clozapine produced dose related sedation. Risperidone, clozapine and haloperidol but not sertindole decreased locomotor activity. Sertindole, risperidone and clozapine had a calming effect at doses below the EPS threshold, unlike haloperidol. Sertindole has many behavioral effects in nonhuman primates that are similar to those seen with the new antipsychotics, risperidone and clozapine, which suggests a favorable antipsychotic benefit/risk ratio in the clinic, especially regarding EPS.

Animals↗

PubMed1995

Inhibition of monoamine oxidases by haloperidol and its metabolites: pharmacological implications for the chemotherapy of schizophrenia.

The effect of haloperidol and its metabolites on human platelet monoamine oxidase B (MAO-B) and human placenta monoamine oxidase A (MAO-A) in vitro has been investigated. We found that 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HP+), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine (HTP) and 4-chlorophenyl-1,2,3,6-tetrahydropyridine (CPTP) are potent inhibitors of MAO. HP+ appeared to be a reversible, uncompetitive and selective MAO-B inhibitor with a Ki of 0.83 microM. HTP was found to be an irreversible, uncompetitive and selective MAO-B inhibitor (Ki of 1.84 microM). CPTP inhibits both MAO-A and MAO-B. Some other haloperidol metabolites, i.e. 4-(4-chlorophenyl)-4-hydroxypyridine (CPHP), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine N-oxide (HTPNO) and reduced haloperidol (RHAL), do not inhibit MAO to any appreciable degree at concentrations up to 100 microM. The results suggest that haloperidol metabolites may contribute to the reduction of platelet MAO-B activity in schizophrenic patients undergoing neuroleptic chemotherapy. An examination of the literature reveals that schizophrenic patients with low platelet MAO activity exhibit a strong association with the use of haloperidol. Other possible pharmacological implications of the inhibition of MAO activity are discussed.

Blood Platelets↗

PubMed1995

Contrasting effects on methamphetamine sensitization of ceruletide, a cholecystokinin-like decapeptide, and haloperidol.

Ceruletide, a cholecystokinin-like decapeptide, and haloperidol show neuroleptic actions through inhibition of dopamine release and blockade of dopamine receptors, respectively. In this study, the effects of both drugs on methamphetamine sensitization were assessed by means of ambulation in mice. The enhancement in ambulation increase caused by five repeated administrations of methamphetamine (2 mg/kg, SC) at 3- to 4-day intervals was dose-dependently reduced when it was administered simultaneously with ceruletide (0.01-0.1 mg/kg, SC) or haloperidol (0.03-0.3 mg/kg, SC). However, only haloperidol could inhibit the induction of methamphetamine sensitization as assessed by challenge with methamphetamine alone. Post-treatment with ceruletide (0.03 mg/kg) 3 h after each methamphetamine accelerated, whereas such post-treatment with ceruletide (0.1 mg/kg) or haloperidol (0.03-0.3 mg/kg) delayed, the induction of methamphetamine sensitization. On the other hand, mice given five pretreatments with ceruletide (0.01-0.1 mg/kg) or haloperidol (0.03-0.3 mg/kg) at 3- to 4-day intervals did not exhibit any significant change in the sensitivity to methamphetamine. The present results suggest that, in contrast to the dose-dependent inhibition of methamphetamine sensitization in the simultaneous administration and post-treatment schedules, although both drugs can antagonize the acute stimulant effect of methamphetamine.

Animals↗