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PubMed2004

Effects of ethanol and haloperidol on plasma levels of hepatic enzymes, lipid profile, and apolipoprotein in rats.

This work studied the effects of ethanol in the absence and presence of haloperidol under two experimental conditions. In protocol 1, rats were treated daily with ethanol (4 g/kg, p.o.) for 7 days, and received only haloperidol (1 mg/kg, i.p.) from the 8th day to the 14th day. In protocol 2, animals received ethanol, and the treatment continued with ethanol and haloperidol from the 8th day to the 14th day. Results show increases in alanine transaminase (ALT; 48% and 55%) and aspartate transaminase (AST; 32% and 22%) levels after ethanol or haloperidol (14 days) treatments, as compared with controls. Apolipoprotein A-1 (APO A1) levels were increased by haloperidol, after 7- (148%) but not after 14-day treatments, as compared with controls. Levels of lipoprotein (high-density lipoprotein (HDL-C)) tended to be increased only by ethanol treatment for 14 days. ALT (80%) and AST (43%) levels were increased in the haloperidol plus ethanol group (protocol 2), as compared with controls. However, an increase in APO A1 levels was observed in the haloperidol group pretreated with ethanol (protocol 1), as compared with controls and ethanol 7-day treatments. Triglyceride (TG) levels were increased in the combination of ethanol and haloperidol in protocol 1 (234%) and 2 (106%), as compared with controls. Except for a small decrease in haloperidol groups, with or without ethanol, as related to ethanol alone, no other effect was observed in HDL-C levels. In conclusion, we showed that haloperidol might be effective in moderating lipid alterations caused by chronic alcohol intake.

Alanine Transaminase↗
PubMed1998

A randomized, placebo-controlled dose-comparison trial of haloperidol for psychosis and disruptive behaviors in Alzheimer's disease.

OBJECTIVE: The goal of this study was to compare the efficacy and side effects of two doses of haloperidol and placebo in the treatment of psychosis and disruptive behaviors in patients with Alzheimer's disease. METHOD: In a 6-week random-assignment, double-blind, placebo-controlled trial (phase A), haloperidol, 2-3 mg/day (standard dose), and haloperidol, 0.50-0.75 mg/day (low dose), were compared in 71 outpatients with Alzheimer's disease. For the subsequent 6-week double-blind crossover phase (phase B), patients taking standard- or low-dose haloperidol were switched to placebo, and patients taking placebo were randomly assigned to standard- or low-dose haloperidol. RESULTS: For the 60 patients who completed phase A, standard-dose haloperidol was efficacious and superior to both low-dose haloperidol and placebo for scores on the Brief Psychiatric Rating Scale psychosis factor and on psychomotor agitation. Response rates according to three sets of criteria were greater with the standard dose (55%-60%) than the low dose (25%-35%) and placebo (25%-30%). The advantage of standard dose over low dose was replicated in phase B. In phase A, extrapyramidal signs tended to be greater with the standard dose than in the other two conditions, primarily because of a subgroup (20%) who developed moderate to severe signs. Low-dose haloperidol did not differ from placebo on any measure of efficacy or side effects. CONCLUSIONS: The results indicated a favorable therapeutic profile for haloperidol in doses of 2-3 mg/day, although a subgroup developed moderate to severe extrapyramidal signs. A starting dose of 1 mg/day with gradual, upward dose titration is recommended. The narrow therapeutic window observed with haloperidol may also apply to other neuroleptics used in Alzheimer's disease patients with psychosis and disruptive behaviors.

Aged↗
PubMed1986

[Studies on the diuretic effect of haloperidol in adult rats].

An increase in urinary flow has been observed in rats during cataleptic response to haloperidol. The present experiment was carried out to study the mechanism of haloperidol-induced diuresis. Wistar-Imamichi adult female rats were injected i.p. with haloperidol in a dose of 0.1, 1 or 10 mg/kg, and the time course of changes in urine volume was observed. The dose-dependent diuretic effect of 1 or 10 mg/kg haloperidol was significant from 4 hr afterward, and the haloperidol-induced diuresis was prevented by pretreatment with phenoxybenzamine, prazosin or yohimbine. Chlorpromazine but not spiperone and pimozide induced a significant increase in urine volume, though the effect of chlorpromazine was less marked as compared with that of haloperidol. Clonidine in a dose of 0.125-1.0 mg/kg enhanced urine flow markedly from 30 min, and the same alpha-adrenergic blockers were also effective in blocking the diuretic effect of clonidine. Urinary osmolarity in 1 mg/kg haloperidol- and 0.125 mg/kg clonidine-treated rats decreased significantly, whereas only clonidine stimulated urinary Na and K excretion. Plasma osmolarity and negative free water clearance did not change in both haloperidol- and clonidine-treated rats. The present results suggest that the haloperidol-induced diuretic effect could be due to the central alpha-adrenoceptor blocking action of haloperidol.

Animals↗
PubMed1982

Sex difference in the development of hypersensitivity or tolerance to haloperidol in the rat.

Sex difference in the cataleptic response to continuous or intermittent administration of haloperidol (1 mg/kg, i.p.) was examined in the rat. Weekly administration of haloperidol induced a hypersensitivity to haloperidol itself to a greater extent in adult female rats as compared to adult males. Five daily injection of haloperidol induced a marked tolerance to haloperidol in adult female rats but not in males. Ovariectomy in adult rats failed to alter the development of hypersensitivity or tolerance to haloperidol. Orchiectomy in adult rats resulted in the development of a hypersensitivity to haloperidol during the weekly administration and a tolerance during daily injection of haloperidol. In immature female rats, weekly administration began at 3 weeks of age induced a marked increase in the intensity of haloperidol-induced catalepsy at 7 weeks of age. Daily injection of haloperidol in 3-week-old rats did not show any significant sex difference. These findings suggest that exposure to sex hormones probably during the time of puberty onset, results in a modification of the activity of dopaminergic and/or related neurons responsible for cataleptic behavior to female and male types. Female sex hormones appear to induce a persistent modification of the dopaminergic system at a certain critical period during the maturation.

Animals↗
PubMed1999

Clinical and economic outcomes of olanzapine compared with haloperidol for schizophrenia. Results from a randomised clinical trial.

OBJECTIVE: The purpose of this study was to compare, from the payor perspective, the clinical and economic outcomes of olanzapine to those of haloperidol for the treatment of schizophrenia. DESIGN AND SETTING: Clinical, quality-of-life and resource utilisation data were prospectively collected for US-residing patients with schizophrenia who were participating in a multicentre, randomised, double-blind clinical trial comparing olanzapine and haloperidol. Direct medical costs were estimated by assigning standardised prices (1995 values) to the resource utilisation data. PATIENTS AND PARTICIPANTS: 817 patients with schizophrenia who had a baseline Brief Psychiatric Rating Scale score (BPRS) > or = 18 (items scored 0 to 6) and/or were no longer tolerating current antipsychotic therapy. INTERVENTIONS: Olanzapine 5 to 20 mg/day (n = 551) or haloperidol 5 to 20 mg/day (n = 266) for 6 weeks. Patients showing a predefined level of clinical response entered a 46-week maintenance phase. MAIN OUTCOME MEASURES AND RESULTS: After acute treatment, BPRS-based clinical improvements were seen in 38 and 27% of olanzapine and haloperidol patients, respectively (p = 0.002). Clinically important improvements on the Quality of Life Scale were achieved during acute treatment in 33% of olanzapine recipients and 25% of haloperidol recipients (p = 0.094). Olanzapine treatment in the acute phase led to significantly lower inpatient ($US5125 vs $US5795, p = 0.038) and outpatient ($US663 vs $US692, p = 0.001) costs, resulting in a significant overall reduction in mean total medical costs of $US388 (p = 0.033). This significant reduction in total costs was found despite olanzapine mean medication costs being significantly greater than haloperidol medication costs ($US326 vs $US15, p < 0.001). No significant differences in clinical improvement were observed in the maintenance phase. Maintenance phase olanzapine mean total medical costs were $US636 lower than haloperidol total costs (p = 0.128). Although olanzapine medication costs were significantly higher than haloperidol medication costs ($US3461 vs $US95, p < 0.001), this difference was offset by significantly lower inpatient ($US8322 vs $US10,662, p = 0.044) and outpatient ($US3810 vs $US5473, p = 0.038) costs. CONCLUSIONS: In this study, olanzapine treatment was more effective than haloperidol in producing clinical response in the acute phase. In addition, olanzapine treatment led to reductions in inpatient and outpatient costs that more than offset olanzapine's higher medication costs relative to haloperidol.

Adult↗
PubMed2000

Behavioral evidence of depolarization block of dopamine neurons after chronic treatment with haloperidol and clozapine.

Electrophysiological studies have shown that chronic treatment with haloperidol causes depolarization block (DB) of dopamine cells in anesthetized and paralyzed rats. It has been proposed that the emergence of DB underlies the therapeutic and side effects of this drug. However, the relevance of DB to the clinical actions of haloperidol has been questioned on the grounds that chronic drug-induced DB has not yet been demonstrated in freely moving animals. In this study, responding for rewarding electrical brain stimulation was used to assess the occurrence of DB in rats chronically treated with haloperidol or clozapine. The time course of the effects of acute haloperidol (7.8-500 microg/kg) and clozapine (5-40 mg/kg) and of withdrawal from chronic drug treatment on reward and performance measures were also characterized. Haloperidol and clozapine dose-dependently attenuated reward and performance, haloperidol producing a predominant suppression of performance, and clozapine preferentially attenuating reward. Chronic (21 d) treatment with haloperidol (500 microg/kg) caused responding to cease in the six rats tested, and repeated injection with apomorphine restored the behavior in all of them; such an effect of apomorphine was observed in only two of six rats treated acutely with the same dose of haloperidol. Chronic treatment with clozapine (20 mg/kg) increased reward thresholds, an effect that was reversed by apomorphine in chronically, but not acutely, treated rats. The times at which chronic haloperidol-treated rats resumed responding was positively correlated with indices of behavioral supersensitivity after withdrawal, suggesting that the effect of apomorphine was not caused by direct stimulation of upregulated postsynaptic receptors. These findings constitute the first behavioral evidence of DB in unanesthetized, freely moving animals treated chronically with antipsychotics. They also demonstrate that the neural substrates mediating reward and performance are functionally independent and differentially sensitive to haloperidol and clozapine.

Animals↗
PubMed1991

Nicotine potentiates the behavioral effects of haloperidol.

Nicotine potentiates the catalepsy produced by haloperidol. Furthermore, nicotine as an adjunct to haloperidol produces a remarkable improvement in motor tics in Tourette's syndrome (TS) patients. The present experiments (1) compared the ability of nicotine to potentiate the catalepsy produced by haloperidol or the selective D1 dopamine receptor antagonist SCH 23390 and (2) examined the effects of various doses of nicotine (0.1, 0.2, or 0.3 mg/kg) on haloperidol-induced (0.1, 0.2, or 0.4 mg/kg) catalepsy and locomotor hypoactivity. In the first experiment, nicotine produced a five-fold increase in catalepsy following haloperidol but had no effect on the catalepsy produced by SCH 23390. In the second experiment, nicotine potentiated the cataleptic effects of both the 0.2 and 0.4 but not the 0.1 mg/kg dose of haloperidol. Haloperidol (0.1 and 0.4 mg/kg) also produced a dose-related decrease in locomotion that was significantly potentiated by nicotine (0.1 mg/kg). Nicotine alone did not produce catalepsy or any significant changes in locomotion. These results indicated that nicotine's potentiation of haloperidol-induced catalepsy is likely related to striatal D2 receptor mechanisms. Nicotine potentiated the locomotor effects of doses of haloperidol that were previously found to be subcataleptic, indicating that catalepsy testing may actually underestimate the behavioral interaction between haloperidol and nicotine. Nicotine may prove useful for treating neuroleptic responsive disorders such as TS, schizophrenia, and Huntington's disease.

Animals↗
PubMed1985

Effects of drugs on schedule-controlled behavior in rats during chronic haloperidol administration.

Dose-response curves for haloperidol, phencyclidine, morphine, meperidine and cimetidine were determined in rats trained under a multiple fixed-ratio 30, fixed-interval 5-min schedule of reinforcement. Haloperidol, morphine, meperidine and cimetidine decreased both fixed-ratio and fixed-interval rates of responding. Phencyclidine had a biphasic effect on overall response rates in both components: response rates increased and then decreased as the dose was increased. After these dose-response curve determinations, chronic daily treatment with haloperidol (0.3 mg/kg i.p.), after the behavioral session, was initiated. After 6 weeks of chronic treatment with haloperidol, the dose-response curves were redetermined for all the drugs, while haloperidol continued to be administered after the session. During chronic haloperidol administration, the dose-effect curves for haloperidol, morphine, meperidine and cimetidine were not modified consistently; however, chronic haloperidol treatment enhanced the effects of phencyclidine as shown by a shift of the dose-response curves to the left during both fixed-ratio and fixed-interval components. Four weeks after chronic haloperidol had been discontinued, low doses of haloperidol produced smaller rate-decreasing effects than they had previously.

Animals↗
PubMed1993

Haloperidol dosing requirements: the contribution of smoking and nonlinear pharmacokinetics.

Previous data suggest the possibility that haloperidol daily dosing requirements may be confounded by smoking and, at higher doses, capacity-limited metabolism. Forty hospitalized patients suffering from an acute exacerbation of schizophrenia were treated for 2 weeks with fixed oral doses of haloperidol ranging from 10 to 70 mg/day (0.13 to 0.95 mg/kg/day) that produced mean steady-state concentrations between 4.5 and 55.4 ng/ml. No significant differences between the smoking and nonsmoking groups were obvious for the factors of weight, age, sex, daily doses, steady-state clearance, and steady-state haloperidol concentrations in plasma at week 1, week 2, and their mean. The hypothesis that the relationship between haloperidol dose and steady-state haloperidol concentration in plasma was affected by patients' smoking status and metabolic capacity was tested by multiple linear regression analysis and initially rejected. The relationship of dose to haloperidol concentration was fitted as a linear function. To improve the curve fit, the haloperidol concentrations and doses were transformed to their natural logs and then the regression line was refitted. The multiple regression analysis was repeated with the data in their transformed state. It was found that, although smoking status and dose of the drug did not independently affect the average haloperidol concentration, together they interacted in such a way that individual haloperidol concentrations were dependent on the smoking status at specific doses. Thus, two haloperidol dosing equations were generated, one for smokers and one for nonsmokers.

Adult↗
PubMed1990

Unusual interactions between the neuroleptic haloperidol, and the dopamine D2 partial agonist, terguride.

Terguride is an ergoline derivative which has been reported to act as a partial agonist at central dopamine D2 receptors. Depending on the state of the receptor, terguride may resemble an agonist or an antagonist in its pharmacological effects. The present study investigated interactions of terguride with the dopamine D2 antagonist haloperidol in the rat. Terguride (0.025 mg/kg, i.p.) lowered, whereas haloperidol (0.025 mg/kg, s.c.) increased serum prolactin levels. When given together there was a tendency for prolactin to be lowered, i.e. terguride fully antagonized the action of haloperidol. Both terguride and haloperidol dose-dependently reduced locomotor activity, with terguride being at least 50 times more potent. However, in the presence of a subthreshold dose of haloperidol (0.1 mg/kg), terguride was effective in reducing locomotor activity. Terguride and haloperidol were equally potent in disrupting performance of lever pressing for food on a VI 120 sec schedule (ED(50) values 0.22 and 0.28 mg/kg, respectively). When given together, there was a statistically significant interaction; a terguride dose of 0.2 mg/kg lowered rates of lever pressing when given with vehicle or a low (0.03 mg/kg) haloperidol dose, but antagonized the effect of 0.3 mg/kg haloperidol. Terguride dose-dependently disrupted lever pressing for intracranial stimulation reward (ED(50) value approx. 0.3 mg/kg). Haloperidol (0.26 mg/kg) also disrupted lever pressing but the two drugs together showed no greater effect than haloperidol alone. These observations are discussed in the context of terguride's suggested partial agonistic properties.

Journal Article↗
PubMed1986

Conditional tolerance to haloperidol-induced catalepsy is not caused by striatal dopamine receptor supersensitivity.

The purpose of this study was to determine if non-pharmacological stimuli influence behavioural tolerance to haloperidol via striatal postsynaptic dopamine receptors. Rats received daily haloperidol and saline in two different environments for a period of 28 days. After this conditioning period half of the rats received haloperidol in the haloperidol-associated environment, whereas the other half received haloperidol in the saline-associated environment. All rats were tested for catalepsy and at the end of the last catalepsy test, striatal DOPAC, HVA and ACh were determined. Only the rats tested in the haloperidol-associated environment were behaviourally tolerant to haloperidol. In contrast, both groups were biochemically tolerant to haloperidol. These results indicate that environmental cue factors govern the development of behavioural tolerance to haloperidol, rather than biochemical factors (striatal DA super-sensitivity). In addition, these factors do not exert their influence on behavioural tolerance via striatal DA receptors.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1976

The demonstration of a change in adrenergic receptor sensitivity in the central nervous system of mice after withdrawal from long-term treatment with haloperidol.

Mice, administered haloperidol (3 mg/kg/d) in their drinking water for 21 days, displayed, 4 days after cessation of the haloperidol-treatment, marked locomotor stimulation to clonidine (100 or 500 mug/kg) which lasted for about 6 h. 25 mug clonidine/kg was inactive. Premedication with FLA-63 (25 mg/kg) blocked the difference in stimulation after clonidine between the haloperidol- and vehicle-treated animals, but locomotor activity was still present in both groups. Haloperidol-treated animals displayed a supersensitive response to dexamphetamine. The difference in stimulation produced by dexamphetamine in the two groups was completely blocked by phenoxybenzamine (2.5 mg/kg), phentolamine (10 mg/kg), which drugs did not, however, block the locomotor stimulation produced by dexamphetamine in vehicle-treated animals. Pimozide (3 mg/kg) blocked all locomotor stimulation produced by dexamphetamine in both vehicle- and haloperidol-treated groups, while 1 mg/kg completely blocked the dexamphetamine response in vehicle-treated animals but not in haloperidol-treated animals. FLA-63 (25 mg/kg) blocked the difference in response between the haloperidol- and vehicle-treated groups to dexamphetamine, but did not antagonise the stimulation in the vehicle-treated animals. The data suggest that long-term haloperidol treatment leads to the development of "supersensitive" adrenergic receptors in the central nervous system, which, appropriately stimulated, effect an increase in locomotor activity. Moreover, the results indicate that a large component of the supersensitive response to dexamphetamine observed after long-term haloperidol-treatment is due to adrenergic receptor supersensitivity. However, the dopamine receptor (which was shown to be supersensitive to apomorphine) is of fundamental importance because phenoxybenzamine and phentolamine, while blocking the supersensitive response to dexamphetamine, failed to block the response to dexamphetamine in vehicle-treated animals, which was, however, blocked by pimozide.

Adrenergic alpha-Antagonists↗
PubMed1984

Differential effects of continuous administration for 1 year of haloperidol or sulpiride on striatal dopamine function in the rat.

Administration of haloperidol (1.4-1.6 mg/kg/day) for up to 12 months or sulpiride (102-109 mg/kg/day) for between 6 and 12 months increased the frequency of purposeless chewing jaw movements in rats. N,n-propylnorapomorphine (NPA) (0.25-2.0 mg/kg SC) did not induce hypoactivity in haloperidol-treated rats at any time; sulpiride treatment for 9 and 12 months caused a reduction in the ability of NPA to induce hypoactivity. Haloperidol, but not sulpiride, treatment enduringly inhibited low dose apomorphine effects (0.125 mg/kg SC). After 12 months, stereotypy induced by high doses of apomorphine (0.5-1.0 mg/kg) was exaggerated in haloperidol-, but not sulpiride-treated rats. Bmax for specific striatal 3H-spiperone binding was increased by haloperidol, but not sulpiride, treatment throughout the study. Bmax for 3H-piflutixol binding was not altered by chronic haloperidol or sulpiride treatment. Striatal dopamine-stimulated adenylate cyclase activity was inhibited for the 1st month of haloperidol treatment, thereafter returning to control levels; dopamine stimulation was increased after 12 months of sulpiride treatment. Striatal acetylcholine content was increased after 3 and 12 months of treatment with haloperidol, but was not affected by sulpiride. Chronic administration of sulpiride does not induce identical changes in striatal dopamine function to those caused by haloperidol.

Acetylcholine↗
PubMed1984

Differential alterations in striatal dopamine receptor sensitivity induced by repeated administration of clinically equivalent doses of haloperidol, sulpiride or clozapine in rats.

Rats received therapeutically equivalent doses of either haloperidol (1.7-1.9 mg/kg/day), sulpiride (112-116 mg/kg/day) or clozapine 30-35 mg/kg/day) continuously for 4 weeks. Treatment with haloperidol, but not sulpiride or clozapine, caused inhibition of stereotyped behaviour induced by apomorphine (0.125-0.25 mg/kg SC). Following drug withdrawal for up to 7 days, haloperidol and sulpiride, but not clozapine treatment caused an exaggeration of stereotyped behaviour induced by apomorphine. Bmax values for striatal 3H-spiperone binding were elevated in animals treated for 2 and 4 weeks with haloperidol, but not with sulpiride or clozapine. Following drug withdrawal, haloperidol, but not sulpiride or clozapine, treatment caused an increase in Bmax for striatal 3H-spiperone binding. Bmax values for striatal 3H-NPA binding revealed no change during haloperidol or clozapine treatment. Sulpiride treatment for 1 week caused an increase in Bmax for 3H-NPA binding, which returned to control levels at 2 and 4 weeks. Following drug withdrawal, there was an increase in Bmax for 3H-NPA binding in rats treated with haloperidol and sulpiride, but not clozapine. On continuous treatment and following withdrawal from haloperidol, sulpiride, or clozapine the ability of dopamine to stimulate striatal adenylate cyclase activity did not differ from that in control animals. Repeated administration of sulpiride or clozapine may not induce striatal dopamine receptor supersensitivity when given in clinically relevant doses, although haloperidol does.

Animals↗
PubMed1995

The effects of D1 (NNC 22-0215) and D2 (haloperidol) antagonists in a chronic double-blind placebo controlled trial in cebus monkeys.

The effects of chronic treatment for 28 days with the oral D1 (NNC 22-0215) or D2 (haloperidol) antagonist were evaluated in nonhuman primates in a double blind, placebo controlled crossover trial. Cebus monkeys, 10-18 years old, which were previously sensitized to neuroleptics, were treated in three different groups with NNC 22-0215 2-3 mg/kg PO (n = 6), haloperidol 2-3 mg/kg PO (n = 5), or lactose placebo (n = 7) each day in a banana slice. At the end of 28 days the NNC 22-0215 group crossed over to haloperidol and the haloperidol group crossed over to NNC 22-0215 for 28 more days. The lactose group continued on lactose. Extrapyramidal symptoms (EPS) of dystonia and sedation were scored daily. Initially both NNC 22-0215 and haloperidol produced equal rates of dystonia. However, the NNC 22-0215 group demonstrated nearly full desensitization by day 2 and showed no EPS by day 6, whereas the haloperidol group had increased EPS during the first week, followed by moderate desensitization to EPS, but continued to have symptoms on each of the 28 days of treatment. At crossover, the previously treated haloperidol group rapidly desensitized with NNC 22-0215 by day 4 to show no EPS, whereas the previously treated NNC 22-0215 group showed full EPS on the first day of haloperidol and had EPS continue over the next 28 days of treatment. Sedation from NNC 22-0215 also desensitized within the first week of treatment. Haloperidol produced minimal sedation that did not change. The profound difference in rates of desensitization between repeated D1 and D2 antagonist treatment suggests that D1 antagonists in the clinic may produce EPS side effects for only the first few days, in contrast to the continuous acute EPS associated with chronic neuroleptic treatment.

Administration, Oral↗
PubMed1995

Effect of haloperidol and its metabolites on dopamine and noradrenaline uptake in rat brain slices.

The effects of haloperidol and its metabolites on dopamine (DA) and noradrenaline (NA) uptake were investigated. Both direct uptake of [3H]DA and [3H]NA into the rat striatal and hippocampus slices and binding of a specific DA uptake inhibitor [3H]GBR-12935 were employed in the present study. Haloperidol pyridinium (HP+), haloperidol 1,2,3,6-tetrahydropyridine (HTP), 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (CPTP) and reduced haloperidol (RHAL) are potent inhibitors of DA uptake. HTP N-oxide (HTPNO) exhibits a relatively weak effect on DA uptake. Other metabolites of haloperidol, i.e. 4-(4-chlorophenyl)-4-hydroxypyridine (CPHP) and haloperidol N-oxide (HNO), as well as haloperidol itself possess negligible inhibitory effect on DA uptake. HP+ has been shown to be an amine releaser. It is possible that HP+ may induce amphetamine-like neurotoxicity. The effects of the metabolites of haloperidol on [3H]NA uptake are similar to those on [3H]DA uptake. HP+ appears to be different from MPP+, which is a more potent [3H]NA uptake blocker than on [3H]DA uptake. Although haloperidol exhibits no DA uptake inhibitory effect, it has a high affinity for the [3H]GBR-12935 binding site. The possible pharmacological implications such inhibitory effects on amine uptake are discussed.

Animals↗
PubMedDate not supplied

Absorption of intramuscularly administered [14C]haloperidol decanoate in rats.

When [14C]haloperidol decanoate, an ester of haloperidol and decanoic acid, was given intramuscularly to rats, levels of total radioactivity and haloperidol decanoate in medial iliac and hypogastric sacral lymph nodes nearest to injection sites were the highest in examined lymph nodes and plasma. These lymph node levels became maximum 16 days after administration and declined gradually with half-life (around 14 days) similar to those of plasma total radioactivity, haloperidol decanoate and haloperidol. However, when the labelled ester was given intravenously, plasma total radioactivity disappeared far more rapidly. Much more radioactivity was found in hind limbs whose femoral muscles had been injected than in other body parts, even at late stages after administration. Haloperidol alone was found in the brain after [14C]haloperidol decanoate was given either intramuscularly or intravenously. It was concluded that haloperidol decanoate injected in rat femoral muscle was rate-limitedly distributed in lymph circulation and that the absorbed ester did not penetrate the brain through the blood-brain barrier but formed haloperidol did.

Absorption↗
PubMed2005

Poor evidence for depolarization block but uncoupling of nigral from striatal dopamine metabolism after chronic haloperidol treatment in the rat.

Chronic haloperidol treatment induces depolarization block in midbrain dopamine neuronal systems. We studied the effect of this treatment on nigrostriatal dopamine catabolism using microwave fixation in situ of the brain to prevent post-mortem changes. Male Sprague-Dawley rats were given haloperidol (0.4 mg/kg/day, i.p.) or vehicle for 21 days. On day 22, some rats in each group received a haloperidol challenge (0.4 mg/kg, i.p.), and the remaining rats were given the vehicle. Dopamine metabolite levels 60 min after the challenge were assayed by combined gas chromatography-mass fragmentography. Haloperidol pretreatment significantly modified haloperidol challenge effect on regional dopamine metabolite contents. The challenge elevated all striatal metabolites studied similarly in the chronic vehicle- or chronic haloperidol-pretreated rats. In contrast, it did not significantly affect nigral dopamine metabolites except it elevated 3,4-dihydroxyphenylacetic acid in the haloperidol-pretreated rats. A linear correlation between the nigral and striatal contents of 3-methoxytyramine (R = 0.72, p = 0.03), and a trend for correlation (R = 0.65, p = 0.06) between the respective 3,4-dihydroxyphenylacetic acid contents were found after the haloperidol challenge in the vehicle-pretreated rats only. These results suggest that chronic haloperidol treatment uncouples somatodendritic dopamine turnover and release from those in the axon terminals of nigrostriatal dopamine neurons.

3,4-Dihydroxyphenylacetic Acid↗