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PubMed2005

Antinociceptive effects of haloperidol and its metabolites in the formalin test in mice.

RATIONALE: Formalin-induced pain is reduced in sigma-1 (sigma1) receptor knockout mice; therefore, we hypothesized that haloperidol and its metabolites I and II, which have affinity for sigma1 receptors, may modulate formalin-induced pain. RESULTS: Intraplantar administration of formalin (2.5%) to CD-1 mice produced a biphasic period of pain. Haloperidol (0.03-1 mg/kg, s.c.) and reduced haloperidol (metabolite II, 0.25-8 mg/kg, s.c.) dose-dependently inhibited both phases of formalin-induced pain. Haloperidol metabolite I (4-128 mg/kg, s.c.) also produced dose-dependent antinociception in the second phase of the formalin test, but was less potent and effective against first-phase pain. Haloperidol metabolite III (16 and 128 mg/kg) and (-)sulpiride (200 mg/kg), which have no affinity for sigma1 receptors, did not produce significant antinociception in either phase of the formalin test. The order of potency of the drugs to produce their antinociceptive effect [haloperidol>metabolite II>metabolite I>>metabolite III= (-)sulpiride=inactive] correlated with their affinity for sigma1 receptors, but not with their affinity for sigma2 or dopamine D2 receptors. Naloxone (1 mg/kg, s.c.) did not antagonize the antinociception induced by haloperidol and its metabolites. None of the antinociceptive drugs in the formalin test produced any antinociception in the tail flick test. CONCLUSION: These results suggest that the antinociceptive effect of haloperidol and its metabolites in the formalin test is not due to unspecific/generalised inhibition of nociception or modulation of opioid receptors, and that it may be related, at least partially, to the ability of these drugs to interact with sigma1 receptors.

Analgesics↗
PubMed1999

Clozapine pretreatment modifies haloperidol-elicited forebrain Fos induction: a regionally-specific double dissociation.

RATIONALE: Acute administration of typical antipsychotic drugs, such as haloperidol, results in the induction of the immediate-early gene c-fos in the dorsolateral striatum. In contrast, the atypical antipsychotic drug clozapine, which lacks significant extrapyramidal side effect liability, does not induce Fos protein in the dorsal striatum. Several studies have attempted to define the mechanisms through which typical antipsychotic drugs induce striatal Fos, often by pretreating animals with specific receptor antagonists. Despite the broad receptor profile of clozapine, there has been no study of the effect of clozapine pretreatment on haloperidol-elicited striatal Fos expression. METHODS: We examined the effects of clozapine pretreatment of rats on haloperidol-elicited forebrain Fos expression, using both immunoblot and immunohistochemical methods. The effects of clozapine pretreatment were assessed in the dorsal striatum and in the different nucleus accumbens compartments, the septum, and the prefrontal cortex. RESULTS: Clozapine pretreatment markedly decreased haloperidol-elicited striatal Fos induction and blocked haloperidol-induced catalepsy. Clozapine also attenuated haloperidol-elicited Fos expression in the nucleus accumbens, but in the prefrontal cortex and ventrolateral septum the effects of haloperidol and clozapine were additive. CONCLUSIONS: An emerging body of literature suggests a high incidence of rapid relapse in schizophrenic patients when clozapine treatment is discontinued. This psychosis is relatively resistant to haloperidol and other neuroleptics, even in patients who had previously responded well to neuroleptics. The present data may shed light on the central sites associated with and perhaps model certain aspects of the relapse associated with clozapine discontinuation.

Animals↗
PubMed1999

Effects of haloperidol and clozapine on tongue dynamics during licking in CD-1, BALB/c and C57BL/6 mice.

RATIONALE: In an initial effort to describe how genetic background influences the differential motor effects of haloperidol, a drug with high extrapyramidal side effect (EPS) liability, and clozapine, an antipsychotic low in EPS, both drugs were studied in inbred strains of mice (BALB/c and C57BL/6) previously shown to have differential sensitivities to haloperidol. OBJECTIVES: Behavioral differences in lick dynamics for male BALB/c, C57BL/6 and CD-1 (an outbred strain) were characterized. Effects of dose ranges of haloperidol and clozapine were then evaluated in the three strains. METHODS: The mice learned to lick milk from a force-sensing disk during daily 2-min sessions, while a computer counted the number of licks and measured lick peak force and lick rhythm. After training, acute doses of haloperidol (0.08-2.0 mg/kg) or clozapine (0.5-8.0 mg/kg) were administered i.p. 45 min before sessions. RESULTS: Prior to drug treatment, substantial quantitative strain differences in licking behavior were observed: C57BL/6 mice made fewer licks, licked with lower peak force per lick, and had a slower lick rhythm than the BALB/c and CD-1 mice. As in rats, clozapine slowed the lick rhythm in all three mouse strains much more than haloperidol did. Haloperidol produced a 50% greater suppression of number of licks in BALB/c than in C57BL/6 mice (ED50 values were 0.82 mg/kg and 1.22 mg/kg, respectively). For clozapine, lick suppression was greater in the C57BL/6 than in the BALB/c strain (ED50 values were 1.88 mg/kg and 2.65 mg/kg, respectively). Among the three strains examined, CD-1 was the most sensitive to haloperidol's suppression of licking, while its sensitivity to clozapine's lick-suppressing effect was similar to C57BL/6 mice. Clozapine lowered the lick peak force in the CD-1 and BALB/c strains more than in the C57BL/6 strain. CONCLUSIONS: Overall, the results suggest that genetic variables may influence both mice's tongue dynamics and their alteration by both typical and atypical antipsychotic drugs. In addition, while the BALB/c strain was more sensitive to haloperidol's lick-disruptive effects than the C57BL/6 strain, the size of the difference between strains was much smaller than the reported difference between the strains in the catalepsy test.

Animals↗
PubMed2003

Compatibility of haloperidol and hyoscine-N-butyl bromide in mixtures for subcutaneous infusion to cancer patients in palliative care.

The administration of drugs by s.c. infusion is routinely practiced in palliative medicine for the management of patients who are no longer able to take oral medication. It is not uncommon for two or more drugs to be combined in s.c. infusion solutions. Unfortunately, the compatibility and stability of haloperidol and hyoscine- N-butyl bromide has not yet been determined. The objective of this study was to study the compatibility and stability of solutions containing both drugs in polypropylene syringes. Nine different solutions were assessed for up to 15 days following preparation. The solutions were prepared in polypropylene syringes with 0.9% saline as a diluent and stored at 4 degrees C and 25 degrees C. High-performance liquid chromatography was the analytical technique used to measure haloperidol and hyoscine- N-butyl bromide. The initial concentration ranges were 0.3125-1.25 mg/ml for haloperidol and 2.5-10.0 mg/ml for hyoscine- N-butyl bromide. Haloperidol was precipitated at a concentration of >/=1.25 mg/ml when it was combined with hyoscine- N-butyl bromide. Concentrations of hyoscine- N-butyl bromide lower than 10 mg/ml in mixtures with haloperidol or 0.625 mg/ml of haloperidol in mixtures with hyoscine- N-butyl bromide for s.c. infusion allow for the administration of both drugs without any significant loss after storage at 25 degrees C for periods of up to 15 days, with approximately >/=90% and 88%, respectively, of haloperidol and hyoscine- N-butyl bromide remaining. However, after storage of the mixtures for equivalent periods at 4 degrees C the losses of hyoscine- N-butyl bromide observed at the end of the study were higher than 20%, while the percentages of haloperidol remaining after 15 days at this temperature were >/=94.37%.

Antiemetics↗
PubMed1989

Effects of short- and long-term haloperidol administration and withdrawal on regional brain cholecystokinin and neurotensin concentrations in the rat.

The effects of oral administration of the neuroleptic, haloperidol, on regional brain concentrations of cholecystokinin (CCK) and neurotensin were examined in the rat. Both short-term (3 weeks) and long-term (8 months) haloperidol administration increased the concentration of CCK in the substantia nigra. While short-term administration significantly increased the concentration of CCK in the ventral tegmental area and decreased the concentration of CCK in the cortex, including the medial prefrontal cortex, these effects were not observed following long-term drug administration. In contrast, long-term, but not short-term, haloperidol administration decreased the concentration of CCK in the olfactory tubercle. Withdrawal from long-term haloperidol did not alter CCK concentrations in any of the brain regions examined. Short-term haloperidol administration significantly increased the concentration of neurotensin in the caudate-putamen. Both short- and long-term administration increased the concentration of neurotensin in the nucleus accumbens, but only the increased following long-term administration reached statistical significance. Withdrawal from long-term haloperidol administration slightly decreased the concentrations of neurotensin in the caudate-putamen and nucleus accumbens. These results indicate that dopamine receptor blockade can affect both CCK- and neurotensin-containing neural systems. Furthermore, these two neuropeptides are affected differently depending upon the duration of haloperidol administration and withdrawal from this drug. The results raise the possibility that chronic administration of haloperidol may be toxic to some neurotensin-containing neurons in the basal ganglia.

Administration, Oral↗
PubMed1981

Brain contribution to the haloperidol-induced increase in plasma homovanillic acid.

Haloperidol increases the plasma concentration of the dopamine (DA) metabolite homovanillic acid (HVA). Since a substantial proportion of plasma HVA originates outside the brain, this effect could be due to a combination of both peripheral and central actions of haloperidol. In order to evaluate the relative contribution of central versus peripheral effects of haloperidol on plasma HVA, the effect of pretreatment with a peripheral monoamine oxidase inhibitor, debrisoquin, on the plasma HVA response to haloperidol was examined. In addition, the effect of haloperidol on plasma HVA was compared with that of domperidone, a peripheral DA receptor blocking agent. Debrisoquin pretreatment did not alter the haloperidol-induced increase in plasma HVA and domperidone had no effect on plasma HVA. Thus, the haloperidol effect on plasma HVA did not appear to be due to increased peripheral HVA production or blockade of peripheral DA receptor sites. It is concluded that the haloperidol-induced increase in plasma HVA is due largely or exclusively to the drug's action on the brain.

Animals↗
PubMed1990

Regional specific effects of clozapine and haloperidol on GABA and dopamine release in rat basal ganglia.

gamma-Aminobutyric acid (GABA) and dopamine release were measured concomitantly in rat dorsolateral striatum, fundus striati (a ventral region of striatum) and globus pallidus following s.c. administration of haloperidol or clozapine. Release was measured by microdialysis in halothane-anesthetized rats. Clozapine (5.0 mg/kg) increased GABA release in the fundus striati and haloperidol (0.5 mg/kg) increased GABA release in the globus pallidus. In contrast, clozapine (2.5-40 mg/kg) failed to increase GABA release in the globus pallidus and haloperidol (0.1-2.0 mg/kg) failed to increase GABA release in the fundus. Thus, haloperidol and clozapine are clearly distinguished by their effects on GABA release in the fundus striati and globus pallidus (both drugs increased GABA release in the dorsolateral striatum). Dopamine release was increased by haloperidol and clozapine in the two regions of the striatum. However, except in the fundus striati where clozapine-induced increases in dopamine and GABA occurred in parallel, both drugs were more potent in releasing dopamine than GABA. Drug-induced increases in GABA and dopamine release were reversed by addition of 1 microM tetrodotoxin to the perfusion medium. These data suggest that (1) regional differences in the effects of haloperidol and clozapine on GABA release in the basal ganglia may parallel the unique clinical profiles of these drugs; and (2) increases in dopamine release may occur independently of a GABAergic component in the dorsolateral striatum following low doses of haloperidol and clozapine and in the fundus striati following all effective doses of haloperidol.

Animals↗
PubMed1990

Decrease in the evoked release of endogenous dopamine and dihydroxyphenylacetic acid from rat striatal slices after withdrawal from repeated haloperidol.

The release of endogenous DA (dopamine) and DOPAC (3,4-dihydroxyphenylacetic acid) from rat striatal slices was measured after withdrawal from a prior long-term treatment of the rat with haloperidol to investigate adaptive changes in striatal DA and DOPAC release induced by chronic haloperidol treatment. Striatal slices prepared 24 h after the last injection of daily treatment with haloperidol for up to 14 days (2.5 mg/kg per day) were superfused and stimulated for 5 min with K+ (50 mM). Haloperidol treatment for 3 or 7 days decreased K(+)-stimulated DA release by maximally 35%, but a 14-day treatment was not effective. The K(+)-stimulated release of DOPAC, which occurred after the change in DA release, was reduced significantly by the treatment for 7 or 14 days. A higher daily dose of haloperidol (10 mg/kg per day) produced a more pronounced decrease in stimulated DA release after a 14-day treatment without having an effect after 3 days. However, the stimulated release of DOPAC decreased markedly after both 3 and 14 days of haloperidol treatment. The slight reduction in the DA content of the slices after K+ stimulation was seen in some haloperidol-treated tissues, although this change did not always parallel the simultaneous decrease in DA release. These results indicate that the K(+)-induced stimulation of endogenous DA release and the synthesis of DA are impaired after withdrawal from repeated haloperidol treatment.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Haloperidol in large doses reduces the cataleptic response and increases noradrenaline metabolism in the brain of the rat.

The neurochemical basis for the clinical observation that some patients receiving a large dose of haloperidol exhibit no extrapyramidal side effects was investigated in rats. Haloperidol at doses of 1, 2.5, 5, 7.5 and 10 mg/kg (i.p.) caused a dose-dependent decrease in the duration of catalepsy. Haloperidol at a dose of 10 mg/kg induced catalepsy lasting for only 20% of that obtained with 1 mg/kg. Haloperidol decreased the content of noradrenaline in the frontal cortex and thalamus in a dose-dependent manner, while the content of 3-methoxy-4-hydroxyphenylglycol (MHPG) showed a dose-dependent increase in the same areas of the brain. Thus, there was an inverse relationship between the duration of catalepsy and the ratio of 3-methoxy-4-hydroxyphenylglycol to noradrenaline in the frontal cortex or thalamus. The concomitant administration of 20 mg/kg of phenoxybenzamine with 10 mg/kg of haloperidol induced a long-lasting catalepsy. The result may indicate that the increased metabolism of noradrenaline by large doses of haloperidol was not secondary to the blocking of dopaminergic receptors. In contrast, haloperidol caused a dose-dependent decrease in the content of homovanillic acid and 3,4-dihydroxyphenylacetic acid in the striatum and mesolimbic area. These results indicate that noradrenergic hyperfunction in the frontal cortex or thalamus induced by large doses of haloperidol may reduce the cataleptogenic effect of the drug via indirect stimulation of a dopaminoceptive neuron in the striatum or mesolimbic area.

Animals↗
PubMed1992

Blockade of dopamine autoreceptors by haloperidol and the apparent dynamics of potassium-stimulated endogenous release of dopamine from and reuptake into striatal suspensions in the rat.

A study was made to determine what effects the blockade of dopamine (DA) autoreceptors has on the dynamics of depolarization-stimulated release of DA from suspensions of the striatum. A rotating disk electrode voltammetric technique and a first order kinetic model were used to measure and quantify time-resolved depolarization-induced release of DA from and reuptake into the same striatal suspension. Multiphasic dose-response relationships between the magnitudes, rates and apparent rate constants of release of DA and the concentration of the autoreceptor antagonist, haloperidol, were observed. At small concentrations of haloperidol, less than or equal to 0.1 microM, the magnitude of release of DA and apparent release rate constants were increased, however, the duration of release, the initial rate of release and the rate constants of reuptake of DA were unaffected. At larger concentrations of haloperidol, greater than 1.0 microM, release of DA was prolonged and reuptake was decreased. The rate constants for release of DA correlated with the magnitude of release of DA at all of the concentrations of haloperidol studied. The concentrations of haloperidol in tissue were estimated and then correlated with functionally significant systemic doses of haloperidol by direct comparison to published data, relating total concentrations of haloperidol in tissue with systemic doses and their behavioral effects. At these doses, haloperidol was found to increase the release rate constant and magnitude of release of DA, without altering the duration of release or the timing of reuptake. Thus, at presumed functionally significant doses, autoreceptor antagonism resulted in a modulation of the amplitude of release of DA only.

Animals↗
PubMed1988

Radiation-induced increases in sensitivity of cataleptic behavior to haloperidol: possible involvement of prostaglandins.

The effects of radiation exposure on haloperidol-induced catalepsy were examined in order to determine whether elevated prostaglandins, through an action on dopaminergic autoreceptors, could be involved in the radiation-induced increase in the potency of this neuroleptic. Cataleptic behavior was examined in animals irradiated with various doses of gamma photons (1-150 Gy) and pretreated with a subthreshold dose of haloperidol (0.1 mg/kg). This approach was chosen to maximize any synergistic effects of radiation and haloperidol. After irradiation with doses less than or equal to 30 Gy, the combined treatment of haloperidol and radiation produced catalepsy, whereas neither treatment alone had an effect. This observed catalepsy could be blocked with prior administration of indomethacin, a prostaglandin synthesis inhibitor. Animals exposed to doses of radiation less than or equal to 50 Gy and no haloperidol, however, displayed apparent catalepsy. This effect was also antagonized by indomethacin. Prostaglandins can induce catalepsy and when administered in subthreshold doses along with subthreshold doses of haloperidol, catalepsy was observed. In order to assess a possible action of prostaglandins and radiation on dopaminergic activity, the functioning of striatal dopaminergic autoreceptors was examined by determining the effects of varying concentrations of haloperidol on the K+-evoked release of dopamine from striatal slices obtained from parallel groups of animals treated as above. Results indicated that sensitivity to haloperidol increased (higher K+-evoked dopamine release) in slices from irradiated or prostaglandin-treated animals and that this increase in sensitivity was blocked by indomethacin. Results from both experiments suggest that radiation-induced increases in endogenous neuronal mediators, such as prostaglandins, can induce catalepsy through an action on dopaminergic autoreceptors.

Animals↗
PubMed1995

Development of tolerance and reverse tolerance to haloperidol- and SCH23390-induced cataleptic effects during withdrawal periods after long-term treatment.

The development of tolerance and reverse tolerance and reverse tolerance to the cataleptic effects of selective D1 antagonist, SCH23390, and the mainly D2 antagonist, haloperidol, was investigated in mice that had been chronically treated (7 or 30 days) with haloperidol (1 mg/kg SC), SCH23390 (0.5 mg/kg SC), or saline (5 ml/kg SC). In control animals, SCH23390 (0.1-1.0 mg/kg IP) and haloperidol (0.1-1.0 mg/kg IP) produced cataleptic responses in a dose-dependent manner, although the responses had different time course profiles. SCH23390 catalepsy had a rapid onset but a short duration, whereas haloperidol catalepsy had a slower onset and longer duration. This could be due to differences in lipid solubility of the drugs, or at least pertly to an action of the drugs on different neuronal pathways. The cataleptic effects of SCH23390 (0.3 mg/kg IP) and haloperidol (0.3 mg/kg IP) were significantly reduced in mice when given 24 h, but not 72 h, after the last dose of a 7 day-pretreatment course (short-term treatment) of SCH23390. However, after long-term treatment (30 days) with SCH23390, a challenge dose of SCH23390 exhibited reverse tolerance (i.e., increased catalepsy) when given 7-21 days, but not 1-3 days, after the last injection of the SCH23390 pretreatment course. In contrast, haloperidol catalepsy was not affected by long-term SCH23390 treatment. However, after the last dose of long-term haloperidol treatment both SCH23390 and haloperidol exhibited tolerance to their cataleptic effects at 1-3 days, a normal response at 7 days, and an exaggerated response (reverse tolerance) at 15-21 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Haloperidol pharmacokinetics: a preliminary study in rhesus monkeys using a new radioimmunoassay procedure.

The development, validation, and application of a new radioimmunoassay for haloperidol in biological fluids is described. The antiserum, raised against N-amino-butyl chlorophenyl piperidine bovine albumin conjugate, could not distinguish between haloperidol and its reduced metabolite, but it could discriminate against chlorophenyl piperidine (cross-reaction 2.6%). The fluorophenyl metabolites of haloperidol were not recognized by the antiserum. Haloperidol determinations were made on less than 100 microliter aliquots of human and rhesus monkey plasma or diluted urine without prior extraction of the sample. The radioimmunoassay was applied to the study of the pharmacokinetics of intravenous haloperidol administration to two male rhesus monkeys. Salient features of the results are as follows. As with man, the plasma concentration versus time curve could be resolved into three compartments, but there were differences in the distribution of haloperidol between the compartments. The apparent volume of distribution for the two monkeys examined was 5.87 L kg-1 and 7.37 L kg-1, considerably smaller than in man, a difference almost entirely due to a much smaller tissue compartment. The biological half-life of 15.97 hr and 7.56 hr was similar to man. The mean hepatic extraction ratio was calculated to be 0.032 and 0.056, and the data suggested that hepatic metabolism of haloperidol may be of lesser importance in rhesus monkey than in man. An insignificant proportion (0.01%) of the administered dose was excreted as haloperidol in the urine.

Animals↗
PubMed1994

Effect of prolonged treatment with haloperidol on "emotional" defecation and movement in rats in a well-habituated environment.

Sixteen adult male Wistar rats were administered either haloperidol (n = 8), 0.5 mg/kg, or saline (placebo) (n = 8) by subcutaneous injection three times per week for 6 weeks, and were again injected after a 6-week drug-free period. The study was conducted in a well-habituated, distinctive environment to which the rats were introduced 1 hour before the injection on each occasion. The fecal bolus counts 1 hour before and 2 hours after drug injection were obtained, as well as movement counts repeatedly in epochs of 90 seconds upon introduction to the cages and after the injections. Haloperidol produced an overall increase in defecation in the 2 hours after drug injection compared with placebo. The post-drug bolus counts for haloperidol-treated rats were lower in week 2 compared with week 1, but the difference from placebo for this reduction was not significant, and it did not persist beyond week 4. The haloperidol-treated group showed a significant increase in the predrug bolus counts from week 5, suggesting a conditioned response to the cage environment. The haloperidol-treated rats were markedly less mobile than the placebo-treated rats, and with repeated exposure to haloperidol, they tended to develop hypomotility earlier. No tolerance to the movement effect was observed. The defecation and movement effects of haloperidol at 12 weeks were no different from those at week 1. This study supports earlier work indicating that haloperidol produces a dysphoric effect in rats, and it suggests that this effect does not habituate over 6 weeks of repeated administration. It does not replicate the motor aspect of akathisia seen in humans.

Akathisia, Drug-Induced↗
PubMed1994

Differential influence of haloperidol and sulpiride on dopamine receptors and peptide mRNA levels in the rat striatum and pituitary.

We examined the effect of chronic administration (14 days) of haloperidol (2 mg/kg/day) or sulpiride (100 mg/kg/day), on the mRNA levels of various genes in the rat striatum and pituitary by quantitative in situ and Northern blot hybridizations. In the pituitary, haloperidol and sulpiride induced similar increases of mRNAs of pro-opiomelanocortin (POMC) (+65% and +73%), prolactin (PRL) (+821% and +840%) and growth hormone (GH) (+32% and +47%), but sulpiride induced a greater increase of D2R mRNA (+125%) than haloperidol (+92%). In the striatum, sulpiride and haloperidol had different effects: sulpiride induced a higher increase than haloperidol of both preproenkephalin A (PPA) mRNA (+67% versus +47%) and D2 dopamine receptor (D2R) mRNAs (+72% versus +40%). Moreover, haloperidol and sulpiride had opposite effects on substance P (SP) mRNA. Haloperidol decreased the amount of SP mRNA by 20% while sulpiride increased it by 20%. The D1 dopamine receptor (D1R) mRNA level was not significantly modified after either treatment. Our results demonstrate that the effect of a chronic haloperidol treatment on striatal dopamine receptors and neuropeptide mRNA levels is different to that of sulpiride, whereas it is similar on pituitary hormones mRNA levels.

Animals↗
PubMed1983

Effect of combined haloperidol-lithium treatment on vitro RBC lithium uptake in patients with affective disorders.

Combined treatment with haloperidol and lithium is a frequently employed strategy for the treatment of acute psychoses. Although this combination regime is safe in most clinical situations, under certain circumstances it has resulted in neurotoxicity, with organic brain syndrome, and ultimately, in some patients, irreversible brain damage and death. Plasma lithium levels in these neurotoxic patients are generally within the clinically acceptable range of 0.7 - 1.5 mEq/l, but RBC-lithium levels, when reported are abnormally elevated. To account for these observations we hypothesized that in vivo haloperidol will alter the transport of lithium across the RBC membrane and thus cause an increase in RBC lithium levels. We report preliminary results from a study that tested this hypothesis by measuring RBC lithium transport in vitro, in patients treated with a) haloperidol only, b) haloperidol, followed by haloperidol and lithium, c) combined haloperidol and lithium. In eight manic depressive patients in vivo haloperidol alone, or in combination with lithium resulted in a statistically significant (p less than 0.0001) reduction of the in vitro RBC Li+ uptake values. These results are interpreted as supportive of our hypothesis, that in vivo haloperidol alters the transport of lithium across the RBC membrane, and this effect can be detected by the use of a sensitive in vitro test. Work is currently in progress to evaluate, whether the RBC Li+ transport alteration is due to a direct effect of the drug on the cell membrane or secondary to some circulating factor, and to extend these findings to a larger sample of patients.

Bipolar Disorder↗
PubMed1983

Behavioural and biochemical alterations following haloperidol treatment and withdrawal: the animal model of tardive dyskinesia reexamined.

Behavioural and biochemical studies were carried out in rats given a single daily dose (1 mg/kg, i.p.) of haloperidol for 30 days and subsequently withdrawn for 7 days. Long-term administration of haloperidol resulted in supersensitivity of dopamine receptors. This was manifested by enhanced stereotypic biting, rearing, locomotor and floor activity of haloperidol withdrawn rats when challenged to a low dose of apomorphine (0.5 mg/kg, s.c.) on the 8th day. Chronic haloperidol treatment significantly decreased dopamine synthesis and release as evidenced by low activity of tyrosine hydroxylase and low level of homovanillic acid in striatum. Dopamine levels did not change in the frontal cortex, striatum and midbrain. Haloperidol treatment significantly increased striatal gamma-aminobutyric acid content and glutamic acid decarboxylase activity by 17% and 16% respectively. The decreased tyrosine hydroxylase activity and homovanillic acid level in corpus striatum might, in part, be due to an inhibitory effect of GABAergic neurons on dopaminergic system. Rats withdrawn from chronic haloperidol treatment showed significant increases in GABA level and glutamic acid decarboxylase activity. This probably resulted in further inhibition of dopamine release as evidenced by marked accumulation of dopamine in the corpus striatum and midbrain. No significant alterations in the endogenous levels of norepinephrine, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid were observed in haloperidol-treated and subsequently withdrawn rats. These data suggest that chronic haloperidol treatment and subsequent withdrawal results in the development of behavioural dopamine supersensitivity as well as biochemical alterations in dopaminergic and GABAergic system. The changes in these two neuronal systems seem to be interrelated.

Animals↗
PubMed1984

The relationship between haloperidol blood levels and clinical responses.

Haloperidol blood levels in patients were determined to elucidate the relationship between blood levels and clinical effects. Determinations of haloperidol serum were performed by radioimmunoassay and the clinical status was estimated using BPRS. The relationship between haloperidol serum levels and BPRS total score was studied in 20 chronic schizophrenics currently receiving haloperidol treatment. The results did not show positive relationship between these two. Another 11 schizophrenic patients were treated with daily doses of average 6 mg of haloperidol. The patients were classified into improved and unchanged group according to the changes of BPRS total score. All 7 cases classified into the improved group had short duration of the illness less than one year. In this group, the levels were lower initially but gradually rised in paralled with the increase of extent of recovery on BPRS. Furthermore, improvement of psychopathology by means of decrease of BPRS total score was still found after haloperidol serum levels reached a plateau. The results did not support the view that high blood concentration of haloperidol might contribute to the clinical effects, but still suggested utility of measuring blood levels in acute or subacute patients being treated with haloperidol medications.

Adult↗