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PubMed2006

A meta-analysis of cognitive change with haloperidol in clinical trials of atypical antipsychotics: dose effects and comparison to practice effects.

Prospective, double-blind, randomized trials comparing atypical antipsychotic drugs (APDs) to typical APDs, such as haloperidol, indicate that atypical APDs provide a modest benefit to cognitive function in schizophrenia. However, the validity of this inference has been contested by suggestions that the cognitive improvements observed with atypical APDs reflect practice effects associated with repeated testing on the same neuropsychological instruments, or an avoidance of a deleterious effect of haloperidol on cognitive function that might be dose related. These alternate hypotheses were assessed by meta-analyses that 1) examined the relationship between cognitive change and dose of haloperidol within the control arms of prospective atypical vs. typical APD clinical trials; and 2) compared the magnitude of change observed within the haloperidol arms of these studies to estimated practice effects for several commonly used neuropsychological measures. The results indicate that overall cognitive performance improves while on haloperidol. Studies that used a low dose of haloperidol (<10 mg) did not yield larger effect sizes for overall cognitive function or specific neuropsychological measures than studies that used a high dose (>10 mg), although doses greater than 24 mg appear to have deleterious effects. For two of the six neuropsychological tests examined (digit symbol substitution and verbal fluency) the magnitude of change observed was significantly less than practice effects. The results indicate that although haloperidol may cause deleterious effects at very high doses, or in specific cognitive domains, these effects are not likely to explain the broader range of cognitive improvements observed with atypical APDs.

Antipsychotic Agents↗
PubMed2000

Differential patterns of induction of NGFI-B, Nor1 and c-fos mRNAs in striatal subregions by haloperidol and clozapine.

Disturbances of retinoid activated transcription mechanisms have recently been implicated as risk factors for schizophrenia. In this study we have compared the regulation of mRNAs for the nuclear orphan receptor NGFI-B, which forms a functional heterodimer with the retinoid x receptor and the related orphan nuclear receptor Nor1 with c-fos mRNA after acute and chronic treatments with haloperidol and clozapine. The antipsychotic drugs haloperidol and clozapine have different clinical profiles. Haloperidol is a typical neuroleptic giving extrapyramidal side effects (EPS), whereas the atypical compound clozapine does not. Acute haloperidol treatment increased NGFI-B, Nor1 and c-fos mRNAs in nucleus accumbens shell and core as well as medial and lateral caudate putamen. In contrast, clozapine lead to an increase of NGFI-B, Nor1 and c-fos only in the accumbens shell. No haloperidol or clozapine effect on these mRNAs was detected in cingulate, sensory or motor cortex. Chronic haloperidol lead to an increase of NGFI-B mRNA in the accumbens core. Acutely, it is possible that the increased levels of NGFI-B, Nor1 and c-fos mRNA levels in striatum and accumbens might indicate a neural activation which possibly can be used when screening for drugs that do not produce EPS. Also, the increased levels of NGFI-B, which is an important component in retinoid signaling, both after acute and chronic treatments of haloperidol suggests altered sensitivity to retinoids which could be an important component for the beneficial antipsychotic effect.

Animals↗
PubMed2002

5-HT(2A) receptor antagonism potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and inhibits that in the nucleus accumbens in a dose-dependent manner.

Combined serotonin (5-HT)(2A) and dopamine (DA) D(2) blockade has been shown to contribute to the ability of atypical antipsychotic drugs (APDs) to increase DA release in rat medial prefrontal cortex (mPFC). We provide additional support for this hypothesis by examining the effect of the selective 5-HT(2A) antagonist M100907 plus haloperidol, a potent D(2) antagonist APD, on DA release in the mPFC and nucleus accumbens (NAC). Haloperidol (0.01-1.0 mg/kg) produced an inverted U-shaped increase in DA release in the mPFC, with a significant increase only at 0.1 mg/kg. Haloperidol (0.1 and 1.0 mg/kg) significantly increased DA release in the NAC. M100907 (0.1 mg/kg) by itself had no effect on DA release in either region. This dose of M100907 potentiated the ability of low (0.01-0.1 mg/kg), but not high dose (0.3-1.0 mg/kg) haloperidol to increase mPFC DA release, whereas it abolished the effect of both 0.1 and 1.0 mg/kg haloperidol on NAC DA release. These results suggest that the relatively higher ratio of 5-HT(2A) to D(2) antagonism may contribute to the potentiation of haloperidol-induced mPFC DA release, whereas 5-HT(2A) antagonism can diminish haloperidol-induced NAC DA release, even when combined with extensive D(2) antagonism, which may not be synergistic with 5-HT(2A) antagonism in the mPFC.

Animals↗
PubMed2000

Repeated haloperidol treatment decreases sigma(1) receptor binding but does not affect its mRNA levels in the guinea pig or rat brain.

The effects of chronic treatment with haloperidol on sigma (sigma) receptors were investigated across brain regions and species. The regional distribution of [3H](+)-pentazocine binding to sigma(1) receptor was similar between the guinea pig and rat brains. The highest level of binding was detected in the brain stem and lowest in the striatum and hippocampus. The regional distribution of [3H]1, 3-di (2-tolyl) guanidine ([3H]DTG) binding in the presence of 100 nM (+)-pentazocine to sigma(2) receptor was similar to that of the [3H](+)-pentazocine binding in the guinea pig brain, while in the rat brain high levels of [3H]DTG binding were detected in the cortex, frontal cortex and cerebellum. The intraperitoneal administration of 2 mg/kg of haloperidol to guinea pig and rats once a day for 21 days produced inhibition of [3H](+)-pentazocine binding but did not affect [3H]DTG binding to sigma(2) receptors in any brain region examined. The effects of haloperidol on [3H](+)-penazocine binding in the rat were much weaker than those in the guinea pig. The regional distribution of the level of sigma(1) receptor mRNA determined by the ribonuclease protection assay was similar to that of the [3H](+)-pentazocine binding activity, except in the cortex and cerebellum where the levels of sigma(1) receptor mRNA were low in guinea pig and rat. Treatment with haloperidol did not affect the levels of sigma(1) receptor mRNA in any brain region in either species. These findings suggested that the sigma receptors differentially distributed in brain regions are down regulated by treatment with haloperidol across sigma receptor subtypes and animal species without changing the transcriptional activity of the sigma(1) receptor. The mechanisms by which sigma receptors could be differently regulated in vivo by chronic treatment with haloperidol in different species may contribute to the therapeutic efficacy of haloperidol.

Animals↗
PubMed1996

Lack of cross-tolerance between haloperidol and clozapine towards Fos-protein induction in rat forebrain regions.

We investigated whether the acute effects of haloperidol and clozapine on Fos expression in the rat forebrain are mediated by the same receptors through evaluation of cross-tolerance, particularly in the commonly affected areas. Acutely administered haloperidol (1 mg/kg. i.p.) and clozapine (20 mg/kg, i.p.) induce regionally different (e.g., the striatum, the hypothalamic paraventricular and supraoptic nuclei, and the central amygdala) and overlapping (e.g., the nucleus accumbens and the lateral septum) patterns of Fos-protein distribution in the rat forebrain. After long-term treatment, part of the acute effects of these drugs disappears in most brain areas, except in the lateral septum, the hypothalamic paraventricular and supraoptic nuclei and the amygdala following haloperidol administration. Cross-tolerance between haloperidol and clozapine was determined by administering a challenge dose of the one antipsychotic, following a 21-day pretreatment with the same or the other drug or saline. In none of the investigated brain regions was cross-tolerance towards Fos-protein induction found after haloperidol challenge in the clozapine-treated rats. Conversely, a competitive dose of clozapine in long-term haloperidol-treated rats showed cross-tolerance in the lateral septum, while the common effect of the drugs in both the dorsomedial and the dorsolateral parts of the striatum was very small. These findings indicate that, for the major part, the responses to haloperidol and clozapine are mediated by different receptors, even in brain areas that are affected by both drugs.

Animals↗
PubMed1999

Chronic haloperidol alters dopamine receptors: effects of cocaine exposure during the preweaning period.

The effect of cocaine exposure during the preweaning period on the function of the central dopaminergic systems was determined in adult rats. The present study investigated the alterations in dopamine receptors in 93-day-old male and female rats treated with cocaine (50 mg kg(-1) day(-1)), 1-[2-[bis(4-fluorophenyl)methoxyl]-4-[3-phenylpropyl]piperazine (GBR 12909) (50 mg kg(-1) every other day) or water during postnatal days 11-20. Haloperidol (2 mg kg(-1) day) or saline was injected during postnatal days 76-90 and the rats were killed on postnatal day 93. Quantitative receptor autoradiography with [3H]R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-b enzazepine ([3H]SCH 23390) for the dopamine D1 receptor and [3H]raclopride for the dopamine D2 receptor was carried out. The results show that haloperidol increased [3H]raclopride binding in many forebrain regions. Preweaning cocaine treatment in males increased the area showing this effect. Males generally were more responsive to haloperidol than females. However, in GBR 12909-treated females, raclopride binding showed widespread increases following haloperidol injection. For SCH 23390 binding, most regions showed a significant interaction between haloperidol, sex and preweaning treatment group. This was due primarily to the GBR 12909-treated males, which showed elevated basal dopamine D1 receptor binding levels and a haloperidol-induced reduction in dopamine D1 receptor binding in most regions evaluated. These data suggest that inhibition of the dopamine transporter during ontogeny produces long-term alterations in dopamine receptor regulation but that selective inhibitors of the dopamine transporter produced greater effects than cocaine on both raclopride and SCH 23390 binding following chronic haloperidol injection.

Animals↗
PubMed2000

Haloperidol-induced catalepsy is absent in dopamine D(2), but maintained in dopamine D(3) receptor knock-out mice.

We have previously found that mice homozygous for the deletion of the dopamine D(2) receptor gene (D(2)(-/-) mice) do not present spontaneous catalepsy when tested in a "bar test". In the present study, we sought to analyse the reactivity of D(2) receptor mutant mice to the cataleptogenic effects of dopamine D(2)-like or D(1)-like receptor antagonists. In parallel, we assessed the cataleptogenic effects of these antagonists in dopamine D(3) receptor mutant mice. D(2)(-/-) mice were totally unresponsive to the cataleptogenic effects of the dopamine D(2)-like receptor antagonist haloperidol (0.125-2 mg/kg i.p.), while D(2)(+/-) mice, at the highest haloperidol doses tested, showed a level of catalepsy about half that of wild-type controls. The degree of haloperidol-induced catalepsy was thus proportional to the level of striatal dopamine D(2) receptor expression (0.50, 0.30 and 0.08 pmol/mg protein as measured at 0.25 nM [3H]spiperone for D(2)(+/+), D(2)(+/-) and D(2)(-/-) mice, respectively). However, D(2)(-/-) and D(2)(+/-) mice were as sensitive as their wild-type counterparts to the cataleptogenic effects of the dopamine D(1)-like receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390: 0.03-0.6 mg/kg s.c.). Striatal dopamine D(1) receptor expression (as measured using [3H]SCH 23390 binding) was not significantly affected by the genotype. The ability of SCH 23390 to induce catalepsy in D(2)(-/-) mice suggests that their resistance to haloperidol-induced catalepsy is due to the absence of dopamine D(2) receptors, and not to the abnormal striatal synaptic plasticity that has been shown by others to occur in these mice. In agreement with the observation that dopamine D(2) and dopamine D(1) receptor expression was essentially identical in D(3)(+/+), D(3)(+/-) and D(3)(-/-) mice, dopamine D(3) receptor homozygous and heterozygous mutant mice, on the whole, did not differ from their controls in the time spent in a cataleptic position following administration of either haloperidol (0.5-2 mg/kg i.p.) or SCH 23390 (0.03-0.6 mg/kg s.c.). Also, dopamine D(3) receptor mutant mice were no more responsive than wild-type controls when co-administered subthreshold doses of haloperidol (0.125 mg/kg) and SCH 23390 (0.03 mg/kg), suggesting that dopamine D(3) receptor knock-out mice are not more sensitive than wild-types to the synergistic effects of concurrent blockade of dopamine D(2) and dopamine D(1) receptors in this model. These results suggest that the dopamine D(2) receptor subtype is necessary for haloperidol to produce catalepsy, and that the dopamine D(3) receptor subtype appears to exert no observable control over the catalepsy produced by dopamine D(2)-like, D(1)-like and the combination of D(1)-like and D(2)-like receptor antagonists.

Animals↗
PubMed2000

CYP3A is responsible for N-dealkylation of haloperidol and bromperidol and oxidation of their reduced forms by human liver microsomes.

We studied the biotransformation of haloperidol, bromperidol and their reduced forms by human liver microsomes. Nifedipine oxidation (CYP3A) activity correlated significantly with N-dealkylation rates of haloperidol and bromperidol and oxidation rates of their reduced forms, while neither ethoxyresorufin O-deethylation (CYP1A2) activity nor dextromethorphan O-deethylation (CYP2D6) activity did. In chemical and immunoinhibition studies, only troleandomycin and anti-CYP3A4 serum inhibited both formation rates of 4-fluorobenzoylpropionic acid, a metabolite of haloperidol and bromperidol, and back oxidation rates. Among 10 recombinant isoforms examined, only CYP3A4 showed catalytic activity. The Vmax and Km values of N-dealkylation of bromperidol and reoxidation of reduced bromperidol were similar to those of haloperidol and reduced haloperidol, respectively. The present study indicates that CYP3A plays a major role in N-dealkylation of and oxidation back to bromperidol as well as haloperidol and suggests that modification of in vivo CYP3A activity by inhibition or induction may affect the pharmacokinetics and therapeutic effects of haloperidol and bromperidol.

Aryl Hydrocarbon Hydroxylases↗
PubMed1998

Effects of haloperidol and GM1 ganglioside treatment on striatal D2 receptor binding and dopamine turnover.

Previous studies have shown that whereas exogenous GM1 ganglioside co-administration leads to an increase of haloperidol-induced behavioral supersensitivity, GM1 significantly attenuates the behavioral parameters of dopaminergic supersensitivity when administered after abrupt haloperidol withdrawal. In the present study, the effects of GM1 and haloperidol co-administration (5 mg/kg GM1 i.p. and 1 mg/kg haloperidol i.p., twice daily, for 30 days) as well as the effects of a 3 day treatment with GM1 were investigated in rats withdrawn from haloperidol administration by measuring striatal D2 dopamine receptor binding and dopamine turnover. The results showed that under these two experimental conditions GM1 modified neither the haloperidol-induced striatal D2 dopamine receptor up regulation nor the decrease in dopamine turnover produced by haloperidol withdrawal. These results suggest that the effects of GM1 on behavioral supersensitivity are not related to modifications in dopamine receptor number or affinity and in the synaptic availability of this catecholamine.

Animals↗
PubMed1999

Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation.

We have examined the effects of a variety of classical and atypical neuroleptic drugs on mitochondrial NADH ubiquinone oxido-reductase (complex I) activity. Sagittal slices of mouse brain incubated in vitro with haloperidol (10 nM) showed time- and concentration-dependent inhibition of complex I. Similar concentrations of the pyridinium metabolite of haloperidol (HPP+) failed to inhibit complex I activity in this model; indeed, comparable inhibition was obtained only at a 10000-fold higher concentration of HPP+ (100 microM). Treatment of brain slices with haloperidol resulted in a loss of glutathione (GSH), while pretreatment of slices with GSH and alpha-lipoic acid abolished haloperidol-induced loss of complex I activity. Incubation of mitochondria from haloperidol treated brain slices with the thiol reductant, dithiothreitol, completely regenerated complex I activity demonstrating thiol oxidation as a feasible mechanism of inhibition. In a comparison of different neuroleptic drugs, haloperidol was the most potent inhibitor of complex I, followed by chlorpromazine, fluphenazine and risperidone while the atypical neuroleptic, clozapine (100 microM) did not inhibit complex I activity in mouse brain slices. The present studies support the view that classical neuroleptics such as haloperidol inhibit mitochondrial complex I through oxidative modification of the enzyme complex.

Animals↗
PubMed2001

Olanzapine versus haloperidol in schizoaffective disorder, bipolar type.

BACKGROUND: The present analysis was performed on data from a subsample of patients with schizoaffective disorder, bipolar type, who participated in a multicenter, double-blind study comparing olanzapine to haloperidol. METHODS: Patients with schizoaffective disorder bipolar type, characterized as currently manic, mixed, depressed, or euthymic, were assessed weekly for 6 weeks during treatment with either olanzapine or haloperidol. Manic symptoms were measured using the sum of six items of the BPRS, and depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale. In addition, cognitive functioning was measured using the sum of seven items from the PANSS. Repeated measures analyses were performed using random coefficients regression of the serial measurement of manic, cognitive, and depressive symptoms. RESULTS: A significant treatment difference was detected overall, indicating that olanzapine was significantly more effective than haloperidol in reducing symptoms of depression and improving patients' cognitive symptoms. The superiority of olanzapine over haloperidol in the reduction of manic symptoms did not reach statistical significance (P=.052). The greatest improvement in both manic and cognitive symptoms was seen in the olanzapine-treated 'currently manic' subgroup, and least improvement in the haloperidol-treated 'euthymic' subgroup. Depressive symptoms were most improved in the olanzapine-treated 'depressed' subgroup, and least improved in the corresponding haloperidol subgroup. CONCLUSIONS: Overall, olanzapine was superior to haloperidol with respect to thymoleptic effects in patients with schizoaffective disorder, bipolar type.

Administration, Oral↗
PubMed1999

The potential role of haloperidol in the treatment of trichotillomania.

BACKGROUND: Trichotillomania is categorized as an impulse control disorder in DSM-IV and is considered by some to be closely related to Obsessive Compulsive Disorder (OCD). We review the clinical phenomenology and pharmacological response of trichotillomania, and suggest that it may be more related to Tourette Syndrome than to OCD. Serotonin reuptake inhibitors (SRIs) are typically employed in the treatment of OCD, while neuroleptic medications such as haloperidol are typically used in the treatment of Tourette Syndrome. Evidence for the efficacy of treatment of trichotillomania with drugs typically used for OCD is equivocal. METHOD: Nine patients with trichotillomania were treated with haloperidol. Six patients unresponsive to SSRI medication had haloperidol added to their treatment. Three patients received only haloperidol. Response to treatment was assessed using descriptions of hair pulling, quantity of hair pulled, and severity of depilation at hair pulling sites. RESULTS: Eight of nine patients responded to haloperidol treatment, with seven experiencing complete or near complete cessation of hair pulling. LIMITATIONS: Inferences from the results of this study are limited by the lack of a control group, the small sample size, and the use of unstandardized ratings as measures of symptom severity. CONCLUSIONS: Results suggest that the addition of haloperidol to SSRIs or haloperidol alone may be effective in the treatment of trichotillomania. Results also encourage speculation about the relation between OCD, Tourette Syndrome, and trichotillomania.

Adult↗
PubMed2000

Pretreatment plasma HVA and haloperidol response in acute mania.

INTRODUCTION: Pretreatment plasma homovanillic acid (HVA) levels have been reported to be a correlate of clinical response to typical antipsychotics for schizophrenic, bipolar manic, and mixed groups of psychotic patients. Biological markers of clinical response to antipsychotics could be useful for optimizing drug treatment. METHOD: Thirty-one consenting acute inpatient subjects between ages 19 and 66 years with a DSM-III-R clinical diagnosis of bipolar disorder, manic with psychotic features were entered into this double-blind study and were randomly assigned to receive either haloperidol 25 mg/day or haloperidol 5 mg for the 3-week study. Subjects also received one of the following concomitant medications: standard lithium, lorazepam 4 mg/day, or placebo. RESULTS: The primary multiple regression analysis, including all subjects on both haloperidol doses, yielded a significant main effect for pretreatment plasma HVA (n=31, F=5.7, P=0.025), indicating that higher pretreatment plasma HVA was predictive of better clinical response. In addition, the interaction between haloperidol dose and pretreatment plasma HVA was also significantly associated with clinical response (F=12.59, P=0.0015). When the two haloperidol doses were analyzed separately, we found that pretreatment plasma HVA was only correlated with clinical response in the low haloperidol 5 mg/day group (n=18, F=11.73, P=0.0038) and was unrelated to clinical response to the high haloperidol 25 mg/day group. LIMITATIONS: The sample size was small. Results may have been confounded by prior antipsychotic treatment and concomitant use of lithium or lorazepam. DISCUSSION: These results suggest that pretreatment plasma HVA could be useful for dosing antipsychotics. Patients with high plasma HVA levels would be good candidates for low-dose treatment because they are more likely to improve on such a dose, while patients with low plasma HVA levels might warrant more rapid dosage escalation.

Acute Disease↗
PubMed1998

An investigation of ethnic and gender differences in the pharmacodynamics of haloperidol.

The objective of this study was to examine neuroleptic effectiveness among Asians and Caucasians, and to investigate inter-ethnic pharmacodynamic differences. Asians and Caucasians suffering a first episode of psychosis were maintained on low oral doses of haloperidol (2 mg/day) for the first week of treatment. Doses were increased weekly until the optimal therapeutic dosage was achieved. This was defined as the point at which subjects: (a) experienced significant clinical improvement; or (b) developed extrapyramidal side effects. Plasma haloperidol and prolactin were measured at intake, at the end of first week of the treatment on haloperidol 2 mg/day, and at optimal therapeutic dosage. The average optimal dosage for Asians and Caucasians was equal. However, at the end of the first week of haloperidol at a fixed dose of 2 mg, Caucasian males had significantly lower plasma haloperidol levels than Asian males while no ethnic differences in haloperidol levels were found among females. There were no ethnicity or gender effects on plasma prolactin response after 1 week of treatment. Ethnicity and gender may affect haloperidol metabolism.

Adult↗
PubMed2002

Differential effects of cyclooxygenase inhibitors on haloperidol-induced catalepsy.

Prostaglandins (PGs) might play a role as putative transmitters or as modulators in the central nervous system (CNS). In the present study, haloperidol (1 mg/kg i.p.)-treated mice showed significant cataleptic behaviour. Naproxen, a nonselective cyclooxygenase (COX) inhibitor, dose-dependently (5 and 10 mg/kg) antagonized the haloperidol-induced catalepsy in mice. Nimesulide, a preferential COX inhibitor, also dose-dependently reduced the cataleptic score in haloperidol treated animals at the first and second hour but not at the third and fourth hour of haloperidol treatment. Rofecoxib, a selective COX-2 inhibitor, did not show any effect on haloperidol-induced catalepsy. The major findings of the present study suggest that PGs might play a significant role in haloperidol-induced catalepsy. The findings of the present study further suggested that COX-1 derived rather than COX-2 derived PGs might play a potential role in haloperidol-induced catalepsy. In conclusions COX inhibitors can be screened as potential drug candidates for the treatment of neuroleptic-induced extrapyramidal side effects (EPS).

Animals↗
PubMed2002

Comparison of prolactin concentrations between haloperidol and bromperidol treatments in schizophrenic patients.

The antipsychotic drug, bromperidol, is a close structural analogue of haloperidol. These two drugs also have similarities in metabolic pathways and pharmacological properties. In the present study, the prolactin concentrations in plasma during bromperidol versus haloperidol treatments were compared in the same individuals. The subjects were 22 schizophrenic inpatients, who first received bromperidol 12 mg/day for at least 2 weeks followed by haloperidol 12 mg/day. The prolactin concentration in plasma during bromperidol treatment (median and range; 24 and 7-93 ng/ml, respectively) was significantly (P< .01) lower than during haloperidol treatment (32 and 8-102 ng/ml), although the difference was small. The mean (+/- S.D.) plasma concentration of bromperidol was significantly lower than that of haloperidol (20.8+/-8.0 vs. 28.0+/-13.1 nmol/l, P<.05). Prolactin concentrations during both treatment phases correlated well in individuals (r's=.813, P<.001), while no correlation was observed between plasma concentrations of haloperidol and bromperidol (r=.053, ns). These findings suggest that slightly higher prolactin concentration does not necessarily lead to increased risk of hyperprolactinemia during bromperidol treatment compared with haloperidol treatment. In addition, it is suggested that both drugs show similar pharmacodynamic response despite the difference in pharmacokinetics in the same individuals.

Adult↗
PubMed1998

Oral Dyskinesias and striatal lesions in rats after long-term co-treatment with haloperidol and 3-nitropropionic acid.

The pathophysiologic basis of tardive dyskinesia remains unclear. It has been proposed that tardive dyskinesia may be a result of excitotoxic neurodegeneration in the striatum caused by a neuroleptic-induced increase in striatal glutamate release and impaired energy metabolism. To investigate this hypothesis, haloperidol decanoate (38 mg/kg/four weeks intramuscularly) and the succinate dehydrogenase inhibitor 3-nitropropionic acid (8 mg/kg/day via subcutaneous osmotic mini-pumps), were administered alone or together for 16 weeks to four-months-old rats. Control rats received sesame oil intramuscularly and had empty plastic tubes subcutaneously. Vacuous chewing movements, a putative analogue to human tardive dyskinesia, were recorded during and after drug treatment. Haloperidol alone, 3-nitropropionic acid alone, and 3-nitropropionic acid+haloperidol treatments induced an increase in vacuous chewing movements. However, vacuous chewing movements were more pronounced and appeared earlier in rats treated with 3-nitropropionic acid+haloperidol. After drug withdrawal, increases in vacuous chewing movements persisted for 16 weeks in the haloperidol alone and 3-nitropropionic acid+haloperidol group and for four weeks in the 3-nitropropionic acid alone group. Brains from each group were analysed for histopathological alterations. Bilateral striatal lesions were present only in rats with high levels of vacuous chewing movements in the 3-nitropropionic acid+haloperidol-treated rats. Nerve cell depletion and astrogliosis were prominent histopathologic features. There was selective neuronal sparing of both large- and medium-sized aspiny striatal neurons. These results suggest that mild mitochondrial impairment in combination with neuroleptics results in striatal excitotoxic neurodegeneration which may underlie the development of persistent vacuous chewing movements in rats and possibly irreversible tardive dyskinesia in humans.

Analysis of Variance↗
PubMed2002

Mechanisms underlying the protective potential of alpha-tocopherol (vitamin E) against haloperidol-associated neurotoxicity.

The undesired side-effects of haloperidol treatment include a number of extrapyramidal side-effects which have been proposed to result from drug-induced damage to the basal ganglia. The drug also causes irregular movements and locomotor patterns in experimental animals. Here we show that haloperidol treatment in rats is associated with increases in the expression of p53 and the ratio of pro-apoptotic (Bax) to anti-apoptotic (Bcl-2/Bcl-x(L)) proteins in the hippocampus and caudate putamen (CPu). In addition, haloperidol induces the DNA binding activity of the redox-sensitive nuclear factor-kappa B (NF-kappaB) and concomitantly upregulates the levels of the phosphorylated form of IkappaBalpha protein in vivo. Similar responses are observed when a mouse hippocampal cell line (HT-22) is treated with haloperidol and/or vitamin E. Interestingly, all of these biochemical effects of haloperidol are significantly attenuated when animals or cultured cells are pretreated with alpha-tocopherol (vitamin E). Consistent with this, vitamin E is demonstrated to substantially reduce the haloperidol-induced impairment of locomotor activity in rats. Collectively, the data indicate the usefulness of vitamin E as an adjunct to haloperidol treatment and provide initial clues about the underlying molecular mechanisms involved in these effects.

Animals↗