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PubMed2000

In vivo effects of the putative cognitive enhancer KA-672.HCl in comparison with 8-hydroxy-2-(di-N-propylamino) tetralin and haloperidol on dopamine, 3,4-dihydroxyphenylacetic acid, serotonin and 5-hydroxyindoleacetic acid levels in striatal and cortical brain regions.

1. KA-672.HCl (7-methoxy-6-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy]-3,4-di methyl-2H-1-benzopyran-2-one hydrochloride), designed as a cognitive enhancer, has been investigated through behavioural and binding studies. However, little is known about its biochemical effects on the dopaminergic and serotoninergic system in vivo. 2. In the present study the authors investigated the effects of KA-672.HCl (0.1 mg/kg and 1 mg/kg), 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) (1 mg/kg), haloperidol (0.1 mg/kg) and a mixture of haloperidol and 8-OH-DPAT on dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels, in striatum and cerebral cortex of rats. 3. Male Wistar rats received an intraperitoneal injection of the drugs or vehicle 1 hour before striatal and cortical brain tissues were dissected out for neurochemical analysis. 4. KA-672.HCl, 8-OH-DPAT and haloperidol significantly reduced striatal DA levels, whereas only KA-672.HCl significantly reduced cortical DA levels. 8-OH-DPAT and haloperidol induced a significant increase in cortical DOPAC levels but only haloperidol significantly elevated the striatal DOPAC content. In contrast, only the higher dose of KA-672.HCl elevated striatal DOPAC levels. Furthermore, KA-672.HCl significantly reduced striatal 5-HT levels and slightly elevated striatal 5-HIAA concentrations. 8-OH-DPAT significantly decreased striatal 5-HIAA levels. All substances were able to enhance the cortical and striatal DA turnover. 5. The cortical and striatal 5-HT turnover was significantly decreased following 8-OH-DPAT treatment and significantly increased in the striatum after haloperidol and KA-672.HCl treatment. 6. The data suggest that KA-672.HCl possesses D2 antagonistic as well as 5-HT1A agonistic properties. However, additional mechanisms of actions by interaction with other neurotransmitter systems such as acetylcholine, excitatory or inhibitory amino acids need to be determined.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Subchronic treatment with either clozapine, olanzapine or haloperidol produces a hyposensitive response of the rat cortical cells to N-methyl-D-aspartate.

Using the technique of intracellular recording in in vitro brain slice preparations, we examined the effects produced by repeated administration of the antipsychotic drugs clozapine, olanzapine and haloperidol, on N-methyl-D-aspartic acid-induced responses in pyramidal cells of the rat medial prefrontal cortex. Rats were anesthetized and decapitated 24h after the conclusion of daily intraperitoneal injection with either clozapine (25mg/kg), olanzapine (1, 5 or 10mg/kg) or haloperidol (0.5mg/kg) for 21 days, and the slices from medial prefrontal cortex were used for electrophysiological recordings. The concentration-response curves for N-methyl-D-aspartic acid to activate cortical cells shifted markedly to the right in rats which received the subchronic antipsychotic drug treatment, compared with those obtained from rats which received repeated injections of vehicle (1ml/kg/day, i.p. for 21 days). In addition, repeated exposure to antipsychotic drugs caused a significant reduction in the ability of these antipsychotic drugs to augment the N-methyl-D-aspartic acid-induced inward current in pyramidal cells of the rat medial prefrontal cortex. Repeated administration of haloperidol, but not clozapine or olanzapine, significantly hyperpolarized the resting membrane potential and increased membrane resistance in pyramidal cells of the medial prefrontal cortex. Moreover, subchronic treatment with haloperidol, but not clozapine or olanzapine, depressed (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-induced responses. The desensitized response of medial prefrontal cortex cells to N-methyl-D-aspartic acid could be the result of a compensatory response to the facilitating action of antipsychotic drugs on N-methyl-D-aspartic acid receptor-mediated transmission. The inhibitory action of haloperidol on (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid responses may also contribute to the rightward shift of the N-methyl-D-aspartic acid concentration-response curve.Thus, the present study suggests that the atypical antipsychotic drugs, clozapine and olanzapine, as well as the typical antipsychotic drug haloperidol strongly modulate glutamatergic transmission after prolonged treatment. This might be an important factor in the mechanisms by which these drugs alleviate symptoms in schizophrenic patients.

Animals↗

PubMed2000

Haloperidol-induced rhabdomyolysis without neuroleptic malignant syndrome in a handicapped child.

A 6-year-old severely handicapped boy with haloperidol-induced mild rhabdomyolysis without neuroleptic malignant syndrome is reported. He had suffered from frontal lobe epilepsy, severe mental retardation and involuntary movements. To reduce the involuntary movements, oral administration of haloperidol was started. Haloperidol was effective for the involuntary movements, and he became well. However, his urine was sometimes dark brown, and the myoglobin level in his urine was increased. After discontinuation of haloperidol, his urine never became dark brown. It was suspected that haloperidol might cause mild rhabdomyolysis without neuroleptic malignant syndrome. Neuroleptic malignant syndrome is a rare but severe adverse effect of neuroleptics, and is usually accompanied by rhabdomyolysis. Although there have been a few adult cases presenting rhabdomyolysis without neuroleptic malignant syndrome, this patient might be the first child case with such symptoms. We have to pay attention to this syndrome when using haloperidol even in children.

Anti-Dyskinesia Agents↗

PubMed2000

Haloperidol administered subchronically reduces the alcohol-deprivation effect in mice.

During the pre-experimental phase, hybrid (CBA x C57BL) male mice having had 16 weeks free access to food, water and flavored 30% alcohol were deprived of alcohol for 3 days. The next day they were given free choice between similarly flavored water and 30% alcohol. The mice were divided into two subgroups having (HD) or lacking (LD) the deprivation-induced elevation in alcohol intake during the first 1.5 h of renewed access compared with their intake during the last 22.5 h of first postdeprivation day. In Experiment 1, alcohol naive, LD, and HD mice received daily injections of haloperidol (Haldol; 1 mg/kg) or vehicle during 14 days of abstinence. The behavior of the mice was evaluated in an exploratory cross-maze and inescapable slip funnel test a day after the 13th injection (before the 14th injection). On the first postinjection day, the mice were again given a free choice between flavored water and alcohol. In Experiment 2, all the mice were administered with vehicle during the first 13 days of abstinence. On 14th day, they received an injection of haloperidol (1 mg/kg) or vehicle and a day later were given choice between flavored water and alcohol. Unlike a single injection, the subchronic administration of haloperidol lowered the alcohol intake by HD mice with a more prominent decrease seen during the first 1.5 h than during the last 22.5 h of first postdeprivation day. The alcohol-deprivation effect in HD mice decreased by 79% after subchronic haloperidol. No significant change in alcohol intake was found in alcohol-naive and LD mice. Water intake did not vary systematically. Among the groups, the effect of subchronic haloperidol on the alcohol-deprivation effect did not parallel changes in most of the measures of exploratory or avoidance behavior. It is proposed that haloperidol administered subchronically may attenuate motivation for alcohol.

Alcohol Drinking↗

PubMed2002

SR46349-B, a 5-HT(2A/2C) receptor antagonist, potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens.

The combination of M100907, a putative antipsychotic drug (APD) and serotonin (5-HT)(2A) antagonist, and the typical APD haloperidol, can enhance dopamine (DA) release in rat medial prefrontal cortex (mPFC), an effect which has been postulated to be of value to improve cognition and negative symptoms. The present study demonstrated that another putative APD and 5-HT(2A/2C) antagonist, SR46349-B (10 mg/kg, but not 1-3 mg/kg) alone, but not M100907 (0.1 and 3 mg/kg) alone, increased mPFC DA release, whereas neither drug alone affected nucleus accumbens (NAC) DA release. Neither SR46349-B nor M100907 alone affected nucleus accumbens (NAC) DA release. Neither SR46349-B nor M100907 alone affected nucleus accumbens (NAC) DA release. SR46349-B (3 mg/kg) potentiated haloperidol-induced DA release in both regions, whereas M100907 (0.1 mg/kg) potentiated haloperidol (0.1 mg/kg)-induced mPFC DA release and inhibited it in the NAC. WAY100635 (0.2 mg/kg), a 5-HT(1A) antagonist, abolished the effects of haloperidol plus M100907 as well as SR46349-B on DA release in the mPFC, but did not do so in the NAC. Thus, 5-HT(2A) and 5-HT(2A/2C) antagonism together with haloperidol-induced D(2) antagonism may potentiate mPFC DA release via 5-HT(1A) agonism, whereas the combined effects of these agents on NAC DA release is not dependent upon 5-HT(1A) receptor stimulation. Interestingly, similar to the effect of SR46349-B, high dose M100907 (3 mg/kg), which might have antagonist activity at 5-HT(2C) receptors, potentiated 1 mg/kg haloperidol-induced DA release in the mPFC and NAC. These results suggest that 5-HT(2A/2C) antagonism may be more advantageous than selective 5-HT(2A) antagonism as an adjunct to D(2) antagonists to improve cognition and negative symptoms in schizophrenia.

Analysis of Variance↗

PubMed1998

Genetics, haloperidol, and the Fos response in the basal ganglia: a comparison of the C57BL/6J and DBA/2J inbred mouse strains.

The haloperidol-induced increase of Fos-like immunoreactive (Fos-li) neurons in the basal ganglia was compared in the C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains. The D2 strain is 10-fold more sensitive than the B6 strain to haloperidol-induced catalepsy, a putative animal model of the extrapyramidal symptoms (EPS) seen after the administration of typical neuroleptics. In contrast, the strains are equally sensitive to the haloperidol facilitation of prepulse inhibition of the acoustic startle response, a measure of drug efficacy on the mesolimbic dopamine system. The haloperidol effects on Fos-li neurons were examined over the range of 0.1 to 6.0 mg/kg; the ED50s for haloperidol-induced catalepsy are 0.4 and 3.8 mg/kg in the D2 and B6 strains, respectively. In neither the core or shell of the nucleus accumbens nor the caudate-putamen (including the dorsolateral aspect) did the D2 strain show a greater Fos response compared to the B6 strain. In fact, in the dorsolateral caudate-putamen, the B6 strain showed a modest but significantly greater Fos response. However, at the output nuclei of the basal ganglia, the entopeduncular nucleus (EP) and the substantia nigra zona reticulata (SNr), the D2 strain consistently showed a greater Fos response. These data suggest that the EP and SNr may be important to understanding the difference in haloperidol-induced catalepsy between the D2 and B6 strains.

Animals↗

PubMed1999

Involvement of adenosine A2A receptors in the induction of c-fos expression by clozapine and haloperidol.

Acute administration of the atypical antipsychotic clozapine induced a regional pattern of c-fos expression characterized by an increase in Fos-like-immunoreactivity (FLI) in the prefrontal and prelimbic/infralimbic cortices, nucleus accumbens, and lateral septum and a weak activation of FLI in the striatum. Haloperidol, similarly to clozapine, increased FLI in the nucleus accumbens and lateral septum, but it did not induce FLI in prefrontal and prelimbic/infralimbic cortices. Moreover, haloperidol increased FLI in the striatum. To gain insight into the mechanism by which clozapine and haloperidol induced FLI in these brain structures, we evaluated whether blockade of adenosine A2A receptors could influence these effects. The selective and high-affinity A2A receptor antagonist SCH 58261 (5 mg/kg) completely abolished FLI induced by clozapine (20 mg/kg) in all subdivisions of the nucleus accumbens (rostral pole, shell and core) and striatum, but did not affect the number of Fos-like positive neurons in the prefrontal, prelimbic/infralimbic cortices, and lateral septum. SCH 58261 (5 mg/kg) reduced FLI induced by haloperidol (0.1 mg/kg) in the striatum, lateral septum, and all nucleus accumbens subdivisions. In contrast, FLI induced by 0.5 mg/kg of haloperidol in the shell and core of the nucleus accumbens was not affected by SCH 58261. The results show that adenosine A2A receptors participate in the induction of FLI by clozapine and haloperidol and support the concept that A2A receptors are involved in the mediation of antipsychotic effects.

Animals↗

PubMed2002

Does cognitive function improve with quetiapine in comparison to haloperidol?

Recent evidence suggests that schizophrenia patients taking atypical antipsychotic medications may perform better on some tests of cognitive function than those treated with older antipsychotics. The current study compared the effects of quetiapine and haloperidol on measures of executive function, memory and attention. Subjects were 58 stable outpatients with schizophrenia (DSM III-R) who received a battery of cognitive tests as part of a randomized, double-blind, multi-site clinical efficacy study conducted by AstraZeneca Pharmaceuticals. Cognitive assessments were conducted prior to randomization when patients were receiving < or =30 mg haloperidol or equivalent (mean: 9.2mg/day haloperidol equivalents), and again after 24 weeks of fixed-dose treatment with either quetiapine 600 or 300 mg/day or haloperidol 12 mg/day. Analyses of covariance with planned comparisons were used to compare scores on cognitive measures at the end of 24 weeks by treatment group with baseline cognitive function scores used as covariates. Patients receiving quetiapine 600 mg/day improved to a greater extent than patients receiving haloperidol on overall cognitive function (p<0.02). Specific differences were found for executive function (Verbal Fluency Test, p<0.04), attention (Stroop Color Word Test, p<.03) and verbal memory (Paragraph Recall Test, p<0.02). Treatment group differences were not solely due to benztropine use, medication side effects, or changes in symptomatology. Treatment with quetiapine at higher doses (600 mg/day) relative to haloperidol appears to have a positive impact on important domains of cognitive performance that have been found to predict role function and community outcomes in patients with schizophrenia.

Antipsychotic Agents↗

PubMed1997

Clinical experience with risperidone, haloperidol, and thioridazine for dementia-associated behavioral disturbances.

The efficacy and safety of risperidone, haloperidol, and thioridazine for treating dementia-associated behavioral disturbances were evaluated in a retrospective study of 186 patients aged 65 years or older with DSM-III-R or DSM-IV diagnoses of Alzheimer's dementia, senile dementia NOS, or organic brain syndrome. Study patients were selected from the charts of 12,000 residents of 60 long-term-care facilities in New Jersey if they were treated with one of the three agents for behaviors dangerous to themselves or others. The 186 selected patients included 60 treated with risperidone (mean, 1 mg/day), 83 with haloperidol (mean, 2 mg/day), and 43 with thioridazine (mean, 33 mg/day). Target behaviors were violence (74 patients), shouting (31), delusions (26), paranoia (19), pacing (3), and mixed behaviors (33). Target behaviors improved in 94% of patients given risperidone, 65% given haloperidol, and 67% given thioridazine (p < .001). Treatment failures (treatment discontinued in patients because of side effects or no improvement) were more frequent in patients started on haloperidol (28) or thioridazine (15) than on risperidone (3). Extrapyramidal symptoms were reported in 7% of patients taking risperidone, 22% taking haloperidol, and 18% taking thioridazine. Safe, effective doses are readily achieved with risperidone but difficult to achieve with haloperidol or thioridazine because their effective doses often cause unacceptable side effects. These data are only suggestive because no guidelines exist for defining or measuring behavioral disturbances or for how they are affected by social, psychological, or environmental factors.

Aged↗

PubMed2003

Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia.

Aripiprazole is a novel atypical antipsychotic for the treatment of schizophrenia. It is a D2 receptor partial agonist with partial agonist activity at 5-HT1A receptors and antagonist activity at 5-HT2A receptors. The long-term efficacy and safety of aripiprazole (30 mg/d) relative to haloperidol (10 mg/d) were investigated in two 52-wk, randomized, double-blind, multicentre studies (using similar protocols which were prospectively identified to be pooled for analysis) in 1294 patients in acute relapse with a diagnosis of chronic schizophrenia and who had previously responded to antipsychotic medications. Aripiprazole demonstrated long-term efficacy that was comparable or superior to haloperidol across all symptoms measures, including significantly greater improvements for PANSS negative subscale scores and MADRS total score (p<0.05). The time to discontinuation for any reason was significantly greater with aripiprazole than with haloperidol (p=0.0001). Time to discontinuation due to adverse events or lack of efficacy was significantly greater with aripiprazole than with haloperidol (p=0.0001). Aripiprazole was associated with significantly lower scores on all extrapyramidal symptoms assessments than haloperidol (p<0.001). In summary, aripiprazole demonstrated efficacy equivalent or superior to haloperidol with associated benefits for safety and tolerability. Aripiprazole represents a promising new option for the long-term treatment of schizophrenia.

Acute Disease↗

PubMed2005

Treatment of behavioural, cognitive and circadian rest-activity cycle disturbances in Alzheimer's disease: haloperidol vs. quetiapine.

This 5-wk, open-label, comparative study investigated the effects of quetiapine and haloperidol on behavioural, cognitive and circadian rest-activity cycle disturbances in patients with Alzheimer's disease (AD). Out of a total of 30 patients enrolled in the study, there were 22 completers, 11 in the quetiapine group (mean age 81.9+/-1.8 yr, mean baseline MMSE 19.9+/-1.3, mean dose 125 mg) and 11 in the haloperidol group (mean age 82.3+/-2.5 yr, mean baseline MMSE 18.1+/-1.3, mean dose 1.9 mg). As shown in the Neuropsychiatric Inventory, both medications reduced delusion and agitation, whereas quetiapine additionally improved depression and anxiety. Haloperidol worsened aberrant motor behaviour and caused extrapyramidal symptoms. In the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological test battery which assessed cognitive parameters, quetiapine improved word recall; significant interaction terms revealed differences between quetiapine and haloperidol in word-list memory and constructional praxis. According to the Nurses' Observation Scale for Geriatric Patients (NOSGER) quetiapine improved instrumental activities of daily living. Actimetry documented the circadian rest-activity cycle before and after treatment. Sleep analysis revealed that patients receiving quetiapine had shorter wake bouts during the night, whereas patients receiving haloperidol had fewer though longer immobile phases. The study provides evidence that quetiapine at a moderate dose may be efficacious in treating behavioural disturbances in AD, with better tolerability than haloperidol.

Activities of Daily Living↗

PubMed1993

Evaluation of the effects of the enantiomers of reduced haloperidol, azaperol, and related 4-amino-1-arylbutanols on dopamine and sigma receptors.

The enantiomers of reduced haloperidol (3a), azaperol (3b), and the related compound BMY-14802 (3c) were prepared in high optical purity. The affinity of these compounds for dopamine D2 and D3 receptors, and sigma S1 and S2 sites was determined in vitro. Both enantiomers of 3a display greatly decreased affinity for D2 and D3 receptors compared to haloperidol, although they still possess affinities in the 100-200-nM range. Both enantiomers of 3a possess potent and equal affinity for S1 sites (Ki: 1-2 nM), only slightly weaker than haloperidol (Ki: 0.33 nM). At S2 sites, (R)-(+)-3a displays similar affinity to haloperidol (Ki: 31 and 26 nM, respectively), while (S)-(-)-3a is slight more potent (Ki: 8.2 nM). The stereoselectivity profile of the enantiomers of 3b at D2 and D3 receptors is quite similar to that of 3a, (S)-(-)-3b being about 4 times more potent than its enantiomer at both receptors. (R)-(+)-3b binds preferentially to sigma S1 over S2 sites, while (S)-(-)-3b displays the opposite selectivity profile. Both enantiomers of 3c possess very weak affinity for D2 and D3 receptors. In a manner similar to the enantiomers of 3b, the affinity of (R)-(+)-3c is greater for S1 than S2 sites, while (S)-(-)-3c displays the opposite selectivity profile. Following parenteral administration of both enantiomers of 3a, dopamine synthesis and turnover in rat striatum, cortex, and mesolimbic areas were increased, in a manner similar to the effects produced by haloperidol itself. Additional studies will be required to assess with certainty whether the effects were due to the compounds themselves or simply were a consequence of the in vivo oxidation to haloperidol.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

Olanzapine versus haloperidol in the treatment of schizophrenia and other psychotic disorders: quality of life and clinical outcomes of a randomized clinical trial.

BACKGROUND: Little information is available on the impact of the atypical antipsychotic olanzapine on quality of life (QOL). A 6-week, double-blind randomized multicenter trial, with a long-term extension, was conducted to evaluate the clinical efficacy and QOL of olanzapine and haloperidol in treating schizophrenia and other psychotic disorders. METHODS: A total of 828 outpatients provided QOL data. Study patients were aged greater than 18 years with a DSM-III-R diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder and baseline BPRS (items scored on 0-6 scale) total scores, > or = 18 were randomized to 6 weeks of treatment with olanzapine 5 to 20 mg/day or haloperidol 5 to 20 mg/day. Patients entered a 46-week double-blind extension if they demonstrated minimal clinical response and were tolerant to study medication. The Quality of Life Scale (QLS) and SF-36 Health Survey were used to evaluate QOL. RESULTS: During the 6-week acute phase, olanzapine treatment significantly improved BPRS total (p = 0.004), PANSS total scores (p = 0.043), QLS total (p = 0.005), intrapsychic foundations (p < 0.001) and interpersonal relations scores (p = 0.036), and SF-36 mental component summary scores (p < 0.001) compared with haloperidol. During the extension phase, olanzapine treatment significantly improved PANSS negative scores (p = 0.035) and improved QLS total (p = 0.001), intrapsychic foundations (p < 0.001), and instrumental role category scores (p = 0.015) versus haloperidol treatment. Significantly more haloperidol patients discontinued treatment due to adverse events during the acute and extension phases (p = 0.041 and p = 0.014, respectively). Changes in QLS total and MCS scores were associated with changes in clinical symptoms, depression scores and extrapyramidal symptoms. CONCLUSIONS: Olanzapine was more effective than haloperidol in reducing severity of psychopathology and in improving QOL in patients with schizophrenia and other psychotic disorders. The QOL benefits of olanzapine, although modest, may be important for long-term treatment.

Adult↗

PubMed1985

Forelimb placing and hopping reflexes in haloperidol- and morphine-treated cataleptic rats.

Although both haloperidol and morphine produce catalepsy, there are fundamental differences in their neurological effects (De Ryck, Schallert, & Teitelbaum, 1980). Haloperidol-treated rats show brisk righting, bracing, and clinging reflexes, effects suggesting that motor subsystems subserving static postural support are dominant over those involved in more phasic locomotor and orienting movements. In contrast, morphine-treated rats show impaired righting, bracing, and clinging, effects suggesting that postural support mechanisms are suppressed. In order to determine whether phasic postural reactions other than righting are also differentially affected by these drugs, forelimb placing and hopping reflexes were evaluated in rats given either haloperidol (0, 0.25, 0.5, 1, and 5 mg/kg) or morphine sulfate (0, 10, 20, and 40 mg/kg). Morphine produced a dose-dependent impairment in all tests. In contrast, haloperidol did not impair contact placing to dorsal stimulation of the limb or chin placing. Hopping and contact placing to lateral stimulation of the limb were impaired by haloperidol, perhaps because stimulation induced a competing tendency to brace. These results provide additional evidence that morphine and haloperidol produce functionally different neurological states.

Animals↗

PubMed1999

State-dependent blockade of haloperidol-induced sensitization of catalepsy by MK-801.

NMDA receptor antagonists have been shown to block several forms of neural and behavioural plasticity. The prototypical and most widely-used noncompetitive NMDA receptor antagonist is dizocilpine (MK-801). Here we have examined the effect of MK-801 on the context-dependent augmentation ('sensitization') of catalepsy in rats which develops with repeated administration of haloperidol. It was found that over a 7-day treatment period animals receiving haloperidol (0.25 or 0.5 mg/kg) plus MK-801 (0.16 mg/kg) showed a context-dependent day-to-day increase in catalepsy similar to animals that received haloperidol alone. However, when all animals were treated with haloperidol alone on day 8 of the experiment, animals that had received haloperidol plus MK-801 before displayed a much smaller cataleptic response, similar to that observed in the haloperidol group on the first treatment day, i.e. the previously-established enhancement of catalepsy was no longer expressed. These results may be explained in terms of state-dependency effects induced by MK-801. Implications of these findings for the clinical use of NMDA receptor antagonists in the treatment of Parkinson's disease are discussed.

Animals↗

PubMed2000

Haloperidol-induced neuronal apoptosis: role of p38 and c-Jun-NH(2)-terminal protein kinase.

We examined patterns and mechanisms of cell death induced by haloperidol. Cortical cell cultures exposed to 10-100 microM: haloperidol for 24 h underwent neuronal death without injuring glia. The degenerating neurons showed hallmarks of apoptosis, featuring cell body shrinkage, nuclear chromatin condensation and aggregation, nuclear membrane disintegration with intact plasma membrane, and prominent internucleosomal DNA fragmentation. Neither glutamate antagonists nor antioxidants prevented the haloperidol-induced neuronal apoptosis. The c-Jun-NH(2)-terminal protein kinase and p38 mitogen-activated protein kinase were activated within 1 h and were sustained over the next 3 h following exposure of cortical neurons to 30 microM haloperidol. Haloperidol-induced neuronal apoptosis was partially attenuated by 10-30 microM PD169316, a selective inhibitor of p38 mitogen-activated protein kinase. Inclusion of 1 microg/ml cycloheximide, a protein synthesis inhibitor, or 100 ng/ml insulin prevented activation of both kinases and subsequent neuronal death. The present study demonstrates that cortical neurons exposed to haloperidol undergo apoptosis depending on activation of p38 mitogen-activated protein kinase and c-Jun-NH(2)-terminal protein kinase sensitive to cycloheximide and insulin.

Animals↗

PubMed2002

cDNA array reveals differential gene expression following chronic neuroleptic administration: implications of synapsin II in haloperidol treatment.

The cDNA expression array is a recently developed scientific tool that can profile the differential expression of several hundreds of genes simultaneously and is therefore advantageous in the study of antipsychotic drug action at the genetic level. Using this technology, we discovered 14 genes in the rat striatum whose expression was changed by >/= 50% following chronic haloperidol treatment. Among them was the synapsin II gene, which was found to be significantly up-regulated after the treatment. Since recent studies have implicated this gene in schizophrenia, further experiments were performed to determine whether chronic haloperidol exposure resulted in concurrent increases in the expression of striatal synapsin II protein. Immunoblotting revealed that protein levels of both the a and b isoforms of synapsin II were also increased by comparable amounts following haloperidol treatment. This study is the first to show the regulation of synapsin II expression by haloperidol at the transcript and protein level in rat striatum. A possible mechanism for the observed haloperidol-induced increase in striatal synapsin II expression, along with the implications of this up-regulation in chronic haloperidol treatment, is presented.

Animals↗

PubMed1983

Haloperidol in acute schizophrenic inpatients. A double-blind comparison of two dosage regimens.

Using a double-blind experimental design, two dosage regimens of haloperidol were compared in acutely decompensated, newly admitted schizophrenic patients. Patients in group A (n = 21) received 5 mg haloperidol tablets, patients in group B (n = 20) 15 mg haloperidol tablets. The number of tablets did not exceed six a day but could be varied according to the condition of each patient. On the average patients of group A were prescribed 4.0 tablets, corresponding to 20.0 mg haloperidol a day, and patients of group B 3.9 tablets, corresponding to 58.0 mg haloperidol a day. A significant amelioration of the psychopathology as measured by BPRS were observed in both groups. Between both groups investigated, no differences were found neither with regard to therapeutic efficacy nor to the tolerance of the treatment. Administration of higher oral haloperidol doses cannot be recommended as a standard procedure.

Acute Disease↗