Chronic Administration Of Haloperidol Research Articles

Effort-related effects of chronic administration of the DA D2 receptor antagonist haloperidol via subcutaneous programmable minipumps: Reversal by co-administration of the adenosine A2A antagonist istradefylline.

Long-acting antipsychotics such as haloperidol decanoate are becoming more commonly used. Long-acting depot formulations have several advantages, but secondary negative effects of prolonged delivery, including motivational dysfunctions, could have debilitating effects. Assessing the behavioral changes that emerge during chronic antipsychotic administration in rats could provide insight regarding the development of motivational dysfunctions and drug tolerance. Acute administration of dopamine D2 antagonists such as haloperidol induce motivational deficits in rats, as marked by a shift towards a low-effort bias during effort-based choice tasks. In the present studies, programmable subcutaneous infusion pumps provided continuous and controlled drug delivery of haloperidol. Animals were assessed using a fixed ratio (FR) 5 lever pressing schedule and the FR5/chow feeding test of effort-based choice. The adenosine A2A antagonist istradefylline was studied for its ability to reverse the effects of chronic haloperidol. Continuous chronic infusions of haloperidol produced significant reductions in FR5 performance and a shift from lever pressing to chow intake in rats tested on FR5/chow feeding choice, with no evidence of tolerance over the 4-week infusion period. Behavior returned to baseline during the vehicle-infusion washout period. Istradefylline significantly reversed the effects of haloperidol, increasing lever pressing and decreasing chow intake in haloperidol-treated rats. These studies provide an important behavioral characterization of the effects of chronically infused haloperidol, and demonstrate that A2A antagonism reverses the effects of chronic haloperidol. This research could contribute to the understanding and treatment of motivational dysfunctions seen in schizophrenia, Parkinson's disease, and other disorders involving dopamine.

Chronic haloperidol administration downregulates select BDNF transcript and protein levels in the dorsolateral prefrontal cortex of rhesus monkeys.

Post-mortem studies in the prefrontal cortex and hippocampal formation from schizophrenia patients have revealed significant disruptions in the expression molecules associated with cytoarchitecture, synaptic structure, function, and plasticity, known to be regulated in part by brain derived neurotrophic factor (BDNF). Interestingly, several studies using postmortem brain tissue from individuals diagnosed with schizophrenia have revealed a significant reduction in BDNF mRNA and protein levels in the dorsolateral prefrontal cortex (DLPFC), hippocampus and related areas; however, differentiating the effects of illness from antipsychotic history has remained difficult. We hypothesized that chronic antipsychotic treatment may contribute to the altered BDNF mRNA and protein expression observed in post-mortem brains of individuals diagnosed with schizophrenia. To address the influence of antipsychotic administration on BDNF expression in the primate brain, rhesus monkeys orally administered haloperidol, clozapine, or vehicle twice daily for 180 days. We found BDNF splice variants 4 and 5 in the DLPFC and variant 2 in the EC were significantly down-regulated following chronic administration of haloperidol. In addition, proBDNF and mature BDNF expression in the DLPFC, but not the EC, were significantly reduced. Based on the known regulation of BDNF expression by BDNF-AS, we assessed the expression of this lncRNA and found expression was significantly upregulated in the DLPFC, but not EC. The results of the present study provide evidence of haloperidol-induced regulation of BDNF mRNA and protein expression in the DLFPC and suggest an important role for BDNF-AS in this regulation. Given the role of BDNF in synaptic plasticity, neuronal survival and maintenance, aberrant expression induced by haloperidol likely has significant ramifications for neuronal populations and circuits in primate cortex.

Neuroprotective Effects of P-Coumaric Acid on Haloperidol-Induced Catalepsy Through Ameliorating Oxidative Stress and Brain Dopamine Level

Objective To evaluate the effect of p-coumaric acid (p-CA) on haloperidol-induced catalepsy in Swiss albino male mice. Methods To induce catalepsy, haloperidol (1 mg/kg i.p.) was administered for 21 consecutive days. p-CA (50, 75, and 100 mg/kg, PO) was administered 30 min before haloperidol injection for 21 consecutive days. For catalepsy, locomotor activity and motor coordination scores were recorded on the 17, 14, and 21 days of drug treatment, while the gait analysis score was recorded on day 21. After behavioral testing, animals were sacrificed, and various biochemical and histopathology tests of the brain were conducted. Dopamine, malondialdehyde, reduced glutathione (GSH), superoxide dismutase (SOD), and catalase activity were examined in the brain. Results Chronic administration of haloperidol significantly increased catalepsy in mice. It also produced hypolocomotion, motor coordination, and gait disturbance in mice. p-CA significantly inhibited haloperidol-induced catalepsy. Haloperidol significantly increased malondialdehyde levels in the brain. While dopamine levels in the brain dropped along with GSH, SOD, and catalase activity levels, which also had an impact on the histology of the brain. p-CA significantly reduced haloperidol-induced increases in brain oxidative stress, dopamine levels in the brain, and brain histology in mice. Discussion p-CA significantly reduced haloperidol-induced catalepsy, possibly through reducing oxidative stress and increasing brain dopamine levels. It can be a good candidate drug for extrapyramidal symptoms in Parkinson’s disease and adjuvant therapy with antipsychotic drugs.

The effects of cannabidiol on behavioural and oxidative stress parameters induced by prolonged haloperidol administration.

We investigated the influence of oral cannabidiol (CBD) on vacuous chewing movements (VCM) and oxidative stress parameters induced by short- and long-term administration of haloperidol in a rat model of tardive dyskinesia (TD). Haloperidol was administered either sub-chronically via the intraperitoneal (IP) route or chronically via the intramuscular (IM) route to six experimental groups only or in combination with CBD. VCM and oxidative stress parameters were assessed at different time points after the last dose of medication. Oral CBD (5 mg/kg) attenuated the VCM produced by sub-chronic administration of haloperidol (5 mg/kg) but had minimal effects on the VCM produced by chronic administration of haloperidol (50 mg/kg). In both sub-chronic and chronic haloperidol groups, there were significant changes in brain antioxidant parameters compared with CBD only and the control groups. The sub-chronic haloperidol-only group had lower glutathione activity compared with sub-chronic haloperidol before CBD and the control groups; also, superoxide dismutase, catalase, and 2,2-diphenyl-1-picrylhydrazyl activities were increased in the sub-chronic (IP) haloperidol only group compared with the CBD only and control groups. Nitric oxide activity was increased in sub-chronic haloperidol-only group compared to the other groups; however, the chronic haloperidol group had increased malondialdehyde activity compared to the other groups. Our findings indicate that CBD ameliorated VCM in the sub-chronic haloperidol group before CBD, but marginally in the chronic haloperidol group before CBD. There was increased antioxidant activity in the sub-chronic group compared to the chronic group.

Effect of 5-HT6 Receptor Ligands Combined with Haloperidol or Risperidone on Antidepressant-/Anxiolytic-Like Behavior and BDNF Regulation in Hippocampus and Prefrontal Cortex of Rats.

BackgroundThe presence of depressive and anxiety symptoms in patients with schizophrenia may have an important impact on treatment and compliance. Hence, interventions addressing such comorbidity in schizophrenia should be explored. One target may be a serotonergic 5-HT6 receptor (5-HT6R) since its ligands displayed antidepressant- and anxiolytic-like activities in preclinical experiments.MethodsAcute and chronic (21 days) administration of haloperidol or risperidone in combination with a selective 5-HT6R agonist (WAY-181187) or antagonist (SB-742457) to rats was performed for detecting antidepressant- and anxiolytic-like behaviors. In addition, the level of brain-derived neurotrophic factor (BDNF) protein and its gene expression in hippocampus and prefrontal cortex were determined.ResultsBoth single and chronic administration of WAY-181187 with haloperidol produced antidepressant- and anxiolytic-like activities. SB-742457 did not provide full benefits in terms of improvement of haloperidol-induced adverse mood effects. However, the administration of SB-742457 with risperidone triggered its anxiolytic-like activity. Both 5-HT6R ligands evoked no changes in haloperidol-induced effects on BDNF level. WAY-181187 induced repression of the BDNF gene while SB-742457 increased its expression in both structures. 5-HT6R ligands, when combined with risperidone, did not change BDNF protein level and increased gene expression in the hippocampus, while they elevated BDNF level and potentiated gene expression in the prefrontal cortex.ConclusionThe combined administration of WAY-181187 and haloperidol provided the greatest benefits, which were manifested by antidepressant-like effects and suppression of the anxiogenic-like properties. The combined administration of risperidone with both agonist and antagonist resulted only in an anxiolytic-like effect. It seems that the anxiolytic-like effects induced by haloperidol or risperidone with the addition of 5-HT6R ligands are task-specific. The data on BDNF protein and gene expression did not fully correspond with the behavioral outcomes, and thus it appears that other factors/mechanisms are involved in the observed antidepressant- and/or anxiolytic-like effects.

Where do we cut the bell-shaped curve of CIAS?

While the long-term administration of antipsychotics is known to cause dopamine supersensitivity psychosis (DSP), recent studies revealed that DSP helps form the foundation of treatment resistance. Electroconvulsive shock (ES) is one of the more effective treatments for treatment-resistant schizophrenia. The objective of this study was to examine whether repeated ES can release rats from dopamine supersensitivity states such as striatal dopamine D2 receptor (DRD2) up-regulation and voluntary hyperlocomotion following chronic administration of haloperidol (HAL). HAL (0.75 mg/kg/day) was administered for 14 days via mini-pumps implanted in rats, and DRD2 density and voluntary locomotion were measured one day after drug cessation to confirm the development of dopamine supersensitivity. The rats with or without dopamine supersensitivity received repeated ES or sham treatments, and then DRD2 density was assessed and a voluntary locomotion test was performed. Chronic treatment with HAL led to the up-regulation of striatal DRD2 and hyperlocomotion in the rats one day after drug cessation. We thus confirmed that these rats experienced a dopamine supersensitivity state. Moreover, after repeated ES, locomotor activity and DRD2 density in the DSP model rats fell to the control level, while an ES sham operation had no effect on the dopamine supersensitivity state. The present study suggests that repeated ES could release DSP model rats from dopamine supersensitivity states. ES may be helpful for patients with DSP.

Effects of repeated electroconvulsive shocks on dopamine supersensitivity psychosis model rats

While the long-term administration of antipsychotics is known to cause dopamine supersensitivity psychosis (DSP), recent studies revealed that DSP helps form the foundation of treatment resistance. Electroconvulsive shock (ES) is one of the more effective treatments for treatment-resistant schizophrenia. The objective of this study was to examine whether repeated ES can release rats from dopamine supersensitivity states such as striatal dopamine D2 receptor (DRD2) up-regulation and voluntary hyperlocomotion following chronic administration of haloperidol (HAL). HAL (0.75 mg/kg/day) was administered for 14 days via mini-pumps implanted in rats, and DRD2 density and voluntary locomotion were measured one day after drug cessation to confirm the development of dopamine supersensitivity. The rats with or without dopamine supersensitivity received repeated ES or sham treatments, and then DRD2 density was assessed and a voluntary locomotion test was performed. Chronic treatment with HAL led to the up-regulation of striatal DRD2 and hyperlocomotion in the rats one day after drug cessation. We thus confirmed that these rats experienced a dopamine supersensitivity state. Moreover, after repeated ES, locomotor activity and DRD2 density in the DSP model rats fell to the control level, while an ES sham operation had no effect on the dopamine supersensitivity state. The present study suggests that repeated ES could release DSP model rats from dopamine supersensitivity states. ES may be helpful for patients with DSP.

133 - Impact of an Employee Behavioral Health Program on All-Cause Healthcare Utilization

There are sex differences associated with schizophrenia, as women exhibit later onset of the disorder, less severe symptomatology, and better response to antipsychotic medications. Estrogens are thought to play a role in these sex differences; estrogens facilitate the effects of antipsychotic medications to reduce the positive symptoms of schizophrenia, but it remains unclear whether estrogens protect against the cognitive symptoms of this disorder. Amphetamine sensitization is used to model some symptoms of schizophrenia in rats, including cognitive deficits like excessive perseveration and slower reversal learning. In this experiment female rats were administered a sensitizing regimen of amphetamine to mimic these cognitive symptoms. They were ovariectomized and administered either low or high estradiol replacement as well as chronic administration of the antipsychotic haloperidol, and were assessed in tests of perseveration and reversal learning. Results of these experiments demonstrated that, in amphetamine-sensitized rats, estradiol alone does not affect perseveration or reversal learning. However, low estradiol facilitates a 0.25 mg/day dose of haloperidol to reduce perseveration and improve reversal learning. Combined high estradiol and 0.25 mg/day haloperidol has no effect on perseveration or reversal learning, but high estradiol facilitates the effects of 0.13 mg/day haloperidol to reduce perseveration and improve reversal learning. Thus, in amphetamine-sensitized female rats, 0.25 mg/day haloperidol only improved perseveration and reversal learning when estradiol was low, while 0.13 mg/day haloperidol only improved these cognitive processes when estradiol was high. These findings suggest that estradiol facilitates the effects of haloperidol to improve perseveration and reversal learning in a dose-dependent manner.

NEUROPROTECTIVE EFFECT OF METHANOLIC EXTRACT OF SARGASSUM WIGHTII ON HALOPERIDOL INDUCED CATALEPSY AND TARDIVE DYSKINESIA IN ALBINO RATS

Objective: The present study was designed to evaluate the neuroprotective effect of methanolic extract of Sargassum wightii on haloperidol-induced catalepsy and tardive dyskinesia in Wistar albino rats.
 Methods: In this study, thirty Wistar albino rats were randomly divided into six groups. Gr-I served as control. Haloperidol (1 mg/kg intraperitoneally) was administered to rats of Gr-II to Gr-V for twenty-one consecutive days to induce catalepsy and tardive dyskinesia. Animals of Gr-II to Gr-V were orally administered with vehicle, levodopa carbidopa combination (30 mg/kg), Sargassum extract 200 and 400 mg/kg respectively. All the drugs and vehicles were given orally one hour before haloperidol injection for twenty one consecutive days. The cataleptic scores were recorded using standard bar test. Tardive dyskinesia was assessed in terms of vacuous chewing movement (VCM) and tongue protrusion (TP) scores. After behavioural testing, all animals were sacrificed on twenty-second day and various biochemical parameters like MDA, SOD and GSH were estimated in brain tissue.
 Results: Chronic administration of haloperidol significantly increased cataleptic scores, VCM and TP scores. (p<0.001) Sargassum wightii extract (400 mg/kg) significantly inhibited haloperidol-induced catalepsy, VCM and TP (p<0.001) Haloperidol increased MDA and decreased SOD and GSH in brain tissue to a highly significant extent (p<0.001) Sargassum extract at 400 mg/kg also significantly reversed the haloperidol-induced alteration in brain oxidative stress markers.
 Conclusion: Sargassum wightii inhibits haloperidol-induced catalepsy and tardive dyskinesia. Thus it may be used as a unique therapeutic adjunct for the prevention of neuroleptic-induced extrapyramidal symptoms, however, it has to be explored more.

Effects of haloperidol on cognitive function and behavioural flexibility in the IntelliCage social home cage environment

This study examined the effects of chronic administration of haloperidol in female C57BL/6 mice. As patients with schizophrenia often show perseverant behaviours and lack of behavioural flexibility, it is important to know whether the effect of haloperidol makes these traits worse. This study, therefore, was designed to evaluate the effects of haloperidol on the learning performance of mice using an automated home cage environment, the IntelliCage. Behavioural shuttling in the IntelliCage enabled us to assess learning in tasks including place discrimination learning and reversal place learning. In reversal place learning, spatial patterns of rewarded and non-rewarded places that mice had learned to discriminate were reversed, and the adaptability of mice to change the previously acquired place learning was measured. Haloperidol (1 mg/kg/day) reduced locomotor activity and water intake. Haloperidol impaired the cognitive flexibility of mice during reversal place learning rewarded by access to water but enhanced the rapid acquisition of behavioural flexibility when airpuff punishment was applied.

Role of D3 dopamine receptors in modulating neuroanatomical changes in response to antipsychotic administration

Clinical research has shown that chronic antipsychotic drug (APD) treatment further decreases cortical gray matter and hippocampus volume, and increases striatal and ventricular volume in patients with schizophrenia. D2-like receptor blockade is necessary for clinical efficacy of the drugs, and may be responsible for inducing these volume changes. However, the role of other D2-like receptors, such as D3, remains unclear. Following our previous work, we undertook a longitudinal study to examine the effects of chronic (9-week) typical (haloperidol (HAL)) and atypical (clozapine (CLZ)) APDs on the neuroanatomy of wild-type (WT) and dopamine D3-knockout (D3KO) mice using magnetic resonance imaging (MRI) and histological assessments in a sub-region of the anterior cingulate cortex (the prelimbic [PL] area) and striatum. D3KO mice had larger striatal volume prior to APD administration, coupled with increased glial and neuronal cell density. Chronic HAL administration increased striatal volume in both WT and D3KO mice, and reduced PL area volume in D3KO mice both at trend level. CLZ increased volume of the PL area of WT mice at trend level, but decreased D3KO PL area glial cell density. Both typical and atypical APD administration induced neuroanatomical remodeling of regions rich in D3 receptor expression, and typically altered in schizophrenia. Our findings provide novel insights on the role of D3 receptors in structural changes observed following APD administration in clinical populations.

Влияние хронического введения галоперидола и рисперидона на количество дофаминовых рецепторов в ткани мозга у крыс

Влияние хронического введения галоперидола и рисперидона на количество дофаминовых рецепторов в ткани мозга у крыс

Haloperidol affects coupling between QT and RR intervals in guinea pig isolated heart

Prolonged QT interval is an independent risk factor for development of ventricular arrhythmias. Haloperidol is one of the drugs inducing QT prolongation. Previous studies showed that haloperidol affects not only QT duration but also heart rate (RR interval). The present work focused on relationship between QT and RR and its changes under acute and chronic haloperidol administration. The study included 14 male guinea pigs divided into control and haloperidol-treated group. After 21-days administration of haloperidol or vehiculum, electrograms in isolated hearts were recorded. QT/RR and dQT/dRR coupling were calculated. Chronic haloperidol administration significantly decreases the coupling between QT and RR. Acute haloperidol exposure significantly decreases the dQT/dRR coupling in both treated and untreated guinea pig hearts. Flatter QT/RR relationship reveals a lack of QT adaptation to increased heart rate. It should be emphasized that in such situation ECG recording will not show significant QT prolongation evaluated according to clinical rules. However, if QT interval does not adapt to increased heart rate sufficiently, the risk of ventricular arrhythmias may be increased despite practically normal QT interval length. The results are supported by findings in biochemical analyses, which proved eligibility of the used model.

Cannabidiol prevents haloperidol-induced vacuos chewing movements and inflammatory changes in mice via PPARγ receptors

The chronic use of drugs that reduce the dopaminergic neurotransmission can cause a hyperkinetic movement disorder called tardive dyskinesia (TD). The pathophysiology of this disorder is not entirely understood but could involve oxidative and neuroinflammatory mechanisms. Cannabidiol (CBD), the major non-psychotomimetic compound present in Cannabis sativa plant, could be a possible therapeutic alternative for TD. This phytocannabinoid shows antioxidant, anti-inflammatory and antipsychotic properties and decreases the acute motor effects of classical antipsychotics. The present study investigated if CBD would attenuate orofacial dyskinesia, oxidative stress and inflammatory changes induced by chronic administration of haloperidol in mice. Furthermore, we verified in vivo and in vitro (in primary microglial culture) whether these effects would be mediated by PPARγ receptors. The results showed that the male Swiss mice treated daily for 21 days with haloperidol develop orofacial dyskinesia. Daily CBD administration before each haloperidol injection prevented this effect. Mice treated with haloperidol showed an increase in microglial activation and inflammatory mediators in the striatum. These changes were also reduced by CBD. On the other hand, the levels of the anti-inflammatory cytokine IL-10 increased in the striatum of animals that received CBD and haloperidol. Regarding oxidative stress, haloperidol induced lipid peroxidation and reduced catalase activity. This latter effect was attenuated by CBD. The combination of CBD and haloperidol also increased PGC-1α mRNA expression, a co-activator of PPARγ receptors. Pretreatment with the PPARγ antagonist, GW9662, blocked the behavioural effect of CBD in our TD model. CBD also prevented LPS-stimulated microglial activation, an effect that was also antagonized by GW9662. In conclusion, our results suggest that CBD could prevent haloperidol-induced orofacial dyskinesia by activating PPARγ receptors and attenuating neuroinflammatory changes in the striatum.

Risperidone and aripiprazole alleviate prenatal valproic acid-induced abnormalities in behaviors and dendritic spine density in mice.

Rodents exposed prenatally to valproic acid (VPA) exhibit autism spectrum disorder (ASD)-like behavioral abnormalities. We recently found that prenatal VPA exposure causes hypofunction of the prefrontal dopaminergic system in mice. This suggests that the dopaminergic system may be a potential pharmacological target for treatment of behavioral abnormalities in ASD patients. In the present study, we examined the effects of antipsychotic drugs, which affect the dopaminergic system, on the social interaction deficits, recognition memory impairment, and reduction in dendritic spine density in the VPA mouse model of ASD. Both acute and chronic administrations of the atypical antipsychotic drugs risperidone and aripiprazole increased prefrontal dopamine (DA) release, while the typical antipsychotic drug haloperidol did not. Chronic risperidone and aripiprazole, but not haloperidol, increased the expression of c-Fos in the prefrontal cortex, although they all increased c-Fos expression in the striatum. Chronic, but not acute, administrations of risperidone and aripiprazole improved the VPA-induced social interaction deficits and recognition memory impairment, as well as the reduction in dendritic spine density in the prefrontal cortex and hippocampus. In contrast, chronic administration of haloperidol did not ameliorate VPA-induced abnormalities in behaviors and dendritic spine density. These findings indicate that chronic risperidone and aripiprazole treatments improve VPA-induced abnormalities in behaviors and prefrontal dendritic spine density, which may be mediated by repeated elevation of extracellular DA in the prefrontal cortex. Our results also imply that loss of prefrontal dendritic spines may be involved in the abnormal behaviors in the VPA mouse model of ASD.

Protective effect of hesperetin against haloperidol-induced orofacial dyskinesia and catalepsy in rats

Objectives: The present study was designed to evaluate the effect of hesperetin on haloperidol-induced orofacial dyskinesia and catalepsy in Wistar male albino rats.Methods: Haloperidol (1 mg/kg, ip) was administered for 21 successive days to induce orofacial dyskinesia and catalepsy. Hesperetin (50 and 100 mg/kg, po) was administered 10 min prior to the injection of haloperidol for 21 successive days. Vacuous chewing movements (VCMs), tongue protrusions, catalepsy, and locomotor activity scores were recorded on 7th, 14th, and 22nd day of drug treatment. After behavioral testing, animals were sacrificed and various biochemical parameters such as brain levels of dopamine, serotonin, malondialdehyde, and reduced glutathione (GSH); and superoxide dismutase (SOD) and catalase activities were estimated.Results: Chronic administration of haloperidol significantly increased VCMs, tongue protrusions, and catalepsy in rats. It also produced hypolocomotion in rats. Hesperetin significantly inhibited haloperidol-induced VCMs, tongue protrusions, and catalepsy. Haloperidol significantly increased brain levels of malondialdehyde, decreased brain GSH, SOD, and catalase activities; and also decreased brain dopamine and serotonin levels. Hesperetin significantly reversed haloperidol-induced increase in brain oxidative stress and decrease in brain dopamine and serotonin levels.Discussion: Hesperetin significantly ameliorated haloperidol-induced orofacial dyskinesia and catalepsy possibly through alleviation of oxidative stress and increase in brain dopamine and serotonin levels. Thus, hesperetin may be explored further as a possible therapeutic agent for clinical management of neuroleptic drug-induced tardive dyskinesia.

Interactions between estradiol and haloperidol on perseveration and reversal learning in amphetamine-sensitized female rats

There are sex differences associated with schizophrenia, as women exhibit later onset of the disorder, less severe symptomatology, and better response to antipsychotic medications. Estrogens are thought to play a role in these sex differences; estrogens facilitate the effects of antipsychotic medications to reduce the positive symptoms of schizophrenia, but it remains unclear whether estrogens protect against the cognitive symptoms of this disorder. Amphetamine sensitization is used to model some symptoms of schizophrenia in rats, including cognitive deficits like excessive perseveration and slower reversal learning. In this experiment female rats were administered a sensitizing regimen of amphetamine to mimic these cognitive symptoms. They were ovariectomized and administered either low or high estradiol replacement as well as chronic administration of the antipsychotic haloperidol, and were assessed in tests of perseveration and reversal learning. Results of these experiments demonstrated that, in amphetamine-sensitized rats, estradiol alone does not affect perseveration or reversal learning. However, low estradiol facilitates a 0.25mg/day dose of haloperidol to reduce perseveration and improve reversal learning. Combined high estradiol and 0.25mg/day haloperidol has no effect on perseveration or reversal learning, but high estradiol facilitates the effects of 0.13mg/day haloperidol to reduce perseveration and improve reversal learning. Thus, in amphetamine-sensitized female rats, 0.25mg/day haloperidol only improved perseveration and reversal learning when estradiol was low, while 0.13mg/day haloperidol only improved these cognitive processes when estradiol was high. These findings suggest that estradiol facilitates the effects of haloperidol to improve perseveration and reversal learning in a dose-dependent manner.

Establishment and Effects of Ginger and Kikyoto of a Haloperidol-Induced Dysphagia Model in Guinea Pigs

Dysphagia induces aspiration and causes aspiration pneumonia. There is no treatment for dysphagia fundamentally. Haloperidol reportedly induces dysphagia. In the present study, we established a haloperidol-induced dysphagia model in guinea pigs, and evaluated the effects of ginger, kikyoto, and a mixture of ginger and kikyoto on swallowing. Swallowing ability was evaluated using behavioral tests, computed tomography (CT), and videofluoroscopic examination of swallowing. To investigate the effect of ginger and kikyoto on swallowing, ginger, kikyoto, or a mixture of ginger and kikyoto was administered orally to guinea pigs with haloperidol-induced dysphagia. Effects of these compounds were evaluated with behavioral tests. Chronic administration of haloperidol reduced the number of swallows, as evaluated by the behavioral test and videofluoroscopic examination of swallowing. In our model, these compounds improved swallowing dysfunction. Our results suggest that this model might be useful in revealing the pathogenesis of dysphagia and evaluating compounds that might improve swallowing.

Neurochemical Metabolomics Reveals Disruption to Sphingolipid Metabolism Following Chronic Haloperidol Administration.

Haloperidol is an effective antipsychotic drug for treatment of schizophrenia, but prolonged use can lead to debilitating side effects. To better understand the effects of long-term administration, we measured global metabolic changes in mouse brain following 3 mg/kg/day haloperidol for 28 days. These conditions lead to movement-related side effects in mice akin to those observed in patients after prolonged use. Brain tissue was collected following microwave tissue fixation to arrest metabolism and extracted metabolites were assessed using both liquid and gas chromatography mass spectrometry (MS). Over 300 unique compounds were identified across MS platforms. Haloperidol was found to be present in all test samples and not in controls, indicating experimental validity. Twenty-one compounds differed significantly between test and control groups at the p < 0.05 level. Top compounds were robust to analytical method, also being identified via partial least squares discriminant analysis. Four compounds (sphinganine, N-acetylornithine, leucine and adenosine diphosphate) survived correction for multiple testing in a non-parametric analysis using false discovery rate threshold < 0.1. Pathway analysis of nominally significant compounds (p < 0.05) revealed significant findings for sphingolipid metabolism (p = 0.015) and protein biosynthesis (p = 0.024). Altered sphingolipid metabolism is suggestive of disruptions to myelin. This interpretation is supported by our observation of elevated N-acetyl-aspartyl-glutamate in the haloperidol-treated mice (p = 0.004), a marker previously associated with demyelination. This study further demonstrates the utility of murine neurochemical metabolomics as a method to advance understanding of CNS drug effects.

Neurochemical Metabolomics Reveals Disruption to Sphingolipid Metabolism Following Chronic Haloperidol Administration

Neurochemical Metabolomics Reveals Disruption to Sphingolipid Metabolism Following Chronic Haloperidol Administration