Administration Of Haloperidol Research Articles

Glutamatergic Contribution to Probabilistic Reasoning and Jumping to Conclusions in Schizophrenia: A Double-Blind, Randomized Experimental Trial

BackgroundImpaired probabilistic reasoning and the jumping-to-conclusions reasoning bias are hallmark features of schizophrenia (SCZ), yet the neuropharmacological basis of these deficits remains unclear. Here we tested the hypothesis that glutamatergic neurotransmission specifically contributes to jumping to conclusions and impaired probabilistic reasoning in SCZ. MethodsA total of 192 healthy participants received either NMDA receptor agonists/antagonists (D-cycloserine/dextromethorphan), dopamine type 2 receptor agonists/antagonists (bromocriptine/haloperidol), or placebo in a randomized, double-blind, between-subjects design. In addition, we tested 32 healthy control participants matched to 32 psychotic inpatients with SCZ—a state associated with compromised probabilistic reasoning due to reduced glutamatergic neurotransmission. All experiments employed two versions of a probabilistic reasoning (beads) task, which required participants to either sample individual amounts of sensory information to infer correct decisions or provide explicit probability estimates for presented sensory information. Our task instantiations assessed both information sampling and explicit probability estimates in different probabilistic contexts (easy vs. difficult conditions) and changing sensory information through random transitions among easy, difficult, and ambiguous trial types. ResultsFollowing administration of D-cycloserine, haloperidol, and bromocriptine, healthy participants displayed data-gathering behavior that was normal compared with placebo and was adequate in the context of all employed task conditions and trial level difficulties. However, healthy participants receiving dextromethorphan displayed a jumping-to-conclusions bias, abnormally increased probability estimates, and overweighting of sensory information. These effects were mirrored in patients with SCZ performing the same versions of the beads task. ConclusionsOur findings provide novel neuropharmacological evidence linking reduced glutamatergic neurotransmission to impaired information sampling and to disrupted probabilistic reasoning, namely to overweighting of sensory evidence, in patients with SCZ.

Effect of methonolic extract of Vitex negundo on haloperidol induced catalepsy in albino mice

Background: Plants are being used in traditional medicine since history of mankind. The knowledge of these medicinal plants has accrued in the course of many centuries leading to medicinal systems in India such as Ayurveda, Unani and Siddha. Objective: In the present study, we evaluated the anticataleptic efficacy of Vitex negundo, a polyherbal formulation in haloperidol induced catalepsy in mice.Methods: Five groups (n=6) of male albino mice were used in the study. Catalepsy was induced by i.p. administration of haloperidol (1 mg/kg). The degree of catalepsy (cataleptic score) was measured as the time the animal maintained an imposed posture. We compared the anticataleptic efficacy of Vitex negundo (50, 100, 200 mg/kg) with standard received Pheniramine maleate 10 mg/kg, i.p.Results: In vehicle treated animals, haloperidol (1 mg/kg. i.p.) produced the maximum catalepsy at 180 min (46.78±3.78 min). Standard treated as Pheniramine maleate 10 mg/kg, i.p. shows maximum at 120 min. 19.24±1.32. Test herb, i.p. Methanolic extract of Vitex negundo (50, 100, 200 mg/kg, i.p.) significantly potentiated haloperidol induced catalepsy at each time interval, in a dose dependent manner. At dose 50, 100 and 200mg/kg, extract of Vitex negundo (Linn.) roots showed maximum cataleptic score 12.34±0.78, 14.43±0.43 and 15.43±0.67 min, respectively at 120 minutes in haloperidol treated animals.Conclusions: The present study indicates that the methanolic extract of Vitex negundo reduces haloperidol-induced catalepsy in mice.

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 inhalation on MK-801- and memantine-induced locomotion in mice

ABSTRACT The administration of therapeutic agents is difficult in many patients, such as patients with post-operative delirium or dementia or patients with schizophrenia, who are upset in an emergency room. Therefore, the development of a new method for administering therapeutic agents to the central nervous system is desired. In this study, we investigated if inhalation was an effective route of administration for haloperidol, a commonly used, strong antipsychotic. Dizocilpine, also known as MK-801, is a noncompetitive antagonist of the N-methyl-D-aspartate receptor. MK-801 or memantine-induced motor hyperactivity was evaluated in mice following either intraperitoneal injection or inhalation of haloperidol or the histamine neuroactivator betahistine. Pretreatment with haloperidol inhalation inhibited the MK-801-induced or memantine-induced increase in locomotor activity. This effect was similar to that of the intraperitoneal administration of haloperidol. However, pretreatment with inhaled betahistine or the intraperitoneal administration of betahistine did not suppress the MK-801-induced or memantine-induced increase in locomotor activity. Thus, haloperidol when inhaled acts on the central nervous system of mice and suppresses the MK-801-induced increase in mouse locomotor activity. Our findings suggest that inhalation may be a novel method for administering haloperidol. Abbreviations ANOVA: analysis of variance

Disparities and Variables Associated With Physical Restraint for Acute Agitation in a Nonpsychiatric Emergency Department.

To determine associations between the rate of physical restraint and demographic variables such as body mass index (BMI), ethnicity, sex, and age in the emergency department (ED) along with clinical variables such as various psychiatric diagnoses and medications. This 6-month (October 1, 2016-March 30, 2017) retrospective chart review was conducted in the ED of a community hospital, which is also a teaching institution for medical students and residents but does not have access to psychiatry consultations via phone or in person. A total of 165 agitated patients were included in the study. Agitated patients who were restrained were compared to those who were not physically restrained. Of the patients, 112 (68%) were physically restrained, and those not physically restrained were included as controls (n = 53, 32%). Younger age (P = .03), lower BMI (P = .04), intoxication (P = .001), preexisting diagnosis of depression (P = .02), and antipsychotics as a home medication (P = .03) were associated with physical restraints. In the ED, administration of haloperidol and olanzapine was associated with physical restraints. Current benzodiazepine prescription (P = .001), ED administration of ketamine (P = .001), and ED administration of diazepam (P = .001) were more common in those not physically restrained. Risk factors for physical restraints can be used to identify high-risk patients early, and other treatments along with behavioral and environmental modifications may then be utilized. Further research to develop protocols using nonpharmacologic and pharmacologic measures to minimize use of restraints is required.

Combination of In Vivo [123I]FP-CIT SPECT and Microdialysis Reveals an Antipsychotic Drug Haloperidol-induced Synaptic Dopamine Availability in the Rat Midbrain and Striatum.

Synaptic dopamine (DA) is mainly regulated by the presynaptic DA transporter (DAT). Single-photon emission computerized tomography (SPECT) with the DAT radiotracer [123I]FP-CIT assesses changes in synaptic DA availability when endogenous DA displaces [123I]FP-CIT or competes for DAT. Here, we investigated the effects of haloperidol (HAL) and clozapine (CLZ) on [123I]FP-CIT binding in the rat striatum and midbrain to assess the utility of [123I]FP-CIT SPECT to quantify changes in synaptic DA availability. Rats underwent [123I]FP-CIT SPECT after intraperitoneal administration of normal saline (vehicle), HAL (1 and 7 mg/kg), CLZ (10 and 54 mg/kg) and bupropion (BUP, a DAT blocker, 20 and 100 mg/kg). In the striatum and midbrain, percent differences in the nondisplaceable binding potential (BPND) of [123I]FP-CIT compared to the vehicle were calculated for the various drugs and doses. In another experiment, changes in endogenous striatal DA concentration were measured by in vivo microdialysis under the conditions used in the SPECT study. BUP dose-dependently occupied DAT at considerable levels. Compared to the vehicle, HAL decreased [123I]FP-CIT BPND in the striatum (−25.29% and −2.27% for 1 and 7 mg/kg, respectively) and to a greater degree in the midbrain (−58.74% and −49.64% for 1 and 7 mg/kg, respectively), whereas the CLZ-treated group showed a decrease in the midbrain (−38.60% and −40.38% for 10 and 54 mg/kg, respectively) but an increase in the striatum (18.85% and 38.64% for 10 and 54 mg/kg, respectively). Antipsychotic-induced changes in endogenous striatal DA concentrations varied across drugs and doses. The data demonstrate that [123I]FP-CIT SPECT may be a useful preclinical technique for detecting increases in synaptic DA availability in the midbrain and striatum in response to HAL, with results comparable to those of in vivo microdialysis.

Dopamine transporter image in CRMP5 associated autoimmune encephalitis

CRMP5 is one of onco-neuronal antibodies and CRMP5 associated encephalitis has been rarely reported. Various clinical features including chorea, myelitis, visual symptoms and gait disturbance were found. Neither the target of CRMP5 antibodies has been determined, nor dopamine transporter image was reported yet. We report a CRMP5 associated encephalitis showing a reduced uptake in the striatum using FP-CIT. A 69 years-old man was admitted because of involuntary movement. Ten months prior to admission, he started to complain gait instability & choreic movement in head & both limbs. Administration of haloperidol failed to progression of abnormal involuntary movement. On examination, he showed repetitive neck movement, flexion & extension while he was walking. He also showed slow and wide based gait, together with choreic movement in his right hand. Parkinsonian features other than slowness were not noted. In the CSF, mildly elevated protein, but no pleocytosis was found. CRAM5 antibody was positive. MRI revealed widening of both anterior horns of ventricles and ill-defined signal change involving both caudate nucleus heads. FP-CIT dopamine transporter imaging showed severely decreased uptake in both striatum, more prominent in caudate. This is a first report of CRMP5 associated encephalitis showing reduced uptake in the striatum using FP-CIT. This finding suggests CRMP5 antibody may be associated with pathological process in the presynaptic nigrostriatal system, more in the caudate. Larger studies including postmortem will be needed to explore the target of CRMP5 associated encephalitis.

Haloperidol Reduces the Activity of Complement and Induces the Anti-Inflammatory Transformation of Peritoneal Macrophages in Rats.

It is known that psychotropic substances affect the immune system. Unfortunately, chronic antipsychotic administration causes side toxicological effects, associated with oxidative stress. The mechanisms of these effects are still unclear. We investigated the impact of sub-chronic administration of haloperidol (Hal) on parameters of innate immunity and related systems in healthy rats and compared them with Hal content. Hal administration (0.5mg/kg, 3weeks) resulted in two-fold decrease of the activity of the complement system and hemostasis. Hal content correlated with the activity of the complement (r = -0.71), phagocytic activity of peritoneal macrophages (r = 0.78), leukocyte elastase (r = -0.71) and glutathione-S-transferase activity (r = -0.67). Hal fully blocked in vitro PMA-induced iNOS expression in macrophages and changed their morphology to "anti-inflammatory" phenotype. The comparison of in vivo and in vitro data showed that Hal has a direct effect on phagocytic component of innate immunity and an indirect effect on leukocyte elastase and antioxidant enzymes. The results obtained in the present study indicated that Hal significantly affects homeostasis and causes a number of complex biological transformations. Graphical Abstract.

Effects of intraplantar administration of Complete Freund's Adjuvant (CFA) on rotarod performance in mice.

Preclinical animal models are crucial to study pain mechanisms and assess antinociceptive effects of medications. One major problem with current animal behavioral models is their lack of face validity with human nociception and the vulnerability for false-positive results. Here, we evaluated the usefulness of rotarod as a new way to assess inflammatory nociception in rodents. Adult male mice were injected with saline or Complete Freund's Adjuvant (CFA) in the left hindpaws. Mechanical allodynia and rotarod performance were evaluated before and after the administration of CFA. Mechanical allodynia was measured using von Frey filaments. Long-term effect of CFA on rotarod performance was also assessed for 2 weeks. Our results showed that CFA administration decreased pain threshold and increased sensitivity to von Frey filaments compared to control group. In rotarod experiments, the starting speed of the rod rotation started at four RPM, and accelerated until it reached 40 RPM in 5 min. Rotarod performance was enhanced from day to day in the control group. However, rotarod performance in CFA group was attenuated after CFA administration, which was significant after 24 h compared to vehicle. This attenuation was blocked by ibuprofen. Haloperidol administration (positive control) produced similar results to CFA administration. CFA did not produce significant attenuation of rotarod performance after 1 week post-injection. Collectively, our findings could encourage the use of rotarod assay to measure acute (but not chronic) inflammatory nociception as a useful tool in rodents.

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.

Does administration of haloperidol or ketorolac decrease opioid administration for abdominal pain patients? A retrospective study

BackgroundHaloperidol and ketorolac have been recommended as therapies that may decrease opioid use for treatment of pain in emergency department patients. The objective of our study is to determine if administration of haloperidol or ketorolac is associated with lower use of i.v. opioids for patients with non-specific abdominal pain. MethodsA retrospective cohort study of adults (Age 18–60) with non-specific abdominal pain presenting to an emergency department in a large healthcare system. Cases were identified using ICD-10 codes and variables were abstracted from electronic health records. The association between administration of haloperidol or ketorolac with 1) any i.v. opioid administration and 2) receiving >1 dose of i.v. opioids were measured using adjusted odds ratios (AOR) from nominal logistic regression. The model included potential confounders related to both opioid and ketorolac or haloperidol administration. ResultsOf 11,688 patients 4091 received one or more doses of an i.v. opioid, 240 received haloperidol and 1788 received ketorolac. The majority of patients were women (67%) and the median age was 32 years. Odds ratios were adjusted for variables associated with opioids, ketorolac or haloperidol use. Haloperidol was not associated with decreased i.v. opioid use (AOR for receiving iv opioids 2.0, 95% CI 1.5 to 2.6) or a lower odds of reciving >1 dose of (AOR 2.0, 95% CI 1.3 to 3.1). Ketorolac was associated with a modest decrease in i.v. opioid use (AOR 0.84 95% CI.0.76 to 0.94 for receiving iv opioids) and a modest decrease for receiving multiple dose of iv opioids (AOR 0.79 95% CI 0.63 to 0.99). ConclusionsHaloperidol was not associated with decreased i.v. opioid use. Ketorolac was associated with a modest decrease in i.v. opioid use. Providers should consider the use of haloperidol and ketorolac as potentially beneficial in some cases, but there is a need for high quality studies before they can be recommended as standard therapy.

Gnal haploinsufficiency causes genomic instability and increased sensitivity to haloperidol

GNAL encodes guanine nucleotide-binding protein subunit Gα(olf) which plays a key role in striatal medium spiny neuron (MSN)-dopamine signaling. GNAL loss-of-function mutations are causally-associated with isolated dystonia, a movement disorder characterized by involuntary muscle contractions leading to abnormal postures. Dopamine D2 receptor (D2R) blockers such as haloperidol are mainstays in the treatment of psychosis but may contribute to the development of secondary acute and tardive dystonia. Administration of haloperidol promotes cAMP-dependent signaling in D2R-expressing indirect pathway MSNs. At present, little is known about the cellular relationships among isolated, acute, and tardive dystonia. Herein, we report the effects of acute D2R blockade on motor behavior, DNA repair, cAMP-mediated histone H3 phosphorylation (Ser10), and cell death in Gnal+/− mice and their isogenic Gnal+/+ littermates. In comparison to Gnal+/+ littermates, Gnal+/− mice exhibited increased catalepsy responses, persistent DNA breaks, decreased cAMP-dependent histone H3 phosphorylation (Ser10), and increased cell death in response to haloperidol. In striatum, aged Gnal+/− mice exhibited increased global DNA methylation, increased euchromatin, and dendritic structural abnormalities. Our results provide evidence that Gα(olf) deficiency intensifies the effects of D2R antagonism and suggests that loss-of-function variants in GNAL may increase risk for movement disorders associated with D2R blockers. We hypothesize that the effects of Gα(olf) dysfunction and/or long-term D2R antagonism may lead to epigenetic silencing, transcriptional dysregulation, and, ultimately, cellular senescence and/or apoptosis in human brain.

The Side Effect of Haloperidol in Schizophrenic Patients: Analysis of Red Blood Cell Distribution Width (RDW) and Mean Platelet Volume (MPV) Values

INTRODUCTION: Like the increase of pro-inflammatory cytokines and oxidative stress as schizophrenia pathophysiology, haloperidol also increases RDW and MPV values. Both of these values ​​have been clinicians concern because they are a risk factor for the various type of vascular disease.
 
 OBJECTIVE: This study aims to determine the side effect of haloperidol on RDW and MPV values in schizophrenic patients. 
 
 METHODS: This research method uses observational analytic design with a prospective cohort approach with pre and posts analysis conducted at the Regional Special Hospital of South Sulawesi Province during May - July 2018 in 30 schizophrenic subjects. The subjects were diagnosed as first episode schizophrenia based on ICD 10, blood samples were taken, for RDW and MPV values ​​before and after haloperidol was given at the 4th and 8th weeks.
 
 RESULTS: The results showed that the mean RDW value at the 4th week was higher in 15 mg/day haloperidol group (15.8) compared to 7.5 mg/day haloperidol group (15.3) with p<0.05. Mean RDW value taken at 8th week was higher in 15 mg/day haloperidol group (16.4) compared to 7.5 mg/day haloperidol group (15.6) with p<0.001. Mean MPV value taken at 8th week was higher in 15 mg/day haloperidol group (13.3) compared to 7.5 mg/day haloperidol group (11.6) with p<0.001. 
 
 CONCLUSION: This study showed an increase in the RDW value in schizophrenia subjects prior to the haloperidol administration. RDW ​​and MPV values were higher after haloperidol treatment compares to before haloperidol treatment. The increase of RDW and MPV values tend to be influenced by haloperidol dosage and administration duration.

Intermittent Administration of Haloperidol after Cortical Impact Injury Neither Impedes Spontaneous Recovery Nor Attenuates the Efficacy of Environmental Enrichment

The administration of haloperidol (HAL) once-daily for 19 days after experimental traumatic brain injury (TBI) impedes recovery and attenuates the efficacy of environmental enrichment (EE). However, it is unknown how intermittent administration of HAL affects the recovery process when paired with EE. Addressing the uncertainty is relevant because daily HAL is not always warranted to manage TBI-induced agitation in the clinic, and indeed intermittent therapy may be a more common approach. Hence, the aim of the study was to test the hypothesis that intermittent HAL would neither impair recovery in standard (STD)-housed controls nor attenuate the efficacy of EE. Anesthetized adult male rats received a cortical impact or sham injury and then were housed in STD or EE conditions. Beginning 24 h later, HAL (0.5 mg/kg; intraperitoneally [i.p.]) was administered either once-daily for 19 days or once every other day, whereas vehicle (VEH; 1 mL/kg; i.p.) was administered once daily. Motor performance and cognition were assessed on post-injury days 1-5 and 14-19, respectively. Cortical lesion volume was quantified on day 21. SHAM controls performed better than all TBI groups on motor and spatial learning [p < 0.05], but did not differ from the TBI + EE + daily VEH group on memory retention [p > 0.05]. The TBI + EE + daily VEH and TBI + EE + intermittent HAL groups did not differ from one another on beam-walk or spatial learning [p > 0.05], and both performed better than all other TBI groups [p < 0.05]. In contrast, the TBI + STD + daily HAL group performed worse than all TBI groups on spatial learning [p < 0.05]. No difference in any endpoint was revealed between the TBI + STD + intermittent HAL and TBI + STD + daily VEH groups [p > 0.05]. The results support the hypothesis that HAL is not detrimental when provided intermittently. If translatable to the clinic, intermittent HAL may be used to control TBI-induced agitation without negatively affecting spontaneous recovery or rehabilitative efficacy.

Tinospora cordifolia attenuates antipsychotic drug induced hyperprolactinemia in Wistar rats

Objective: To evaluate the anti-hyperprolactinemic effect of methanolic extract of Tinospora cordifolia against antipsychotic/neuroleptic drug induced hyperprolactinemia. Methods: A total of 48 Wistar albino rats were chosen in the study. To induce hyperprolactinemia, haloperidol at 5 mg/kg/day was intraperitoneally administered for 16 continuous days and sulpiride at 20 mg/kg/day was administered intraperitoneally for 28 continuous days. Methanolic extract of Tinospora cordifolia at 200 mg/kg/day and 400 mg/kg/day were administered orally 30 min before administration of haloperidol and sulpiride for 16 and 28 days, respectively. Then, we had evaluated prolactin, dopamine and antioxidant status in the treatment group as compared to haloperidol and sulpiride. Results: There was a significant (P Conclusions: Methanolic extract of Tinospora cordifolia has a significant anti-hyperprolactinemic effect which may be attributed to neuroprotective and antioxidant effects of its signature constituents like stepharanine.

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.

Conditioned increase of locomotor activity induced by haloperidol.

Dopamine antagonist drugs have profound effects on locomotor activity. In particular, the administration of the D2 antagonist haloperidol produces a state that is similar to catalepsy. In order to confirm whether the modulation of the dopaminergic activity produced by haloperidol can act as an unconditioned stimulus, we carried out two experiments in which the administration of haloperidol was repeatedly paired with the presence of distinctive contextual cues that served as a Conditioned Stimulus. Paradoxically, the results revealed a dose-dependent increase in locomotor activity following conditioning with dopamine antagonist (Experiments 1) that was susceptible of extinction when the conditioned stimulus was presented repeatedly by itself after conditioning (Experiment 2). These data are interpreted from an associative perspective, considering them as a result of a classical conditioning process.

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.