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ELife Apr 2024Psychosis is characterized by a diminished ability of the brain to distinguish externally driven activity patterns from self-generated activity patterns. Antipsychotic...
Psychosis is characterized by a diminished ability of the brain to distinguish externally driven activity patterns from self-generated activity patterns. Antipsychotic drugs are a class of small molecules with relatively broad binding affinity for a variety of neuromodulator receptors that, in humans, can prevent or ameliorate psychosis. How these drugs influence the function of cortical circuits, and in particular their ability to distinguish between externally and self-generated activity patterns, is still largely unclear. To have experimental control over self-generated sensory feedback, we used a virtual reality environment in which the coupling between movement and visual feedback can be altered. We then used widefield calcium imaging to determine the cell type-specific functional effects of antipsychotic drugs in mouse dorsal cortex under different conditions of visuomotor coupling. By comparing cell type-specific activation patterns between locomotion onsets that were experimentally coupled to self-generated visual feedback and locomotion onsets that were not coupled, we show that deep cortical layers were differentially activated in these two conditions. We then show that the antipsychotic drug clozapine disrupted visuomotor integration at locomotion onsets also primarily in deep cortical layers. Given that one of the key components of visuomotor integration in cortex is long-range cortico-cortical connections, we tested whether the effect of clozapine was detectable in the correlation structure of activity patterns across dorsal cortex. We found that clozapine as well as two other antipsychotic drugs, aripiprazole and haloperidol, resulted in a strong reduction in correlations of layer 5 activity between cortical areas and impaired the spread of visuomotor prediction errors generated in visual cortex. Our results are consistent with the interpretation that a major functional effect of antipsychotic drugs is a selective alteration of long-range layer 5-mediated communication.
Topics: Humans; Animals; Mice; Antipsychotic Agents; Clozapine; Haloperidol; Brain; Aripiprazole
PubMed: 38578678
DOI: 10.7554/eLife.86805 -
Biomedicine & Pharmacotherapy =... May 2024This study evaluates the antiallodynic and antihyperalgesic effects of LMH-2, a new haloperidol (HAL) analog that acts as sigma-1 receptor (σ1 R) antagonist, in...
This study evaluates the antiallodynic and antihyperalgesic effects of LMH-2, a new haloperidol (HAL) analog that acts as sigma-1 receptor (σ1 R) antagonist, in diabetic mice using a model of neuropathic pain induced by chronic hyperglycemia. Additionally, we compared its effects with those of HAL. Hyperglycemia was induced in mice by nicotinamide-streptozotocin administration (NA-STZ, 50-130 mg/kg). Four weeks later, mechanical allodynia was assessed using the up-down method, and hyperalgesia was evoked with formalin 0.5%. We evaluated antiallodynic and antihyperalgesic effects of LMH-2 (5.6-56.2 mg/kg), HAL (0.018-0.18 mg/kg) and gabapentin (GBP, 5.6-56.2 mg/kg). The results showed that LMH-2 had a more significant antiallodynic effect compared to HAL and GBP (90.4±8.7 vs 75.1±3.1 and 41.9±2.3%, respectively; P<0.05), as well as an antihyperalgesic effect (96.3±1.2 vs 86.9±7.41 and 86.9±4.8%, respectively; P<0.05). Moreover, the antiallodynic and antihyperalgesic effect of both LMH-2 and HAL were completely abolished by PRE-084 (σ1 R agonist); and partially by pramipexole (a D-like receptor agonist). Finally, the effect of all treatments on the rotarod test, barra, open field and exploratory behaviors showed that LMH-2 did not alter the animals' balance or the exploratory behavior, unlike as HAL or GBP. The molecular docking included indicate that LMH-2 has lower affinity to the DR than HAL. These results provide evidence that LMH-2 exerts its antinociceptive effects as a σ1 R antagonist without the adverse effects induced by HAL or GBP. Consequently, LMH-2 can be considered a good and safe strategy for treating neuropathic pain caused by hyperglycemia in patients with diabetes.
Topics: Animals; Receptors, sigma; Haloperidol; Sigma-1 Receptor; Diabetes Mellitus, Experimental; Male; Mice; Analgesics; Neuralgia; Hyperalgesia; Diabetic Neuropathies; Molecular Docking Simulation; Streptozocin; Dose-Response Relationship, Drug; Gabapentin
PubMed: 38574622
DOI: 10.1016/j.biopha.2024.116524 -
European Review For Medical and... Mar 2024Methyl-2-(4-chloro- phenyl)-5-benzoxazoleacetate (MCBA), a synthetic benzoxazole derivative with established antipsoriatic efficacy, was investigated for potential...
OBJECTIVE
Methyl-2-(4-chloro- phenyl)-5-benzoxazoleacetate (MCBA), a synthetic benzoxazole derivative with established antipsoriatic efficacy, was investigated for potential antinociceptive effects. This study employs various nociceptive assays in mice to elucidate MCBA's antinociceptive mechanisms.
MATERIALS AND METHODS
MCBA's antinociceptive potential was tested against various nociception models induced by formalin, glutamate, capsaicin, a transient receptor potential vanilloid 1 (TRPV1) receptor agonist, and phorbol 12-myristate 13-acetate, a protein kinase C (PKC) activator. It was then assessed using the hot plate test and examined within the acetic acid-induced writhing test. During the acetic acid-induced writhing test, MCBA was pre-challenged against selective receptor antagonists such as naloxone, caffeine, atropine, yohimbine, ondansetron, and haloperidol. It was also pre-challenged with ATP-sensitive potassium channel inhibitor (glibenclamide) to further elucidate its antinociceptive mechanism.
RESULTS
The results showed that oral administration of MCBA led to a dose-dependent and significant inhibition (p < 0.05) of nociceptive effects across all evaluated models at doses of 60, 120, and 240 mg/kg. Moreover, the efficacy of MCBA's antinociceptive potential was significantly counteracted (p < 0.0001) by specific antagonists: (i) directed at adenosinergic, alpha-2 adrenergic, and cholinergic receptors using caffeine, yohimbine, and atropine, respectively; and (ii) targeting ATP-sensitive potassium channels, employing glibenclamide. Antagonists aimed at opioidergic and serotoninergic receptors (naloxone and ondansetron, respectively) had poor utility in inhibiting antinociceptive activity. Conversely, the dopaminergic receptor antagonist haloperidol potentiated locomotor abnormalities associated with MCBA treatment.
CONCLUSIONS
MCBA-induced antinociception involves modulation of glutamatergic-, TRVP1 receptors- and PKC-signaling pathways. It impacts adenosinergic, alpha-2 adrenergic, and cholinergic receptors and opens ATP-sensitive potassium channels.
Topics: Animals; Mice; Caffeine; Glyburide; Haloperidol; Nociception; Ondansetron; Adrenergic Agents; Atropine; KATP Channels; Naloxone; Receptors, Cholinergic; Yohimbine; Analgesics; Acetates
PubMed: 38497888
DOI: 10.26355/eurrev_202403_35620 -
CNS Neuroscience & Therapeutics Feb 2024Widely used second-generation antipsychotics are associated with adverse metabolic effects, contributing to increased cardiovascular mortality. To develop strategies to...
AIM
Widely used second-generation antipsychotics are associated with adverse metabolic effects, contributing to increased cardiovascular mortality. To develop strategies to prevent or treat adverse metabolic effects, preclinical models have a clear role in uncovering underlying molecular mechanisms. However, with few exceptions, preclinical studies have been performed in healthy animals, neglecting the contribution of dysmetabolic features inherent to psychotic disorders.
METHODS
In this study, methylazoxymethanol acetate (MAM) was prenatally administered to pregnant Sprague-Dawley rats at gestational day 17 to induce a well-validated neurodevelopmental model of schizophrenia mimicking its assumed pathogenesis with persistent phenotype. Against this background, the dysmetabolic effects of acute treatment with olanzapine and haloperidol were examined in female rats.
RESULTS
Prenatally MAM-exposed animals exhibited several metabolic features, including lipid disturbances. Half of the MAM rats exposed to olanzapine had pronounced serum lipid profile alteration compared to non-MAM controls, interpreted as a reflection of a delicate MAM-induced metabolic balance disrupted by olanzapine. In accordance with the drugs' clinical metabolic profiles, olanzapine-associated dysmetabolic effects were more pronounced than haloperidol-associated dysmetabolic effects in non-MAM rats and rats exposed to MAM.
CONCLUSION
Our results demonstrate metabolic vulnerability in female prenatally MAM-exposed rats, indicating that findings from healthy animals likely provide an underestimated impression of metabolic dysfunction associated with antipsychotics. In the context of metabolic disturbances, neurodevelopmental models possess a relevant background, and the search for adequate animal models should receive more attention within the field of experimental psychopharmacology.
Topics: Pregnancy; Rats; Female; Animals; Haloperidol; Methylazoxymethanol Acetate; Olanzapine; Rats, Sprague-Dawley; Antipsychotic Agents; Lipids; Disease Models, Animal
PubMed: 38421095
DOI: 10.1111/cns.14565 -
International Journal of Molecular... Feb 2024Antipsychotic drug (APD) medication can lead to metabolic dysfunctions and weight gain, which together increase morbidity and mortality. Metabolically active visceral...
Antipsychotic drug (APD) medication can lead to metabolic dysfunctions and weight gain, which together increase morbidity and mortality. Metabolically active visceral adipose tissue (VAT) in particular plays a crucial role in the etiopathology of these metabolic dysregulations. Here, we studied the effect of 12 weeks of drug medication by daily oral feeding of clozapine and haloperidol on the perirenal fat tissue as part of VAT of male and female Sprague Dawley rats in the context of complex former investigations on brain, liver, and blood. Adipocyte area values were determined, as well as triglycerides, non-esterified fatty acids (NEFAs), glucose, glycogen, lactate, malondialdehyde equivalents, ferric iron and protein levels of Perilipin-A, hormone-sensitive-lipase (HSL), hepcidin, glucose transporter-4 (Glut-4) and insulin receptor-ß (IR-ß). We found increased adipocyte mass in males, with slightly higher adipocyte area values in both males and females under clozapine treatment. Triglycerides, NEFAs, glucose and oxidative stress in the medicated groups were unchanged or slightly decreased. In contrast to controls and haloperidol-medicated rats, perirenal adipocyte mass and serum leptin levels were not correlated under clozapine. Protein expressions of perilipin-A, Glut-4 and HSL were decreased under clozapine treatment. IR-ß expression changed sex-specifically in the clozapine-medicated groups associated with higher hepcidin levels in the perirenal adipose tissue of clozapine-treated females. Taken together, clozapine and haloperidol had a smaller effect than expected on perirenal adipose tissue. The perirenal adipose tissue shows only weak changes in lipid and glucose metabolism. The main changes can be seen in the proteins examined, and probably in their effect on liver metabolism.
Topics: Rats; Male; Female; Animals; Antipsychotic Agents; Clozapine; Haloperidol; Hepcidins; Rats, Sprague-Dawley; Adipocytes; Adipose Tissue; Liver; Triglycerides; Glucose; Fatty Acids, Nonesterified; Brain; Perilipins
PubMed: 38396865
DOI: 10.3390/ijms25042188 -
Neuropsychopharmacology Reports Mar 2024Impairments in emotional memory are frequently observed in several mental disorders, highlighting their significance as potential therapeutic targets. Recent research on...
AIM
Impairments in emotional memory are frequently observed in several mental disorders, highlighting their significance as potential therapeutic targets. Recent research on the cued fear conditioning model has elucidated the neural circuits involved in fear memory processing. However, contradictory findings have been reported concerning the role of dopamine and the impact of dopamine D2 receptor (D2R) antagonists. There is notably limited knowledge regarding the clinical utility of chronic D2R antagonist treatments. This study aimed to uncover how such treatments affect fear memory processing.
METHODS
We utilized a cued fear conditioning rat model and conducted chronic haloperidol treatment for 14 days. Subsequently, to investigate the effect of chronic haloperidol treatment on fear-conditioned memory expression and extinction, we observed freezing behavior under exposure to a conditioned stimulus for 14 days.
RESULTS
Chronic haloperidol treatment suppressed freezing time on the fear memory expression. In contrast, a single haloperidol administration enhanced the freezing time on fear memory expression and delayed extinction.
CONCLUSION
The results of this study suggest that chronic administration of antipsychotic drugs affects fear memory processing differently from single-dose administration. This indicates that the effects of chronic D2R antagonist treatment are distinct from the nonspecific effects of the drugs. This study provides fundamental insights that may contribute to our understanding of therapeutic mechanisms for fear memory disorders related to D2R in the future.
Topics: Humans; Rats; Animals; Haloperidol; Fear; Conditioning, Classical; Cues; Antipsychotic Agents
PubMed: 38356296
DOI: 10.1002/npr2.12418 -
BMC Anesthesiology Feb 2024To systematically review the evidence about the effect of haloperidol on postoperative delirium in elderly patients. (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To systematically review the evidence about the effect of haloperidol on postoperative delirium in elderly patients.
METHODS
PubMed, Embase, the Cochrane Library and China National Knowledge Infrastructure were used to find concerned studies for meta-analysis. The main outcome was the incidence of postoperative delirium, and the secondary outcomes were side effects of haloperidol and the length of hospital stay. The meta-analyses were conducted using the Review Manager Version 5.1. This study was conducted based on the PRISMA statement.
RESULTS
Eight RCTs (1569 patients) were included in the meta-analysis. There was a significant difference in the incidence of postoperative delirium between haloperidol and control groups (OR = 0.62, 95%CI 0.48-0.80, P = 0.0002, I = 20%). In addition, side effects of haloperidol and the duration of hospitalization were comparable (OR = 0.58, 95%CI 0.25-1.35, P = 0.21, I = 0%; MD =-0.01, 95%CI -0.16-0.15, P = 0.92, I = 28%). Subgroup analysis implied the effect of haloperidol on postoperative delirium might vary with the dose (5 mg daily: OR = 0.40, 95%CI 0.22-0.71, P = 0.002, I = 0%; <5 mg daily: OR = 0.72, 95%CI 0.42-1.23, P = 0.23, I = 0%).
CONCLUSIONS
The meta-analysis revealed perioperative application of haloperidol could decrease the occurrence of postoperative delirium without obvious side effects in elderly people, and high-dose haloperidol (5 mg daily) possessed a greater positive effect.
Topics: Humans; Aged; Haloperidol; Antipsychotic Agents; Emergence Delirium; Delirium; Hospitalization
PubMed: 38308229
DOI: 10.1186/s12871-024-02434-8 -
JAMA Network Open Jan 2024Antipsychotic medications, often prescribed for delirium in intensive care units (ICUs), may contribute to QTc interval prolongation. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Antipsychotic medications, often prescribed for delirium in intensive care units (ICUs), may contribute to QTc interval prolongation.
OBJECTIVE
To determine whether antipsychotics increase the QTc interval in patients with delirium in the ICU.
DESIGN, SETTING, AND PARTICIPANTS
An a priori analysis of a randomized clinical trial in medical/surgical ICUs within 16 centers across the US was conducted. Participants included adults with delirium in the ICU with baseline QTc interval less than 550 ms. The study was conducted from December 2011 to August 2017. Data analysis was performed from April 25 to August 18, 2021.
INTERVENTIONS
Patients were randomized 1:1:1 to intravenous haloperidol, ziprasidone, or saline placebo administered twice daily until resolution of delirium, ICU discharge, or 14 days.
MAIN OUTCOMES AND MEASURES
Twelve-lead electrocardiograms were used to measure baseline QTc before study drug initiation and telemetry was used to measure QTc before each subsequent dose of study drug. Unadjusted day-to-day changes in QTc were calculated and multivariable proportional odds regression was used to estimate the effects of antipsychotics vs placebo on next-day maximum QTc interval, adjusting for prespecified baseline covariates and potential interactions with sex. Safety end points, including the occurrence of torsade de pointes, were evaluated. All analyses were conducted based on the intention to treat principle.
RESULTS
A total of 566 patients were randomized to haloperidol (n = 192), ziprasidone (n = 190), or placebo (n = 184). Median age was 60.1 (IQR, 51.4-68.7) years; 323 were men (57%). Baseline median QTc intervals across the groups were similar: haloperidol, 458.0 (IQR, 432.0-479.0) ms; ziprasidone, 451.0 (IQR, 424.0-472.0) ms; and placebo, 452.0 (IQR, 432.0-472.0) ms. From day 1 to day 2, median QTc changed minimally: haloperidol, -1.0 (IQR, -28.0 to 15.0) ms; ziprasidone, 0 (IQR, -23.0 to 20.0) ms; and placebo, -3.5 (IQR, -24.8 to 17.0) ms. Compared with placebo, neither haloperidol (odds ratio [OR], 0.95; 95% CI, 0.66-1.37; P = .78) nor ziprasidone (OR, 1.09; 95% CI, 0.75-1.57; P = .78) was associated with next-day QTc intervals. Effects were not significantly modified by sex (P = .41 for interaction). There were 2 occurrences of nonfatal torsade de pointes, both in the haloperidol group. Neither was associated with study drug administration.
CONCLUSIONS AND RELEVANCE
The findings of this trial suggest that daily QTc interval monitoring during antipsychotic use may have limited value in patients in the ICU with normal baseline QTc and few risk factors for QTc prolongation.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01211522.
Topics: Adult; Male; Humans; Middle Aged; Female; Antipsychotic Agents; Haloperidol; Torsades de Pointes; Electrocardiography; Intensive Care Units; Delirium; Piperazines; Thiazoles
PubMed: 38252439
DOI: 10.1001/jamanetworkopen.2023.52034 -
BMC Psychiatry Jan 2024Developmental dyslexia is characterized by reading and writing deficits that persist into adulthood. Dyslexia is strongly associated with academic underachievement, as...
BACKGROUND
Developmental dyslexia is characterized by reading and writing deficits that persist into adulthood. Dyslexia is strongly associated with academic underachievement, as well as impulsive, compulsive, and criminal behaviors. The aims of this study were to investigate impulsive or compulsive reading comprehension, analyzing the differences in reading errors between two distinct groups -one with Antisocial Personality Disorder (ASPD) and another with Obsessive-Compulsive Personality Disorder (OCPD) and examine their correlation with criminal behavior within a prison population.
METHODS
We gathered data from 194 participants: 81 with ASPD and 113 with OCPD from a prison center. Participants took part in interviews to gather data on demographic, criminal, and behavioral data. Additionally, the participants underwent various assessments, including the International Examination for Personality Disorders; Symptom Inventory, and Battery for the Assessment of Reading Processes in Secondary and High School - Revised.
RESULTS
Our analysis revealed differences in reading skills between the ASPD and OCPD groups. Specifically, the OCPD group showed poorer performance on lexical selection, semantic categorization, grammar structures, grammatical judgements, and expository comprehension when compared with the ASPD group. Conversely, the OCPD group obtained higher scores on narrative comprehension relative to the ASPD group.
CONCLUSIONS
The OCPD group showed slow lexical-phonological coding and phonological activation.
Topics: Humans; Obsessive-Compulsive Disorder; Comprehension; Prisons; Language Disorders; Spiperone
PubMed: 38216979
DOI: 10.1186/s12888-023-05372-w -
Frontiers in Public Health 2023Previous research has outlined the health benefits of exercise including its therapeutic potential for substance use disorders (SUD). These data have already been...
BACKGROUND
Previous research has outlined the health benefits of exercise including its therapeutic potential for substance use disorders (SUD). These data have already been utilized and it is now common to find exercise as part of SUD treatment and relapse prevention programs. However, we need to better understand different exercise regimens and determine which would be the most beneficial for SUDs. Recently, high intensity interval training (HIIT) has gained attention in comparison with aerobic and resistance exercise. Little is known regarding the neurobiological mechanisms of HIIT, including its effects on dopamine signaling and receptor levels in the brain. The present study examined the effects of chronic HIIT exercise on dopamine signaling as measured by dopamine type 1-like receptor (D1R)-like, dopamine type 2-like receptor (D2R)-like, and tyrosine hydroxylase (TH) quantification in the brains of male and female rats as measured by [H] SCH 23390 and [H] spiperone autoradiography, and TH-immunoreactive optical density values.
METHODS
Rats were separated in two groups: sedentary and HIIT exercise. Exercise was on a treadmill for 30 min daily (10 3 min cycles) for six weeks with progressive speed increased up to 0.8 mph (21.5 m/min).
RESULTS
Results showed for D2R-like binding, a significant effect across the ventral caudate putamen (V CPU) between sexes, such that mean D2R-like binding was 14% greater for males than females. In the nucleus accumbens shell (Nac Shell), the HIIT Exercise rats showed 16% greater D2R-like binding as compared to the sedentary rats. No significant effects of HIIT exercise were found across groups for brain D1R-like binding levels or TH expression.
CONCLUSION
These results suggest that HIIT exercise can modulate dopamine signaling by way of increased D2R. These findings support the premise that HIIT exercise plays an important role in dopamine signaling and, may provide a potential mechanism for how HIIT exercise can impact the brain and behavior.
Topics: Female; Male; Animals; Rats; Dopamine; High-Intensity Interval Training; Brain; Signal Transduction; Spiperone
PubMed: 38192549
DOI: 10.3389/fpubh.2023.1257629