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1.
Wiad Lek ; 74(9 cz 1): 2105-2108, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34725284

RESUMO

OBJECTIVE: The aim: To analyze and compare the features of changes in the motor activity of rats on the background of pharmacological models of depressive disorders. PATIENTS AND METHODS: Materials and methods: Depressive-like state was simulated on 40 mature male Wistar rats using: reserpine (15 mg/kg), clonidine (0.1 mg/kg), haloperidol (0.25 mg/kg). The control group was given as a single dose 0.5 ml of a 0.9% sodium chloride solution intraperitoneally. After 3, 12, 24, 48 and 72 hours from the beginning of the experiment, changes in motor activity in the "open field" test were examined by the number of crossed squares, the calculation was carried out within 5 minutes. RESULTS: Results: Reserpine at a dose of 15 mg/kg caused probable motor activity disorders in rats in the "open field" test during all study periods. The most pronounced inhibition of motor activity was observed within 12-48 hours from the beginning of the experiment. 3 hours after clonidine administration, the number of crossed squares decreased by 310% (p<0.001), after 12 hours - by 180% (p<0.001), after 24 hours - by 140% (p<0.001), after 48 hours - by 50% (p<0.005) in comparison with the control group. On 3rd day, the motor activity of rats was almost completely restored. The use of haloperidol after 3 hours most significantly impaired the motor activity of rats in the "open field" test, and its recovery was observed after 24 hours. CONCLUSION: Conclusions: Reserpine inhibited the motor activity of rats, most pronounced from 12 to 48 hours of the experiment. Clonidine inhibited mainly in the first hours of the study. Haloperidol impaired motor activity at 3rd and 12th hours of observation.


Assuntos
Atividade Motora , Reserpina , Animais , Clonidina/farmacologia , Haloperidol/farmacologia , Masculino , Ratos , Ratos Wistar , Reserpina/farmacologia
2.
Phytomedicine ; 91: 153706, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34517264

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cause of cancer-related death worldwide. Curcumin (C) has been extensively investigated in different types of malignancies, including hepatocellular carcinoma, but its physicochemical properties have significantly influenced its clinical use. Several approaches are being explored to enhance curcumin's therapeutic response, including its combination with various drugs. PURPOSE: This study aimed to evaluate the anti-tumor effect of curcumin (C) in combination with F2 (N-n-butyl haloperidol iodide) on hepatocellular carcinoma and its potential underlying mechanism in vitro and in vivo. METHODS: Cell proliferation was evaluated by CCK-8 and colony formation assays, and apoptosis was measured by flow cytometry. The migratory and invasive abilities of Hep3B and SMMC-7721 cells were measured by wound-healing and matrigel transwell assays. In order to investigate the molecular pathways, various experiments such as western blotting, qPCR, RNA-seq, immunostaining and transfection were performed. To evaluate the anti-HCC effects in vivo, a xenograft tumor model was used. RESULTS: Our findings showed that the combination of curcumin (C) & F2 (F2C) strongly inhibited malignant proliferation and migration in SMMC-7721 and Hep3B cells. The F2C treatment downregulates enhancer of zeste homolog 2 (EZH2) transcription and protein expression, which is key epigenetic regulator responsible for HCC development. Moreover, the inhibition of EZH2 by F2C led to Wnt/ß-catenin signaling inhibition by decreasing tri-methylation of histone H3 at lysine 27 (H3K27me3) and long non-coding RNA H19 expression. The inhibition of F2C was associated with the suppression of tumorigenicity in xenograft HCC models. CONCLUSION: These findings suggested that, F2C inhibited HCC formation, migration and its modulatory mechanism seemed to be associated with downregulation of EZH2, silencing Wnt/ß-catenin signaling by interacting with H19, suggesting that F2C may be a promising drug in the clinical treatment of HCC.


Assuntos
Carcinoma Hepatocelular , Curcumina , Haloperidol/análogos & derivados , Neoplasias Hepáticas , RNA Longo não Codificante , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células , Curcumina/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação Neoplásica da Expressão Gênica , Haloperidol/farmacologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Camundongos Nus , RNA Longo não Codificante/genética , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cells ; 10(9)2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34571834

RESUMO

We previously reported that claudin-5, a tight junctional protein, mediates lung vascular permeability in a murine model of acute lung injury (ALI) induced by lipopolysaccharide (LPS). Recently, it has been reported that haloperidol, an antipsychotic medication, dose-dependently increases expression of claudin-5 in vitro and in vivo, in brain endothelium. Notably, claudin-5 is highly expressed in both brain and lung tissues. However, the effects of haloperidol on EC barrier function are unknown. We hypothesized that haloperidol increases lung EC claudin-5 expression and attenuates agonist-induced lung EC barrier disruption. Human pulmonary artery ECs were pretreated with haloperidol at variable concentrations (0.1-10 µM) for 24 h. Cell lysates were subjected to Western blotting for claudin-5, in addition to occludin and zona occludens-1 (ZO-1), two other tight junctional proteins. To assess effects on barrier function, EC monolayers were pretreated for 24 h with haloperidol (10 µM) or vehicle prior to treatment with thrombin (1 U/mL), with measurements of transendothelial electrical resistance (TER) recorded as a real-time assessment of barrier integrity. In separate experiments, EC monolayers grown in Transwell inserts were pretreated with haloperidol (10 µM) prior to stimulation with thrombin (1 U/mL, 1 h) and measurement of FITC-dextran flux. Haloperidol significantly increased claudin-5, occludin, and ZO-1 expression levels. Measurements of TER and FITC-dextran Transwell flux confirmed a significant attenuation of thrombin-induced barrier disruption associated with haloperidol treatment. Finally, mice pretreated with haloperidol (4 mg/kg, IP) prior to the intratracheal administration of LPS (1.25 mg/kg, 16 h) had increased lung claudin-5 expression with decreased lung injury as assessed by bronchoalveolar lavage (BAL) fluid protein content, total cell counts, and inflammatory cytokines, in addition to lung histology. Our data confirm that haloperidol results in increased claudin-5 expression levels and demonstrates lung vascular-protective effects both in vitro and in vivo in a murine ALI model. These findings suggest that haloperidol may represent a novel therapy for the prevention or treatment of ALI and warrants further investigation in this context.


Assuntos
Células Endoteliais/efeitos dos fármacos , Haloperidol/farmacologia , Pulmão/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Animais , Permeabilidade Capilar/efeitos dos fármacos , Células Cultivadas , Impedância Elétrica , Células Endoteliais/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismo
5.
Neurochem Res ; 46(8): 2097-2111, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34024016

RESUMO

Although antipsychotics are routinely used in the treatment of schizophrenia for the last decades, their precise mechanism of action is still unclear. In this study, we investigated changes in the PC12 cells' proteome under the influence of clozapine, risperidone, and haloperidol to identify protein pathways regulated by antipsychotics. Analysis of the protein profiles in two time points: after 12 and 24 h of incubation with drugs revealed significant alterations in 510 proteins. Further canonical pathway analysis revealed an inhibition of ciliary trophic factor signaling after treatment with haloperidol and showed a decrease in acute phase response signaling in the risperidone group. Interestingly, all tested drugs have caused changes in PC12 proteome which correspond to inhibition of cytokines: tumor necrosis factor (TNF) and transforming growth factor beta 1 (TGF-ß1). We also found that the 12-h incubation with clozapine caused up-regulation of protein kinase A signaling and translation machinery. After 24 h of treatment with clozapine, the inhibition of the actin cytoskeleton signaling and Rho proteins signaling was revealed. The obtained results suggest that the mammalian target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) play a central role in the signal transduction of clozapine.


Assuntos
Citoesqueleto de Actina/efeitos dos fármacos , Antipsicóticos/farmacologia , Clozapina/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Proteoma/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Reação de Fase Aguda/metabolismo , Animais , Fator Neurotrófico Ciliar/metabolismo , Haloperidol/farmacologia , Células PC12 , Proteoma/metabolismo , Ratos , Risperidona/farmacologia , Proteínas rho de Ligação ao GTP/metabolismo
6.
Am J Physiol Renal Physiol ; 320(5): F963-F971, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33843270

RESUMO

Psychotropic drugs may be associated with hyponatremia, but an understanding of how they induce water retention in the kidney remains elusive. Previous studies have postulated that they may increase vasopressin production in the hypothalamus without supporting evidence. In this study, we investigated the possibility of drug-induced nephrogenic syndrome of inappropriate antidiuresis using haloperidol, sertraline, and carbamazepine. Haloperidol, sertraline, or carbamazepine were treated in inner medullary collecting duct (IMCD) suspensions and primary cultured IMCD cells prepared from male Sprague-Dawley rats. The responses of intracellular cAMP production, aquaporin-2 (AQP2) protein expression and localization, vasopressin-2 receptor (V2R) and AQP2 mRNA, and cAMP-responsive element-binding protein (CREB) were tested with and without tolvaptan and the protein kinase A (PKA) inhibitors H89 and Rp-cAMPS. In IMCD suspensions, cAMP production was increased by haloperidol, sertraline, or carbamazepine and was relieved by tolvaptan cotreatment. In primary cultured IMCD cells, haloperidol, sertraline, or carbamazepine treatment increased total AQP2 and decreased phosphorylated Ser261-AQP2 protein expression. Notably, these responses were reversed by cotreatment with tolvaptan or a PKA inhibitor. AQP2 membrane trafficking was induced by haloperidol, sertraline, or carbamazepine and was also blocked by cotreatment with tolvaptan or a PKA inhibitor. Furthermore, upregulation of V2R and AQP2 mRNA and phosphorylated CREB was induced by haloperidol, sertraline, or carbamazepine and was blocked by tolvaptan cotreatment. We conclude that, in the rat IMCD, psychotropic drugs upregulate AQP2 via V2R-cAMP-PKA signaling in the absence of vasopressin stimulation. The vasopressin-like action on the kidney appears to accelerate AQP2 transcription and dephosphorylate AQP2 at Ser261.NEW & NOTEWORTHY It is unclear whether antipsychotic drugs can retain water in the kidney in the absence of vasopressin. This study demonstrates that haloperidol, sertraline, and carbamazepine can produce nephrogenic syndrome of inappropriate antidiuresis because they directly upregulate vasopressin-2 receptor and aquaporin-2 (AQP2) via cAMP/PKA signaling. We showed that, in addition to AQP2 trafficking, AQP2 protein abundance was rapidly increased by treatment with antipsychotic drugs in association with dephosphorylation of AQP2 at Ser261 and accelerated AQP2 transcription.


Assuntos
Aquaporina 2/metabolismo , Fármacos do Sistema Nervoso Central/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Túbulos Renais Coletores/citologia , Receptores de Vasopressinas/metabolismo , Animais , Carbamazepina/administração & dosagem , Carbamazepina/farmacologia , Fármacos do Sistema Nervoso Central/administração & dosagem , AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Quimioterapia Combinada , Regulação da Expressão Gênica/efeitos dos fármacos , Haloperidol/administração & dosagem , Haloperidol/farmacologia , Masculino , Fosforilação , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Vasopressinas/genética , Sertralina/administração & dosagem , Sertralina/farmacologia , Vasopressinas/administração & dosagem , Vasopressinas/farmacologia
7.
Int J Mol Sci ; 22(9)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922377

RESUMO

Microglial cells are resident macrophages in the brain that have been implicated in the pathophysiology of schizophrenia. There is a lack of studies covering the effects of antipsychotics on microglial cells. The current literature points to a possible anti-inflammatory action without clear mechanisms of action. The aim of this study is to characterize the effects of haloperidol, risperidone and aripiprazole on BV-2 microglial cells in in vitro conditions. We have used immunofluorescence and flow cytometry to analyze the classical pro and anti-inflammatory markers, while a real-time metabolic assay (Seahorse) was used to assess metabolic function. We analyzed the expression of p70S6K to evaluate the mTOR pathway activity with Western blot. In this study, we demonstrate the varying effects of haloperidol, risperidone and aripiprazole administration in BV-2 microglial cells. All three tested antipsychotics were successful in reducing the pro-inflammatory action of microglial cells, although only aripiprazole increased the expression of anti-inflammatory markers. Most significant differences in the possible mechanisms of action were seen in the real-time metabolic assays and in the mTORC1 signaling pathway activity, with aripiprazole being the only antipsychotic to reduce the mTORC1 activity. Our results shed some new light on the effects of haloperidol, risperidone and aripiprazole action in microglial cells, and reveal a novel possible mechanism of action for aripiprazole.


Assuntos
Aripiprazol/farmacologia , Haloperidol/farmacologia , Mediadores da Inflamação/metabolismo , Microglia/efeitos dos fármacos , Risperidona/farmacologia , Antipsicóticos/farmacologia , Sobrevivência Celular , Células Cultivadas , Humanos , Microglia/imunologia , Microglia/metabolismo
8.
Science ; 372(6537)2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33795430

RESUMO

Hallucinations, a central symptom of psychotic disorders, are attributed to excessive dopamine in the brain. However, the neural circuit mechanisms by which dopamine produces hallucinations remain elusive, largely because hallucinations have been challenging to study in model organisms. We developed a task to quantify hallucination-like perception in mice. Hallucination-like percepts, defined as high-confidence false detections, increased after hallucination-related manipulations in mice and correlated with self-reported hallucinations in humans. Hallucination-like percepts were preceded by elevated striatal dopamine levels, could be induced by optogenetic stimulation of mesostriatal dopamine neurons, and could be reversed by the antipsychotic drug haloperidol. These findings reveal a causal role for dopamine-dependent striatal circuits in hallucination-like perception and open new avenues to develop circuit-based treatments for psychotic disorders.


Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Alucinações/fisiopatologia , Percepção , Animais , Percepção Auditiva , Feminino , Alucinações/psicologia , Haloperidol/farmacologia , Humanos , Ketamina/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Transtornos Psicóticos/fisiopatologia , Ratos , Recompensa , Estriado Ventral/metabolismo
9.
J Ethnopharmacol ; 273: 113994, 2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-33711439

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Barley maiya from gramineous plants (Hordeum vulgare L.) is obtained from ripe fruits through germination and drying. It is often used to treat diseases associated with high prolactin levels. OBJECTIVE: To investigate the anti-hyperprolactinemia (anti-HPRL) mechanisms of total barley maiya alkaloids (TBMA) and hordenine. METHODS: This experiment included 9 groups: Normal group, TBMA group, hordenine group, TBMA + haloperidol group, TBMA + forskolin group, TBMA + 8-bromo-cAMP group, hordenine + haloperidol group, hordenine + forskolin group, and hordenine + 8-bromo-cAMP group. The prolactin (PRL) concentration in the supernatant and the total cAMP concentration in the cells were detected by ELISA. The expression levels of PRL, dopamine D2 receptor (DRD2) and cAMP/PKA/CREB protein were measured by Western Blot. RESULTS: In the TBMA group and the hordenine group, the PRL level in MMQ cells was significantly decreased, but in GH3 cells there was no change. DRD2 expression level was markedly increased, cAMP concentration was decreased, and the activity of PKA and CREB declined in MMQ cells. Compared with the TBMA group, there was a significant decrease of DRD2 expression level, a remarkable increase of PRL secretion and an increase of cAMP/PKA/CREB expression in MMQ cells within the TBMA + haloperidol group. Compared with the forskolin group, there was no significant change in PRL secretion and cAMP/PKA/CREB expression level in MMQ cells within the TBMA + forskolin group. There was a decrease in PRL secretion and cAMP/PKA/CREB expression level in MMQ cells within the TBMA + 8-bromo-cAMP group compared with the 8-bromo-cAMP group. Compared with the hordenine group, DRD2 expression level was significantly decreased, PRL secretion was markedly increased, and cAMP/PKA/CREB expression level was increased in MMQ cells within the hordenine + haloperidol group. There was no significant change in PRL secretion and cAMP/PKA/CREB expression level in MMQ cells within the hordenine + forskolin group compared with the forskolin group and within the hordenine + 8-bromo-cAMP group compared with the 8-bromo-cAMP group. CONCLUSION: TBMA and hordenine can both play an anti-HPRL role via DRD2, and TBMA can also act on PKA targets to exert its anti-HPRL effect. TBMA and hordenine may be potential treatment strategies for HPRL.


Assuntos
Alcaloides/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Hordeum/química , Prolactina/antagonistas & inibidores , Tiramina/análogos & derivados , Alcaloides/química , Animais , Antieméticos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Colforsina/química , Colforsina/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Haloperidol/farmacologia , Ratos , Receptores de Dopamina D2 , Transdução de Sinais , Tiramina/química , Tiramina/farmacologia
10.
Psychopharmacology (Berl) ; 238(6): 1609-1619, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33590311

RESUMO

RATIONALE: Depressed individuals demonstrate debilitating symptoms, including depressed mood, anhedonia, and effort-related deficits. Effort-related decision-making can be measured through providing subjects with a choice between high effort/reward and low effort/reward options, which is a dopamine (DA)-dependent behavior. While previous research has shown sex differences in depression rates, this has not been examined within operant-based effort-related decision-making tasks nor has DA been shown to underlie this behavior in female rats. OBJECTIVES: The current study investigated sex differences in an effort-related decision-making task prior to and following administration of the DA D2 receptor antagonist haloperidol (HAL). METHODS: Adult rats were food restricted or fed freely and trained in an effort-related progressive ratio choice task. After stable responding, HAL was administered acutely (0.05-0.2 mg/kg) prior to testing. RESULTS: Results indicate a significant effect of sex on training variables, with males having a greater number of lever presses, higher ratios, and longer active lever times. Pretreatment with HAL significantly reduced the same measures in both sexes for the high-valued reward, while increasing chow consumption in the food restricted males. Food restricted rats showed a greater number of total lever presses and achieved higher ratios; however, the effect in male food restricted rats was greatest. CONCLUSIONS: These data suggest that, although there are sex differences in training, HAL decreases behavior across sexes, demonstrating that the D2 mechanism is similar in both sexes. These findings provide a better understanding of motivational dysfunction in both sexes and potential treatment targets for depression.


Assuntos
Comportamento de Escolha/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Haloperidol/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Dopamina/metabolismo , Feminino , Alimentos , Masculino , Motivação , Ratos , Ratos Sprague-Dawley , Recompensa , Fatores Sexuais
11.
Psychopharmacology (Berl) ; 238(4): 1069-1085, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33432392

RESUMO

RATIONALE: There is an urgent need for novel drugs for treating cognitive deficits that are defining features of schizophrenia. The individual d- and l-enantiomers of the tetrahydroprotoberberine (THPB) d,l-govadine have been proposed for the treatment of cognitive deficiencies and positive symptoms of schizophrenia, respectively. OBJECTIVES: We examined the effects of d-, l-, or d,l-govadine on two distinct forms of cognitive flexibility perturbed in schizophrenia and compared them to those induced by a selective D1 receptor agonist and D2 receptor antagonist. METHODS: Male rats received d-, l-, or d,l-govadine (0.3, 0.5, and 1.0 mg/kg), D1 agonist SKF81297(0.1, 0.3, and 1.0 mg/kg), or D2 antagonist haloperidol (0.1-0.2 mg/kg). Experiment 1 used a strategy set-shifting task (between-subjects). In experiment 2, well-trained rats were tested on a probabilistic reversal task (within-subjects). RESULTS: d-Govadine improved set-shifting across all doses, whereas higher doses of l-govadine impaired set-shifting. SKF81297 reduced perseverative errors at the lowest dose. Low/high doses of haloperidol increased/decreased set-shifting errors, the latter "improvement" attributable to impaired retrieval of a previous acquired rule. Probabilistic reversal performance was less affected by these drugs, but d-govadine reduced errors during the first reversal, whereas l-govadine impaired initial discrimination learning. d,l-Govadine had no reliable cognitive effects but caused psychomotor slowing like l-govadine and haloperidol. CONCLUSIONS: These findings further highlight differences between two enantiomers of d,l-govadine that may reflect differential modulation of D1 and D2 receptors. These preclinical findings give further impetus to formal clinical evaluation of d-govadine as a treatment for cognitive deficiencies related to schizophrenia.


Assuntos
Alcaloides de Berberina/farmacologia , Cognição/efeitos dos fármacos , Dopaminérgicos/farmacologia , Animais , Benzazepinas/farmacologia , Alcaloides de Berberina/química , Aprendizagem por Discriminação/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Aprendizagem/efeitos dos fármacos , Masculino , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Long-Evans , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Psicologia do Esquizofrênico , Estereoisomerismo
12.
Eur J Pharmacol ; 891: 173702, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33152334

RESUMO

Preclinical studies have reported that sigma-1 receptor antagonists may have efficacy in neuropathic pain states. The sigma-1 receptor is a unique ligand-operated chaperone present in crucial areas for pain control, in both the peripheral and central nervous system. This study assesses the synergistic antihyperalgesic and antiallodynic effect of haloperidol, a sigma-1 antagonist, combined with gabapentin in rats with peripheral neuropathy. Wistar rats male were subjected to chronic constriction injury (CCI) of the sciatic nerve. The effects of systemic administration of gabapentin and the sigma-1 receptor antagonist, haloperidol, were examined at 11 days post-CCI surgery. An analysis of Surface of Synergistic Interaction was used to determine whether the combination's effects were synergistic. Twelve combinations showed various degrees of interaction in the antihyperalgesic and antiallodynic effects. In hyperalgesia, three combinations showed additive effects, four combinations showed supra-additive effects, and three combinations produced an effect limited by the maximum effect. In allodynia, five combinations showed additive effects, two combinations showed supra-additive effects, and five combinations produced antihyperalgesic effects limited by the maximum effect. These findings indicate that the administration of some specific combination of gabapentin and haloperidol can synergistically reduce nerve injury-induced allodynia and hyperalgesia. This suggests that the haloperidol-gabapentin combination can improve the antiallodynic and antihyperalgesic effects in a neuropathic pain model.


Assuntos
Analgésicos/farmacologia , Gabapentina/farmacologia , Haloperidol/farmacologia , Hiperalgesia/prevenção & controle , Nociceptividade/efeitos dos fármacos , Dor Nociceptiva/prevenção & controle , Ciática/tratamento farmacológico , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Masculino , Dor Nociceptiva/metabolismo , Dor Nociceptiva/fisiopatologia , Ratos Wistar , Receptores sigma/antagonistas & inibidores , Receptores sigma/metabolismo , Ciática/metabolismo , Ciática/fisiopatologia , Transdução de Sinais
13.
Basic Clin Pharmacol Toxicol ; 128(1): 154-168, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32860481

RESUMO

Antipsychotics (APs) are widely used medications with reported diabetogenic side effects. This study investigated the effect of commonly used APs, namely chlorpromazine (CPZ), haloperidol (HAL) and clozapine, on the bioenergetics of male CD1 mice isolated pancreatic beta cells as an underlying mechanism of their diabetogenic effects. The effect of APs on Alamar blue reduction, adenosine triphosphate (ATP) production and glucose-stimulated insulin secretion (GSIS) of isolated beta cells was evaluated. Then, the effects of APs on the activities of mitochondrial complexes and their common coding genes expression, oxygen consumption rate (OCR), mitochondrial membrane potential (MMP) and lactate production were investigated. The effects of APs on the mitochondrial membrane fluidity (MMF) and mitochondrial membrane fatty acid composition were also examined. Results showed that the tested APs significantly decreased cellular ATP production and GSIS of the beta cells. The APs significantly inhibited the activities of mitochondrial complexes and their coding gene expression, MMP and OCR of the treated cells, with a parallel increase in lactate production to different extents with the different APs. CPZ and HAL showed increased MMF and mitochondrial membrane polyunsaturated fatty acid content. In conclusion, the tested APs-induced mitochondrial disruption can play a role in their diabetogenic side effect.


Assuntos
Antipsicóticos/farmacologia , Clorpromazina/farmacologia , Clozapina/farmacologia , Metabolismo Energético/efeitos dos fármacos , Haloperidol/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Animais , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Mitocôndrias/metabolismo
14.
Eur J Pharmacol ; 893: 173825, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33347818

RESUMO

Haloperidol is an antipsychotic agent recently described as an antinociceptive drug able to mediate the antagonism of sigma-1 receptors while morphine is an opioid used in the treatment of neuropathic pain. The objectives of this work were to determine the type of interaction generated by the combination of morphine and haloperidol in neuropathic pain induced by chronic constriction injury and to evaluate morphine tolerance and side effects. The antiallodynic and anti-hyperalgesic effects of morphine (0.01-3.16 mg/kg, s.c.) and haloperidol (0.0178-0.1778 mg/kg, s.c.) were determined after single-doses, in monotherapy and combined, using the acetone and von Frey tests, respectively. Evaluations were performed until 10-days postsurgery. Data were processed using "Surface of Synergic Interaction analysis". The rotarod test was used to evaluate motor coordination, and the constipation test was performed using 5% charcoal. The effects of haloperidol and BD-1063, sigma-1 receptor antagonists, naloxone and PRE-084 (sigma-1 agonist) were determined using the morphine-tolerance model. Morphine (0.0316 mg/kg)+haloperidol (0.0178 mg/kg) was determined to be the optimal combination. Morphine-tolerance was observed on day 5 after 11 administrations, although in animals that received the combination, tolerance was delayed until day 8. PRE-084 and naloxone administered on day 5 in animals treated with the combination resulted in a blockade of its antiallodynic effects. Adverse effects of constipation or motor incoordination were not shown in animals treated with morphine + haloperidol. In conclusion, haloperidol enhances the antinociceptive effects of morphine without significant adverse effects, as it is able to disrupt or delay the morphine-tolerance in neuropathic pain.


Assuntos
Analgésicos Opioides/farmacologia , Tolerância a Medicamentos , Haloperidol/farmacologia , Morfina/farmacologia , Neuralgia/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Receptores sigma/antagonistas & inibidores , Analgésicos Opioides/toxicidade , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Masculino , Morfina/toxicidade , Neuralgia/metabolismo , Neuralgia/fisiopatologia , Ratos Wistar , Receptores sigma/metabolismo , Transdução de Sinais , Fatores de Tempo
15.
Mol Neurobiol ; 58(1): 304-316, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32935232

RESUMO

Haloperidol is a typical antipsychotic drug commonly used to treat a broad range of psychiatric disorders related to dysregulations in the neurotransmitter dopamine (DA). DA modulates important physiologic functions and perturbations in Caenorhabditis elegans (C. elegans) and, its signaling have been associated with alterations in behavioral, molecular, and morphologic properties in C. elegans. Here, we evaluated the possible involvement of dopaminergic receptors in the onset of these alterations followed by haloperidol exposure. Haloperidol increased lifespan and decreased locomotor behavior (basal slowing response, BSR, and locomotion speed via forward speed) of the worms. Moreover, locomotion speed recovered to basal conditions upon haloperidol withdrawal. Haloperidol also decreased DA levels, but it did not alter neither dop-1, dop-2, and dop-3 gene expression, nor CEP dopaminergic neurons' morphology. These effects are likely due to haloperidol's antagonism of the D2-type DA receptor, dop-3. Furthermore, this antagonism appears to affect mechanistic pathways involved in the modulation and signaling of neurotransmitters such as octopamine, acetylcholine, and GABA, which may underlie at least in part haloperidol's effects. These pathways are conserved in vertebrates and have been implicated in a range of disorders. Our novel findings demonstrate that the dop-3 receptor plays an important role in the effects of haloperidol.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Haloperidol/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Haloperidol/farmacologia , Locomoção/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Modelos Biológicos , Mutação/genética , Degeneração Neural/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
16.
Behav Brain Res ; 396: 112919, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32956773

RESUMO

In the suited rat-models, we focused on the stable pentadecapeptide BPC 157, L-NAME, NOS-inhibitor, and L-arginine, NOS-substrate, relation, the effect on schizophrenia-like symptoms. Medication (mg/kg intraperitoneally) was L-NAME (5), L-arginine (100), BPC 157 (0.01), given alone and/or together, at 5 min before the challenge for the acutely disturbed motor activity (dopamine-indirect/direct agonists (amphetamine (3.0), apomorphine (2.5)), NMDA-receptor non-competitive antagonist (MK-801 (0.2)), or catalepsy, (dopamine-receptor antagonist haloperidol (2.0)). Alternatively, BPC 157 10 µg/kg was given immediately after L-NAME 40 mg/kg intraperitoneally. To induce or prevent sensitization, we used chronic methamphetamine administration, alternating 3 days during the first 3 weeks, and challenge after next 4 weeks, and described medication (L-NAME, L-arginine, BPC 157) at 5 min before the methamphetamine at the second and third week. Given alone, BPC 157 or L-arginine counteracted the amphetamine-, apomorphine-, and MK-801-induced effect, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization. L-NAME did not affect the apomorphine-, and MK-801-induced effects, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization, but counteracted the acute amphetamine-induced effect. In combinations (L-NAME + L-arginine), as NO-specific counteraction, L-NAME counteracts L-arginine-induced counteractions in the apomorphine-, MK-801-, haloperidol- and methamphetamine-rats, but not in amphetamine-rats. Unlike L-arginine, BPC 157 maintains its counteracting effect in the presence of the NOS-blockade (L-NAME + BPC 157) or NO-system-over-stimulation (L-arginine + BPC 157). Illustrating the BPC 157-L-arginine relationships, BPC 157 restored the antagonization (L-NAME + L-arginine + BPC 157) when it had been abolished by the co-administration of L-NAME with L-arginine (L-NAME + L-arginine). Finally, BPC 157 directly inhibits the L-NAME high dose-induced catalepsy. Further studies would determine precise BPC 157/dopamine/glutamate/NO-system relationships and clinical application.


Assuntos
Anfetamina/farmacologia , Apomorfina/farmacologia , Arginina/farmacologia , Catalepsia , Maleato de Dizocilpina/farmacologia , Dopaminérgicos/farmacologia , Inibidores Enzimáticos/farmacologia , Haloperidol/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase , Fragmentos de Peptídeos/farmacologia , Proteínas/farmacologia , Esquizofrenia , Anfetamina/administração & dosagem , Animais , Apomorfina/administração & dosagem , Arginina/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Catalepsia/fisiopatologia , Modelos Animais de Doenças , Maleato de Dizocilpina/administração & dosagem , Dopaminérgicos/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Haloperidol/administração & dosagem , Masculino , NG-Nitroarginina Metil Éster/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Óxido Nítrico Sintase/antagonistas & inibidores , Fragmentos de Peptídeos/administração & dosagem , Proteínas/administração & dosagem , Ratos , Ratos Wistar , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia
18.
Sci Rep ; 10(1): 18513, 2020 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-33116174

RESUMO

Nuclear distribution element-like 1 (NDEL1) enzyme activity is important for neuritogenesis, neuronal migration, and neurodevelopment. We reported previously lower NDEL1 enzyme activity in blood of treated first episode psychosis and chronic schizophrenia (SCZ) compared to healthy control subjects, with even lower activity in treatment resistant chronic SCZ patients, implicating NDEL1 activity in SCZ. Herein, higher NDEL1 activity was observed in the blood and several brain regions of a validated animal model for SCZ at baseline. In addition, long-term treatment with typical or atypical antipsychotics, under conditions in which SCZ-like phenotypes were reported to be reversed in this animal model for SCZ, showed a significant NDEL1 activity reduction in blood and brain regions which is in line with clinical data. Importantly, these results support measuring NDEL1 enzyme activity in the peripheral blood to predict changes in NDEL1 activity in the CNS. Also, acute administration of psychostimulants, at levels reported to induce SCZ-like phenotype in normal rat strains, increased NDEL1 enzyme activity in blood. Therefore, alterations in NDEL1 activity after treatment with antipsychotics or psychostimulants may suggest a possible modulation of NDEL1 activity secondary to neurotransmission homeostasis and provide new insights into the role of NDEL1 in SCZ pathophysiology.


Assuntos
Cisteína Endopeptidases/metabolismo , Cisteína Endopeptidases/fisiologia , Esquizofrenia/metabolismo , Animais , Antipsicóticos/farmacologia , Encéfalo/metabolismo , Estimulantes do Sistema Nervoso Central/uso terapêutico , Clozapina/farmacologia , Cisteína Endopeptidases/sangue , Haloperidol/farmacologia , Hipocampo/metabolismo , Masculino , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Transtornos Psicóticos/tratamento farmacológico , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Esquizofrenia/fisiopatologia
19.
Pharmacol Biochem Behav ; 198: 173035, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32910928

RESUMO

Considerable evidence indicates that adenosine and dopamine systems interact in the regulation of basal ganglia function. Nonselective adenosine antagonists such as the methylxanthine caffeine as well as selective adenosine A2A antagonists have been shown to produce antiparkinsonian and antidepressant effects in animal models. The present studies were conducted to assess if another methylxantine, theophylline, can reverse motor and motivational impairments induced by dopamine antagonism in rats. RESULTS: Theophylline (3.75-30.0 mg/kg, IP) reversed tremulous jaw movements (TJMs), catalepsy, and locomotor suppression induced by the dopamine D2 antagonist pimozide. It also reversed TJMs induced by the muscarinic receptor agonist pilocarpine, which is a well-known tremorogenic agent. Parallel studies assessed the ability of theophylline (5.0-20.0 mg/kg, IP) to reverse the changes in effort-related choice behavior induced by the dopamine D1 antagonist ecopipam (0.2 mg/kg, IP) and the D2 antagonist haloperidol (0.1 mg/kg, IP). Rats were tested on two different operant choice tasks which assess the tendency to work for a preferred reinforcer by lever pressing (for palatable pellets or a high 5% sucrose solution) vs. approaching and consuming a less preferred reinforcer (freely available lab chow or a less concentrated 0.3% sucrose solution). Theophylline restored food and sucrose-reinforced lever pressing in animals treated with the D2 antagonist. However, it was unable to reverse the effects of the D1 antagonist. Overall, the effects of theophylline resembled those previously reported for adenosine A2A antagonists, and suggest that theophylline could be clinically useful for the treatment of motor and motivational symptoms in humans.


Assuntos
Comportamento de Escolha/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Atividade Motora/efeitos dos fármacos , Antagonistas de Receptores Purinérgicos P1/farmacologia , Teofilina/farmacologia , Tremor/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Benzazepinas/farmacologia , Catalepsia/tratamento farmacológico , Catalepsia/metabolismo , Condicionamento Operante/efeitos dos fármacos , Haloperidol/farmacologia , Humanos , Masculino , Motivação/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Pilocarpina/farmacologia , Pimozida/farmacologia , Ratos , Ratos Sprague-Dawley , Sacarose/farmacologia , Tremor/tratamento farmacológico
20.
Pharmacol Biochem Behav ; 198: 173036, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32891708

RESUMO

Previous research have shown that repeated administration of 0.5 mg/kg of haloperidol in a given context gives rise to an increase in activity when spontaneous locomotor activity is recorded in a drug-free test conducted in such context. In order to confirm whether this type of response is based on processes of a Pavlovian nature, we conducted two experiments involving two manipulations that disrupt conditioning in typical classical conditioning procedures: preexposure of the to-be-conditioned stimulus (latent inhibition), and an increase in the length of the inter-stimulus interval. The results revealed that both manipulations were effective in reducing the conditioned increase of the locomotor response. This kind of conditioning can be explained in terms of the differential effects of low vs. high doses of haloperidol, and the temporal dynamics of conditioned response.


Assuntos
Condicionamento Clássico/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Locomoção/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de Tempo
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