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1.
Eur Neuropsychopharmacol ; 60: 48-54, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35635996

RESUMO

The nitric oxide (NO)-donor, sodium nitroprusside (SNP) has been proposed as an adjunct treatment to enhance the effect of antipsychotic drugs (APDs). As NO constitutes an important downstream signaling molecule of N-methyl-D-aspartate receptors, SNP may alleviate symptoms of schizophrenia by modulating glutamatergic signaling. We previously showed that SNP enhances the antipsychotic-like effect of a sub-effective dose of risperidone in the conditioned avoidance response (CAR) test, indicating that adjunct SNP may be used to lower the dose of risperidone and in this way reduce the risk of side effects. By using the CAR test, we here investigated if SNP also enhances the antipsychotic-like effect of olanzapine or clozapine. Importantly, SNP (1.5 mg/kg) significantly enhanced the antipsychotic-like effect of olanzapine (1.25 and 2.5mg/kg) to a clinically relevant level, supporting the potential clinical use of SNP as an adjunct treatment to improve the effect of APDs. However, SNP (1.5 mg/kg) did not increase the antipsychotic-like effect of clozapine (5 and 6 mg/kg). Moreover, we found that the rats developed tolerance towards clozapine after repeated administrations. Thus, our study motivates further investigation using different preclinical models to assess the effect of adjunct treatment of SNP to APDs, also targeting the negative symptoms and cognitive deficits seen in schizophrenia.


Assuntos
Antipsicóticos , Clozapina , Animais , Antipsicóticos/farmacologia , Aprendizagem da Esquiva , Benzodiazepinas/farmacologia , Clozapina/farmacologia , Nitroprussiato/farmacologia , Olanzapina/farmacologia , Ratos , Ratos Sprague-Dawley , Risperidona/farmacologia
2.
Schizophr Bull ; 48(4): 814-825, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35556138

RESUMO

BACKGROUND AND HYPOTHESIS: In treatment-resistant schizophrenia (TRS), Clozapine is only approved treatment with undesirable side-effects, warranting better alternatives. Our hypothesis is acute followed by maintenance Electroconvulsive Therapy (M-ECT) will be comparable in efficacy and safety to Clozapine in TRS. STUDY DESIGN: In this open-label trial, 60 TRS patients were randomized equally to M-ECT (following an acute-course) or Clozapine. Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Schizophrenia Scale (CGI-SCH), Montreal Cognitive Assessment (MoCA), and Global assessment of functioning (GAF) were measured and compared within and between the groups at baseline, 6 weeks, 12 weeks, and 24 weeks. SPECT-CT brain was done at baseline and 24 weeks to compare the changes in regional cerebral perfusion between the groups and correlate with the changes in the outcome-measures. STUDY RESULTS: The PANSS-T scores changes from baseline over the observation-points were significant in both M-ECT and clozapine groups (P < .001), with comparatively better reduction with M-ECT (P < .001). Similar trends were observed in PANSS subscales, CGI-SCH and GAF in both groups, with significantly better improvement with M-ECT over the study-period. After 24 weeks, there was significantly better perfusion with M-ECT in bilateral prefrontal and temporal cortices (P < .05). With M-ECT, a positive correlation was found between changes in PANSS-P scores and left-lateral Temporal cortical perfusion (r = .465, P = .017). CONCLUSIONS: Acute followed by M-ECT was more effective than clozapine over 6 months in reducing the positive and negative symptoms, general psychopathology, illness-severity, and improving the global functionality in TRS [clinicaltrials.gov: NCT03807882].


Assuntos
Antipsicóticos , Clozapina , Eletroconvulsoterapia , Esquizofrenia , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Circulação Cerebrovascular , Clozapina/farmacologia , Clozapina/uso terapêutico , Eletroconvulsoterapia/efeitos adversos , Humanos , Esquizofrenia/tratamento farmacológico , Resultado do Tratamento
3.
Psychoneuroendocrinology ; 142: 105775, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35594830

RESUMO

BACKGROUND: Antipsychotic drug (APD) treatment has been associated with metabolic abnormalities. Brown adipose tissue (BAT) is the main site of adaptive thermogenesis and secretes various metabolism-improving factors known as batokines. We explored the association of BAT activity with APD treatment and metabolic abnormalities in patients with schizophrenia by measuring the blood levels of bone morphogenetic protein 8b (BMP8b), a batokine secreted by mature BAT. METHODS: BMP8b levels were compared among 50 drug-free, 32 aripiprazole-treated, and 91 clozapine-treated patients with schizophrenia. Regression analysis was used to explore factors, including APD types, that might be associated with BMP8b levels and the potential effect of BMP8b on metabolic syndrome (MS). RESULTS: APD-treated patients had decreased BMP8b levels relative to drug-free patients. The difference still existed after adjustment for body mass index and Brief Psychiatric Rating Scale scores. Among APD-treated group, clozapine was associated with even lower BMP8b levels than the less obesogenic APD, aripiprazole. Furthermore, higher BMP8b levels were associated with lower risks of MS after adjustment for BMI and APD treatment. CONCLUSION: Using drug-free patients as the comparison group to understand the effect of APDs, this is the first study to show APD treatment is associated with reduced BAT activity that is measured by BMP8b levels, with clozapine associated a more significant reduction than aripiprazole treatment. BMP8b might have a beneficial effect against metabolic abnormalities and this effect is independent of APD treatment. Future studies exploring the causal relationship between APD treatment and BMP8b levels and the underlying mechanisms are warranted.


Assuntos
Antipsicóticos , Clozapina , Síndrome Metabólica , Esquizofrenia , Tecido Adiposo Marrom/metabolismo , Antipsicóticos/efeitos adversos , Aripiprazol/metabolismo , Aripiprazol/farmacologia , Clozapina/metabolismo , Clozapina/farmacologia , Clozapina/uso terapêutico , Humanos , Síndrome Metabólica/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Termogênese
4.
Chem Res Toxicol ; 35(6): 1001-1010, 2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35575633

RESUMO

The atypical antipsychotic drugs, quetiapine and clozapine, are associated with idiosyncratic drug reactions (such as agranulocytosis or neutropenia) that are thought to involve reactive metabolites. Neutrophil myeloperoxidase (MPO) metabolism of quetiapine is not well-studied, but is metabolized by cytochrome P450. Based on structural similarity to clozapine, we hypothesized that quetiapine can be metabolized by MPO and that there is overlap between cytochrome P450 and MPO metabolism of quetiapine. The interaction of quetiapine and clozapine with MPO and MPO chlorination activity was studied using UV-vis spectrophotometry. The metabolites were characterized using liquid chromatography-mass spectrometry (LC-MS), and electron paramagnetic resonance (EPR) spectroscopy was used for detecting drug-catalyzed glutathione oxidation. In the presence of quetiapine, MPO compound II accumulated for about 7.5 min, whereas in the presence of clozapine, MPO compound II was not observed as it was rapidly reduced back to the resting state. Increasing quetiapine concentrations resulted in a decrease in MPO chlorination activity, while the opposite result was found in the case of clozapine. UV-vis spectral studies showed no change when quetiapine was oxidized in the absence and presence of chloride anion (Cl-, to catalyze chlorination reactions). Significant changes, however, were observed in the same assay with clozapine, where Cl- appeared to hinder the rate of clozapine metabolism. The MPO-catalyzed hydroxylated and dealkylated metabolites of quetiapine and hydroxylated metabolites of clozapine were observed from the LC-MS analyses, particularly when Cl- was included in the reaction. In addition, hydroxylated, dealkylated, and a proposed sulfoxide metabolite of quetiapine were also observed in the reaction catalyzed by human microsomes/NADPH. Lastly, compared to quetiapine, clozapine metabolism by MPO/H2O2 and glutathione produced more glutathionyl radicals using EPR spin trapping. In conclusion, MPO/H2O2/Cl- was shown to metabolize quetiapine to S-oxidation and P450-like dealkylation products, and quetiapine metabolites were generally less reactive than clozapine.


Assuntos
Clozapina , Clozapina/metabolismo , Clozapina/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Desmetilação , Glutationa/metabolismo , Humanos , Peróxido de Hidrogênio , Neutrófilos/metabolismo , Peroxidase/metabolismo , Fumarato de Quetiapina
5.
J Psychopharmacol ; 36(4): 479-488, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35475374

RESUMO

BACKGROUND: Although numerous studies reported some changes of cortical silent period (CSP), an indicator of gamma-aminobutyric acid (GABA) function in central nervous system, in schizophrenia patients, it has been unknown how the disease stage and antipsychotic medication affect CSP values. METHODS: The present study conducted a systematic review of previous literature comparing CSP between schizophrenia patients and healthy subjects, and then performed meta-analysis on the effects of (1) the disease stage and (2) antipsychotics on CSP. RESULTS: (1) In the comparison of the disease stage comprising a total of 17 reports, there was no significant difference in CSP between patients under drug-naïve first-episode psychoses and healthy controls, or between patients with antipsychotic medication and healthy controls. (2) In the comparison of the antipsychotic class, patients treated with clozapine were longer in CSP compared to healthy controls. Patients treated with olanzapine/quetiapine or with other type of antipsychotics were not different from healthy controls. Regarding other type of antipsychotics, the iteration analysis after leaving out one literature showed that patients were shorter in CSP than healthy controls. CONCLUSION: The results showed that clozapine seems to surely prolong CSP, indicating the enhancement of GABA transmission via GABAB receptors, suggesting the possible relationship between the CSP prolongation by clozapine and its high efficacy in psychopathology. The finding of shorter CSP in patients with other type of antipsychotics was distinct from clozapine/olanzapine/quetiapine, but was difficult to interpret since this group included a variety of transcranial magnetic stimulation (TMS) methodologies and patients' background.


Assuntos
Antipsicóticos , Clozapina , Esquizofrenia , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Clozapina/farmacologia , Clozapina/uso terapêutico , Humanos , Inibição Neural , Olanzapina/farmacologia , Fumarato de Quetiapina/uso terapêutico , Receptores de GABA , Esquizofrenia/tratamento farmacológico , Ácido gama-Aminobutírico/uso terapêutico
6.
Int J Mol Sci ; 23(7)2022 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-35408792

RESUMO

Patients with schizophrenia, and rodent models of the disease, both exhibit suppressed neurogenesis, with antipsychotics possibly enhancing neurogenesis in pre-clinical models. Nestin, a cytoskeletal protein, is implicated in neuronal differentiation and adult neurogenesis. We hypothesized that schizophrenia pathogenesis involves nestin downregulation; however, few studies have related nestin to schizophrenia. We assessed nestin protein concentration, prepulse inhibition (PPI), and social interaction in the MK-801 model of schizophrenia, with or without antipsychotic (clozapine) treatment. Adult male Sprague-Dawley rats were intraperitoneally administered saline or MK-801 (0.1 mg/kg) to produce a schizophrenia-like phenotype, with concomitant subcutaneous injections of vehicle or clozapine (5 mg/kg). PPI was assessed on days 1, 8, and 15, and social interaction was assessed on day 4. Hippocampus tissue samples were dissected for Western blotting of nestin concentration. MK-801 alone did not alter nestin concentration, while clozapine alone enhanced hippocampal nestin concentration; this effect was not apparent in animals with MK-801 and clozapine co-administration. MK-801 also produced schizophrenia-like PPI disruptions, some of which were reversed by clozapine. Social interaction deficits were not detected in this model. This is the first report of clozapine-induced enhancements of hippocampal nestin concentration that might be mediated by NMDA receptors. Future studies will explore the impact of neurodevelopmental nestin concentration on symptom onset and antipsychotic treatment.


Assuntos
Antipsicóticos , Clozapina , Hipocampo , Nestina , Animais , Antipsicóticos/farmacologia , Clozapina/farmacologia , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Nestina/metabolismo , Ratos , Ratos Sprague-Dawley
7.
Neuroscience ; 492: 92-107, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35367290

RESUMO

Amantadine and clozapine have proved to reduce abnormal involuntary movements (AIMs) in preclinical and clinical studies of L-DOPA-Induced Dyskinesias (LID). Even though both drugs decrease AIMs, they may have different action mechanisms by using different receptors and signaling profiles. Here we asked whether there are differences in how they modulate neuronal activity of multiple striatal neurons within the striatal microcircuit at histological level during the dose-peak of L-DOPA in ex-vivo brain slices obtained from dyskinetic mice. To answer this question, we used calcium imaging to record the activity of dozens of neurons of the dorsolateral striatum before and after drugs administration in vitro. We also developed an analysis framework to extract encoding insights from calcium imaging data by quantifying neuronal activity, identifying neuronal ensembles by linking neurons that coactivate using hierarchical cluster analysis and extracting network parameters using Graph Theory. The results show that while both drugs reduce LIDs scores behaviorally in a similar way, they have several different and specific actions on modulating the dyskinetic striatal microcircuit. The extracted features were highly accurate in separating amantadine and clozapine effects by means of principal components analysis (PCA) and support vector machine (SVM) algorithms. These results predict possible synergistic actions of amantadine and clozapine on the dyskinetic striatal microcircuit establishing a framework for a bioassay to test novel antidyskinetic drugs or treatments in vitro.


Assuntos
Clozapina , Discinesia Induzida por Medicamentos , Amantadina/farmacologia , Animais , Antiparkinsonianos/farmacologia , Cálcio , Clozapina/farmacologia , Corpo Estriado , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/tratamento farmacológico , Discinesia Induzida por Medicamentos/patologia , Levodopa/toxicidade , Camundongos , Neurônios , Oxidopamina/farmacologia
8.
Cells ; 11(7)2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-35406745

RESUMO

Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin. EGIS 11150 enhanced H-PFC coherence, and increased the 8-9 Hz theta band of the EEG power spectrum (from 0.002 mg/kg i.p, at >30× lower doses than clozapine, and >100× for olanzapine, risperidone, or haloperidol). EGIS 11150 fully blocked the effects of phencyclidine (PCP) or ketamine on EEG. Inhibition of long-term potentiation (LTP) in H-PFC was blocked by platform stress, but was fully restored by EGIS 11150 (0.01 mg/kg i.p.), whereas clozapine (0.3 mg/kg ip) only partially restored LTP. EGIS 11150 has a unique electrophysiological profile, so phenotypical screening on H-PFC connectivity can reveal novel antipsychotics.


Assuntos
Antipsicóticos , Clozapina , Animais , Antipsicóticos/farmacologia , Clozapina/farmacologia , Hipocampo , Plasticidade Neuronal , Córtex Pré-Frontal , Ratos , Ratos Wistar , Risperidona/farmacologia
9.
Schizophr Res ; 243: 163-169, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35358857

RESUMO

INTRODUCTION: Patients with severe mental illness are falsely characterized as aggressive by the media, perpetuating stigma. While exaggerated, some patients with severe mental illness are more aggressive without treatment. Clozapine may have a unique anti-aggressive effect in patients with schizophrenia-related disorders, independent of antipsychotic or sedative effects. Limited data in forensic and involuntary committed patients is currently available. PURPOSE: This study evaluates clozapine's effects on hostility and aggression in court-ordered Black patients. METHODS: This study analyzes a subgroup of Black patients from a larger prospective 24-week open-label clozapine study. All patients were involuntarily committed and enrolled from two participating state psychiatric hospitals. The primary outcome measured was total use of 'as needed' (PRN) or 'immediate need' (STAT) medications for aggression/hostility. Secondary outcomes included number and duration of seclusion and restraint (S/R) episodes, and changes in Brief Psychiatric Rating Scale (BPRS) hostility factor score. RESULTS: Sixty-nine patients were included in our analysis. Significant reductions were noted in PRN/STAT medication use over time (χ2 = 6.90; p = 0.008) and the BPRS hostility factor score was reduced by 30% over the 24 weeks (F = 4.34, df = 62, p = 0.002). CONCLUSIONS: Treatment with clozapine effectively reduced hostility and aggression within this cohort of involuntarily committed Black patients with mental illness compared to baseline. Specifically, it helped lower the total number of PRN/STAT medication administrations and improved clinician-rated hostility factor scores on the BPRS. Our findings are pertinent as data in forensic settings is lacking and Black patients have been infrequently included in large prospective clinical trials with clozapine. GOV IDENTIFIER: NCT02404155.


Assuntos
Antipsicóticos , Clozapina , Esquizofrenia , Agressão , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Clozapina/farmacologia , Clozapina/uso terapêutico , Humanos , Estudos Prospectivos , Esquizofrenia/tratamento farmacológico
10.
Neuroscience ; 491: 176-184, 2022 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-35351573

RESUMO

The chemogenetic procedure DREADD (designer receptor exclusively activated by designer drugs) is an inventive way to selectively affect g-coupled protein receptors. In theory, DREADD receptors are only activated by administering inert compounds, primarily clozapine N-oxide (CNO). Research has shown that CNO does not cross the blood-brain barrier, and CNO is converted back to clozapine and N-desmethylclozapine (N-Des) in the brain. Clozapine and N-Des have many neurological effects including alterations in glutamate and dopamine (DA) levels in multiple brain regions. The current study examined the effects of peripheral administration of CNO on glutamate and DA levels in the medial prefrontal cortex (mPFC). Wistar rats were administered CNO, and microdialysis samples were collected from the mPFC. Administration of CNO significantly increased glutamate (31-87%) and DA (65-126%), CNO-induced increases in DA occurred for a longer duration than glutamate, and that for the two highest doses of CNO there was a significant correlation between the increase in glutamate and DA in the mPFC. In the mPFC, CNO-induced increases in DA occurred at 0.5 mg/kg, while increases in glutamate were observed at doses greater than 1.0 mg/kg. The source of the DA and glutamate could be caused by activation of projection neurons or local effects. The data replicate findings that CNO is not an inert compound and that interpretation of CNO-activated DREADD findings should be done with caution. The data indicate that low ('safe') doses of CNO still have neurochemical effects and that controlling for the actions of clozapine/N-Des in CNO-DREADD studies has many concerns.


Assuntos
Clozapina , Animais , Clozapina/análogos & derivados , Clozapina/farmacologia , Dopamina , Ácido Glutâmico , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar
11.
J Neurosci ; 42(12): 2552-2561, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-35110390

RESUMO

The chemogenetic technology referred to as designer receptors exclusively activated by designer drugs (DREADDs) offers reversible means to control neuronal activity for investigating its functional correlation with behavioral action. Deschloroclozapine (DCZ), a recently developed highly potent and selective DREADD actuator, displays a capacity to expand the utility of DREADDs for chronic manipulation without side effects in nonhuman primates, which has not yet been validated. Here we investigated the pharmacokinetics and behavioral effects of orally administered DCZ in female and male macaque monkeys. Pharmacokinetic analysis and PET occupancy examination demonstrated that oral administration of DCZ yielded slower and prolonged kinetics, and that its bioavailability was 10%-20% of that in the case of systemic injection. Oral DCZ (300-1000 µg/kg) induced significant working memory impairments for at least 4 h in monkeys with hM4Di expressed in the dorsolateral prefrontal cortex (Brodmann's area 46). Repeated daily oral doses of DCZ consistently caused similar impairments over two weeks without discernible desensitization. Our results indicate that orally delivered DCZ affords a less invasive strategy for chronic but reversible chemogenetic manipulation of neuronal activity in nonhuman primates, and this has potential for clinical application.SIGNIFICANCE STATEMENT The use of designer receptors exclusively activated by designer drugs (DREADDs) for chronic manipulation of neuronal activity for days to weeks may be feasible for investigating brain functions and behavior on a long time-scale, and thereby for developing therapeutics for brain disorders, such as epilepsy. Here we performed pharmacokinetics and in vivo occupancy study of orally administered deschloroclozapine to determine a dose range suitable for DREADDs studies. In monkeys expressing hM4Di in the prefrontal cortex, single and repeated daily doses significantly induced working-memory impairments for hours and over two weeks, respectively, without discernible desensitization. These results indicate that orally delivered deschloroclozapine produces long-term stable chemogenetic effects, and holds great promise for the translational use of DREADDs technology.


Assuntos
Clozapina , Drogas Desenhadas , Animais , Controle Comportamental , Clozapina/farmacologia , Drogas Desenhadas/farmacologia , Feminino , Macaca mulatta , Masculino , Neurônios
12.
Eur J Nucl Med Mol Imaging ; 49(7): 2251-2264, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35122511

RESUMO

PURPOSE: Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) imaging. In the past decades, FDG-PET has been instrumental in the understanding of brain function in health and disease. The source of the FDG-PET signal has been attributed to neuronal uptake, with hypometabolism being considered as a direct index of neuronal dysfunction or death. However, other brain cells are also metabolically active, including astrocytes. Based on the astrocyte-neuron lactate shuttle hypothesis, the activation of the glutamate transporter 1 (GLT-1) acts as a trigger for glucose uptake by astrocytes. With this in mind, we investigated glucose utilization changes after pharmacologically downregulating GLT-1 with clozapine (CLO), an anti-psychotic drug. METHODS: Adult male Wistar rats (control, n = 14; CLO, n = 12) received CLO (25/35 mg kg-1) for 6 weeks. CLO effects were evaluated in vivo with FDG-PET and cortical tissue was used to evaluate glutamate uptake and GLT-1 and GLAST levels. CLO treatment effects were also assessed in cortical astrocyte cultures (glucose and glutamate uptake, GLT-1 and GLAST levels) and in cortical neuronal cultures (glucose uptake). RESULTS: CLO markedly reduced in vivo brain glucose metabolism in several brain areas, especially in the cortex. Ex vivo analyses demonstrated decreased cortical glutamate transport along with GLT-1 mRNA and protein downregulation. In astrocyte cultures, CLO decreased GLT-1 density as well as glutamate and glucose uptake. By contrast, in cortical neuronal cultures, CLO did not affect glucose uptake. CONCLUSION: This work provides in vivo demonstration that GLT-1 downregulation induces astrocyte-dependent cortical FDG-PET hypometabolism-mimicking the hypometabolic signature seen in people developing dementia-and adds further evidence that astrocytes are key contributors of the FDG-PET signal.


Assuntos
Astrócitos , Clozapina , Animais , Clozapina/metabolismo , Clozapina/farmacologia , Fluordesoxiglucose F18/metabolismo , Glucose/metabolismo , Ácido Glutâmico/metabolismo , Ácido Glutâmico/farmacologia , Humanos , Masculino , Tomografia por Emissão de Pósitrons , Ratos , Ratos Wistar
13.
eNeuro ; 9(1)2022.
Artigo em Inglês | MEDLINE | ID: mdl-35115382

RESUMO

G-protein-coupled receptors (GPCRs) coupled to Gi signaling, in particular downstream of monoaminergic neurotransmission, are posited to play a key role during developmental epochs (postnatal and juvenile) in shaping the emergence of adult anxiodepressive behaviors and sensorimotor gating. To address the role of Gi signaling in these developmental windows, we used a CaMKIIα-tTA::TRE hM4Di bigenic mouse line to express the hM4Di-DREADD (designer receptor exclusively activated by designer drugs) in forebrain excitatory neurons and enhanced Gi signaling via chronic administration of the DREADD agonist, clozapine-N-oxide (CNO) in the postnatal window (postnatal days 2-14) or the juvenile window (postnatal days 28-40). We confirmed that the expression of the HA-tagged hM4Di-DREADD was restricted to CaMKIIα-positive neurons in the forebrain, and that the administration of CNO in postnatal or juvenile windows evoked inhibition in forebrain circuits of the hippocampus and cortex, as indicated by a decline in expression of the neuronal activity marker c-Fos. hM4Di-DREADD-mediated inhibition of CaMKIIα-positive forebrain excitatory neurons in postnatal or juvenile life did not impact the weight profile of mouse pups, and also did not influence the normal ontogeny of sensory reflexes. Further, postnatal or juvenile hM4Di-DREADD-mediated inhibition of CaMKIIα-positive forebrain excitatory neurons did not alter anxiety- or despair-like behaviors in adulthood and did not impact sensorimotor gating. Collectively, these results indicate that chemogenetic induction of Gi signaling in CaMKIIα-positive forebrain excitatory neurons in postnatal and juvenile temporal windows does not appear to impinge on the programming of anxiodepressive behaviors in adulthood.


Assuntos
Clozapina , Neurônios , Afeto , Animais , Clozapina/metabolismo , Clozapina/farmacologia , Hipocampo/fisiologia , Camundongos , Neurônios/fisiologia , Prosencéfalo , Transmissão Sináptica
14.
Br J Pharmacol ; 179(14): 3675-3692, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35088415

RESUMO

BACKGROUND AND PURPOSE: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABAA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal α5 subunit-containing GABAA receptors. The purpose of this study is to investigate the effects of tricyclic compounds on α5 subunit-containing receptor subtypes. EXPERIMENTAL APPROACH: Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABAA receptor subtypes by two-electrode voltage-clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the α5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings. KEY RESULTS: The antipsychotic drugs clozapine and chlorpromazine exerted functional inhibition on multiple GABAA receptor subtypes, including those containing α5-subunits. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in α5 GABAA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands. CONCLUSION AND IMPLICATIONS: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The chlorpromazine site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABAA receptor subtypes.


Assuntos
Antipsicóticos , Clozapina , Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Clorpromazina/farmacologia , Clozapina/farmacologia , Humanos , Ligantes , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico
15.
BMC Pharmacol Toxicol ; 23(1): 8, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-35033194

RESUMO

BACKGROUND: Patients with liver diseases often have some form of anemia. Hematological dyscrasias are known side effects of antipsychotic drug medication and the occurrence of agranulocytosis under clozapine is well described. However, the sex-dependent impact of clozapine and haloperidol on erythrocytes and symptoms like anemia, and its association with hepatic iron metabolism has not yet been completely clarified. Therefore, in the present study, we investigated the effect of both antipsychotic drugs on blood parameters and iron metabolism in the liver of male and female Sprague Dawley rats. METHODS: After puberty, rats were treated orally with haloperidol or clozapine for 12 weeks. Blood count parameters, serum ferritin, and liver transferrin bound iron were determined by automated counter. Hemosiderin (Fe3+) was detected in liver sections by Perl's Prussian blue staining. Liver hemoxygenase (HO-1), 5'aminolevulinate synthase (ALAS1), hepcidin, heme-regulated inhibitor (HRI), cytochrome P4501A1 (CYP1A1) and 1A2 (CYP1A2) were determined by Western blotting. RESULTS: We found anemia with decreased erythrocyte counts, associated with lower hemoglobin and hematocrit, in females with haloperidol treatment. Males with clozapine medication showed reduced hemoglobin and increased red cell distribution width (RDW) without changes in erythrocyte numbers. High levels of hepatic hemosiderin were found in the female clozapine and haloperidol medicated groups. Liver HRI was significantly elevated in male clozapine medicated rats. CYP1A2 was significantly reduced in clozapine medicated females. CONCLUSIONS: The characteristics of anemia under haloperidol and clozapine medication depend on the administered antipsychotic drug and on sex. We suggest that anemia in rats under antipsychotic drug medication is a sign of an underlying liver injury induced by the drugs. Changing hepatic iron metabolism under clozapine and haloperidol may help to reduce these effects of liver diseases.


Assuntos
Antipsicóticos , Clozapina , Síndrome Metabólica , Animais , Antipsicóticos/farmacologia , Clozapina/farmacologia , Eritrócitos , Feminino , Haloperidol/farmacologia , Humanos , Ferro/metabolismo , Fígado , Masculino , Síndrome Metabólica/metabolismo , Ratos , Ratos Sprague-Dawley
16.
J Psychiatry Neurosci ; 47(1): E1-E10, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35027443

RESUMO

BACKGROUND: Abnormalities in the anterior cingulate cortex (ACC) are thought to play an important role in the pathophysiology of schizophrenia. Given regional variations in ACC structure, the present study aimed to examine ACC structural subdivisions and their relationships to treatment resistance and glutamatergic levels in schizophrenia. METHODS: This study included 100 patients with schizophrenia and 52 healthy controls from 2 cohorts. We applied non-negative matrix factorization to identify accurate and stable spatial components of ACC structure. Between groups, we compared ACC structural indices in each spatial component based on treatment resistance or response and tested relationships with ACC glutamate + glutamine levels. RESULTS: We detected reductions in cortical thickness and increases in mean diffusivity in the spatial components on the surface of the cingulate sulcus, especially in patients with treatment-resistant and clozapine-resistant schizophrenia. Notably, mean diffusivity in these components was higher in patients who did not respond to clozapine compared to those who did. Furthermore, these ACC structural alterations were related to elevated ACC glutamate + glutamine levels but not related to symptomatology or antipsychotic dose. LIMITATIONS: Sample sizes, cross-sectional findings and mixed antipsychotic status were limitations of this study. CONCLUSION: This study identified reproducible abnormalities in ACC structures in patients with treatment-resistant and clozapine-resistant schizophrenia. Given that these spatial components play a role in inhibitory control, the present study strengthens the notion that glutamate-related disinhibition is a common biological feature of treatment resistance in schizophrenia.


Assuntos
Antipsicóticos , Clozapina , Esquizofrenia , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Clozapina/farmacologia , Clozapina/uso terapêutico , Estudos Transversais , Ácido Glutâmico , Glutamina , Giro do Cíngulo/diagnóstico por imagem , Humanos , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/tratamento farmacológico
17.
Mult Scler Relat Disord ; 58: 103522, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35063906

RESUMO

INTRODUCTION: The high efficacy of atypical antipsychotics (AAP) in treating diverse psychiatric disorders has been partly attributed to their capacity to curb neuroinflammation, a shared aspect of these diseases. These immunomodulatory properties of AAP have lately been explored in the context of multiple sclerosis (MS), an autoimmune demyelinating disease of the CNS. METHODS: This study aimed to review in vivo studies reporting on the therapeutic effects of AAP both in EAE, the main animal model of MS and in cuprizone-induced demyelination. For that matter we conducted a literature search and a screening process that eventually yielded 8 eligible studies. RESULTS: All studies agreed on the efficiency of AAP to dramatically reduce EAE severity and delay its onset, while suppressing the production of numerous inflammatory cytokines. Clozapine showcased similar yet more intense effects than risperidone, quetiapine and olanzapine, significantly attenuating CD4 T cell infiltration and myeloid cell activation, while upregulating Tregs. Clozapine also downregulated chemokines responsible for the migration of immune cells in the CNS and caused dopamine receptor levels in the brain of EAE mice to rise. DISCUSSION: Taken together, these findings unanimously attest to the anti-inflammatory and immunomodulatory properties of AAP, suggesting that their therapeutic potential expands beyond their current neuropsychiatric applications. Despite the salutary effects of AAP in MS reported in vivo, a clinical trial of clozapine on MS patients failed to confirm preclinical findings due to low acceptability of AAP and early participant withdrawal. CONCLUSION: Although preclinical evidence unquestionably supports the multifaceted beneficial properties of AAP in MS, further investigation is required to elucidate the pharmacodynamic profile of these agents and allow for their proper clinical testing on MS patients.


Assuntos
Antipsicóticos , Clozapina , Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Clozapina/farmacologia , Clozapina/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Humanos , Camundongos , Esclerose Múltipla/tratamento farmacológico , Olanzapina , Fumarato de Quetiapina
18.
Pharmacogenomics ; 23(1): 5-14, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34787483

RESUMO

Aim: To explore possible differences in genome-wide methylation between schizophrenia patients who consume various antipsychotics. Methods: We compared DNA methylation in leukocytes between the following cohorts: clozapine (n = 19) versus risperidone (n = 19), clozapine (n = 12) versus olanzapine (n = 12), clozapine (n = 9) versus quetiapine (n = 9) and clozapine (n = 33) versus healthy controls (n = 33). Subjects were matched for age, sex, ethnicity, smoking status and leukocyte proportions. Results: No single CpG site reached genome-wide significance for clozapine versus risperidone/olanzapine/quetiapine. For clozapine versus quetiapine, one significantly differentially methylated region was found - ch5: 176797920-176798049 (fwer = 0.075). Clozapine versus healthy controls yielded thousands of significantly differentially methylated CpG sites. Conclusions: Establishing antipsychotic induced genome-wide methylation patterns will further elucidate the biological and clinical effects of antipsychotic administration.


Assuntos
Antipsicóticos/farmacologia , Metilação de DNA , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/uso terapêutico , Clozapina/farmacologia , Ilhas de CpG , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fumarato de Quetiapina/farmacologia , Esquizofrenia/genética , Adulto Jovem
19.
Neurosci Lett ; 770: 136354, 2022 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-34801642

RESUMO

Calcium Voltage-Gated Channel Subunit Alpha1 C (CACNA1C) is one of the most important genes associated with schizophrenia. In this study, 45 male Wistar rats were divided into 5 groups of saline, control, ketamine, clozapine, and risperidone. Animals in ketamine, risperidone, and clozapine groups received ketamine (30 mg/kg-i.p.) for 10 days. After the last injection of ketamine, we started injecting clozapine (7.5 mg/kg-i.p.), risperidone (1 mg/kg-i.p.), up to 28 days. Twenty-four hours after the last injection, open field, social interaction, and elevated plus-maze tests and gene expression in hippocampus were performed. The results of the social interaction test revealed a significant decrease in cumulative time with ketamine, compared with the saline group, and an increase with clozapine and risperidone compared with the ketamine group. Moreover, results from the elevated plus-maze test demonstrated a critical decrease in open arm time and increase in close arm time with ketamine compared with saline, as well as increased in open arm time with risperidone compared with ketamine. Further results revealed a significant increase in rearing and grooming with ketamine compared to saline, as well as a decrease with risperidone and clozapine compared to ketamine. There were no significant differences in CACNA1C gene expression between groups in the rat hippocampus. In brief, the results of this study indicated that clozapine and risperidone could partially improve cognitive impairments in the rat. However, our findings demonstrated that this treatment is not related to CACNA1C gene expression.


Assuntos
Antipsicóticos/farmacologia , Canais de Cálcio Tipo L/metabolismo , Clozapina/farmacologia , Hipocampo/efeitos dos fármacos , Risperidona/farmacologia , Esquizofrenia/metabolismo , Animais , Canais de Cálcio Tipo L/genética , Cognição , Antagonistas de Aminoácidos Excitatórios/toxicidade , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Ketamina/toxicidade , Masculino , Aprendizagem em Labirinto , Ratos , Ratos Wistar , Esquizofrenia/etiologia , Esquizofrenia/fisiopatologia , Comportamento Social
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