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2.
Artigo em Inglês | MEDLINE | ID: mdl-32479008

RESUMO

Glutamatergic N-methyl-D-aspartate (NMDA) receptors have critical roles in several neurological and psychiatric diseases. Dizocilpine (MK-801) is a ligand at phencyclidine recognition sites that is associated with NMDA receptor-coupled cation channels, where it acts as a potent noncompetitive antagonist of central glutamate receptors. In this study, we investigate the effect of clozapine on MK-801-induced neurochemical and neurobehavioral alterations in the prefrontal cortex of mice. Acute administration of NMDA noncompetitive antagonist MK-801 impairs motor coordination, grip strength, and locomotor activity. Clozapine is the only medication that is indicated for treating refractory schizophrenia, due to its superior efficacy among all antipsychotic agents; however, its mechanism is not well understood. To understand its mechanism, we investigated the effects of clozapine on motor coordination, locomotor activity, and grip strength in mice against the NMDA receptor antagonist MK-801. MK-801 induced elevations in acetylcholinesterase (AChE) activity, monoamine oxidase (MAO) activity, and c-fos expression. The administration of clozapine inhibited the effects caused by MK-801 (0.2 mg/kg body weight). Motor coordination and grip strength paradigms that had been altered by MK-801 were restored by clozapine. Moreover, clozapine also ameliorated MK-801-induced elevation in AChE and MAO activity. Our immunostaining results demonstrated that clozapine treatment reduced overexpression of the neuronal activity marker c-fos in cortices of the brain. Results of the current study determine that clozapine ameliorated cognition in MK-801-treated mice via cholinergic and neural mechanisms. These findings show that clozapine possesses the potential to augment cognition in diseases such as schizophrenia.


Assuntos
Clozapina/farmacologia , Maleato de Dizocilpina/toxicidade , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Antagonistas da Serotonina/farmacologia , Animais , Antipsicóticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/toxicidade , Masculino , Camundongos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/induzido quimicamente
3.
Am J Physiol Heart Circ Physiol ; 319(1): H3-H12, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32412778

RESUMO

Heart failure (HF) is characterized by autonomic imbalance with sympathetic hyperactivity and loss of parasympathetic tone. Intracardiac ganglia (ICG) neurons represent the final common pathway for vagal innervation of the heart and strongly regulate cardiac functions. This study tests whether ICG cholinergic neuron activation mitigates the progression of cardiac dysfunction and reduces mortality that occurs in HF. HF was induced by transaortic constriction (TAC) in male transgenic Long-Evans rats expressing Cre recombinase within choline acetyltransferase (ChAT) neurons. ChAT neurons were selectively activated by expression and activation of excitatory designer receptors exclusively activated by designer receptors (DREADDs) by clozapine-N-oxide (TAC + treatment and sham-treated groups). Control animals expressed DREADDs but received saline (sham and TAC groups). A separate set of animals were telemetry instrumented to record blood pressure (BP) and heart rate (HR). Acute activation of ICG neurons resulted in robust reductions in BP (∼20 mmHg) and HR (∼100 beats/min). All groups of animals were subjected to weekly echocardiography and treadmill stress tests from 3 to 6 wk post-TAC/sham surgery. Activation of ICG cholinergic neurons reduced the left ventricular systolic dysfunction (reductions in ejection fraction, fractional shortening, stroke volume, and cardiac output) and cardiac autonomic dysfunction [reduced HR recovery (HRR) post peak effort] observed in TAC animals. Additionally, activation of ICG ChAT neurons reduced mortality by 30% compared with untreated TAC animals. These data suggest that ICG cholinergic neuron activation reduces cardiac dysfunction and improves survival in HF, indicating that ICG neuron activation could be a novel target for treating HF.NEW & NOTEWORTHY Intracardiac ganglia form the final common pathway for the parasympathetic innervation of the heart. This study has used a novel chemogenetic approach within transgenic ChAT-Cre rats [expressing only Cre-recombinase in choline acetyl transferase (ChAT) neurons] to selectively increase intracardiac cholinergic parasympathetic activity to the heart in a pressure overload-induced heart failure model. The findings from this study confirm that selective activation of intracardiac cholinergic neurons lessens cardiac dysfunction and mortality seen in heart failure, identifying a novel downstream cardiac-selective target for increasing cardioprotective parasympathetic activity in heart failure.


Assuntos
Neurônios Colinérgicos/fisiologia , Insuficiência Cardíaca/fisiopatologia , Coração/inervação , Função Ventricular , Animais , Sistema Nervoso Autônomo/fisiopatologia , Pressão Sanguínea , Colina O-Acetiltransferase/genética , Colina O-Acetiltransferase/metabolismo , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Clozapina/análogos & derivados , Clozapina/farmacologia , Coração/fisiopatologia , Insuficiência Cardíaca/etiologia , Frequência Cardíaca , Masculino , Ratos , Ratos Long-Evans , Obstrução do Fluxo Ventricular Externo/complicações
4.
Nat Neurosci ; 23(6): 730-740, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32393896

RESUMO

Descending command neurons instruct spinal networks to execute basic locomotor functions, such as gait and speed. The command functions for gait and speed are symmetric, implying that a separate unknown system directs asymmetric movements, including the ability to move left or right. In the present study, we report that Chx10-lineage reticulospinal neurons act to control the direction of locomotor movements in mammals. Chx10 neurons exhibit mainly ipsilateral projection, and their selective unilateral activation causes ipsilateral turning movements in freely moving mice. Unilateral inhibition of Chx10 neurons causes contralateral turning movements. Paired left-right motor recordings identified distinct mechanisms for directional movements mediated via limb and axial spinal circuits. Finally, we identify sensorimotor brain regions that project on to Chx10 reticulospinal neurons, and demonstrate that their unilateral activation can impart left-right directional commands. Together these data identify the descending motor system that commands left-right locomotor asymmetries in mammals.


Assuntos
Tronco Encefálico/fisiologia , Vias Eferentes/fisiologia , Locomoção/fisiologia , Neurônios/fisiologia , Animais , Clozapina/análogos & derivados , Clozapina/farmacologia , Proteínas de Homeodomínio/imunologia , Camundongos , Técnicas de Rastreamento Neuroanatômico , Neurônios/efeitos dos fármacos , Toxina Tetânica/farmacologia , Fatores de Transcrição/imunologia
5.
Life Sci ; 249: 117535, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32151688

RESUMO

AIM: Schizophrenia is a chronic, disabling and one of the major neurological illnesses affecting nearly 1% of the global population. Currently available antipsychotic medications possess limited effects. The current research aimed at investigating potential therapeutic add-on benefit to enhance the effects of clozapine anti-schizophrenic. MAIN METHODS: To induce schizophrenia, ketamine was administered at a dose of 25 mg/kg i.p. for 14 consecutive days. Naringin was administered to Wistar rats at a dose of 100 mg/kg orally, alone or in combination with clozapine 5 mg/kg i.p from day 8 to day 14. Furthermore, behavioral tests were conducted to evaluate positive, negative and cognitive symptoms of schizophrenia. In addition, neurotransmitters' levels were detected using HPLC. Moreover, oxidative stress markers were assessed using spectrophotometry. Furthermore, apoptotic and wnt/ß-catenin pathway markers were determined using western blotting (Akt, GSK-3ß and ß-catenin), colorimetric methods (Caspase-3) and immunohistochemistry (Bax, Bcl2 and cytochrome c). KEY FINDINGS: Ketamine induced positive, negative and cognitive schizophrenia symptoms together with neurotransmitters' imbalance. In addition, ketamine treatment caused significant glutathione depletion, lipid peroxidation and reduction in catalase activity. Naringin and/or clozapine treatment significantly attenuated ketamine-induced schizophrenic symptoms and oxidative injury. Additionally, ketamine provoked apoptosis via increasing Bax/Bcl2 expression, caspase-3 activity, and Cytochrome C and Akt protein expression while naringin/clozapine treatment significantly inhibited this apoptotic effect. Moreover, naringin activated the neurodevelopmental wnt/ß-catenin signaling pathway evidenced by increasing pGSK-3ß and reducing pß-catenin protein expression. SIGNIFICANCE: These findings may suggest that naringin possesses a potential therapeutic add-on effect against ketamine-induced schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Flavanonas/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Ketamina/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Esquizofrenia/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/uso terapêutico , Clozapina/administração & dosagem , Clozapina/farmacologia , Clozapina/uso terapêutico , Modelos Animais de Doenças , Flavanonas/administração & dosagem , Flavanonas/uso terapêutico , Masculino , Ratos , Ratos Wistar , Esquizofrenia/induzido quimicamente
6.
J Neurosci ; 40(11): 2282-2295, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32024781

RESUMO

Oxytocin (OT) is critical for the expression of social behavior across a wide array of species; however, the role of this system in the encoding of socially relevant information is not well understood. In the present study, we show that chemogenetic activation of OT neurons within the paraventricular nucleus of the hypothalamus (PVH) of male mice (OT-Ires-Cre) enhanced social investigation during a social choice test, while chemogenetic inhibition of these neurons abolished typical social preferences. These data suggest that activation of the OT system is necessary to direct behavior preferentially toward social stimuli. To determine whether the presence of a social stimulus is sufficient to induce activation of PVH-OT neurons, we performed the first definitive recording of OT neurons in awake mice using two-photon calcium imaging. These recordings demonstrate that social stimuli activate PVH-OT neurons and that these neurons differentially encode social and nonsocial stimuli, suggesting that PVH-OT neurons may act to convey social salience of environmental stimuli. Finally, an attenuation of social salience is associated with social disorders, such as autism. We therefore also examined possible OT system dysfunction in a mouse model of autism, Shank3b knock-out (KO) mice. Male Shank3b KO mice showed a marked reduction in PVH-OT neuron number and administration of an OT receptor agonist improved social deficits. Overall, these data suggest that the presence of a social stimulus induces activation of the PVH-OT neurons to promote adaptive social behavior responses.SIGNIFICANCE STATEMENT Although the oxytocin (OT) system is well known to regulate a diverse array of social behaviors, the mechanism in which OT acts to promote the appropriate social response is poorly understood. One hypothesis is that the presence of social conspecifics activates the OT system to generate an adaptive social response. Here, we selectively recorded from OT neurons in the paraventricular hypothalamic nucleus (PVH) to show that social stimulus exposure indeed induces activation of the OT system. We also show that activation of the OT system is necessary to promote social behavior and that mice with abnormal social behavior have reduced numbers of PVH-OT neurons. Finally, aberrant social behavior in these mice was rescued by administration of an OT receptor agonist.


Assuntos
Neurônios/fisiologia , Ocitocina/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Comportamento Social , Potenciais de Ação/efeitos dos fármacos , Animais , Comportamento Apetitivo/efeitos dos fármacos , Comportamento Apetitivo/fisiologia , Transtorno Autístico/fisiopatologia , Benzodiazepinas/farmacologia , Sinalização do Cálcio , Clozapina/farmacologia , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Genes Reporter , Masculino , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Ocitocina/análise , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Técnicas de Patch-Clamp , Pirazóis/farmacologia , Receptores de Ocitocina/agonistas , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/fisiologia , Vigília
7.
Neuron ; 105(6): 1036-1047.e5, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-31954621

RESUMO

Dopamine is involved in physiological processes like learning and memory, motor control and reward, and pathological conditions such as Parkinson's disease and addiction. In contrast to the extensive studies on neurons, astrocyte involvement in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics, and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca2+ elevations to synaptically released dopamine, a phenomenon enhanced by amphetamine. In brain slices, synaptically released dopamine increases astrocyte Ca2+, stimulates ATP/adenosine release, and depresses excitatory synaptic transmission through activation of presynaptic A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent A1 receptor activation. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the dopamine- and amphetamine-induced synaptic regulation, revealing a novel cellular pathway in the brain reward system.


Assuntos
Astrócitos/fisiologia , Dopamina/fisiologia , Núcleo Accumbens/fisiologia , Transmissão Sináptica/fisiologia , Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Anfetamina/farmacologia , Animais , Astrócitos/metabolismo , Cálcio/metabolismo , Clozapina/análogos & derivados , Clozapina/farmacologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Atividade Motora/fisiologia , Optogenética , Receptores de Dopamina D1/genética , Recompensa
8.
Psychopharmacology (Berl) ; 237(4): 957-966, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31897573

RESUMO

RATIONALE AND OBJECTIVES: Although clozapine is effective in treating schizophrenia, it is associated with adverse side effects including weight gain and metabolic syndrome. Despite this, the role of clozapine on feeding behaviour and food intake has not been thoroughly characterised. Clozapine has a broad pharmacological profile, with affinities for several neurotransmitter receptors, including serotonin (5-hydroxytriptamine, 5-HT) and histamine. Given that the serotonin 5-HT2C receptor and histaminergic H1 receptor are involved in aspects of feeding behaviour, the effect of clozapine on feeding may be linked to its action at these receptors. METHODS: We assessed, in rats, the effect of acute and subchronic administration of clozapine on responding for food under a progressive ratio (PR) schedule under conditions of food restriction and satiety. We also examined the effect of antagonists of the serotonin 5-HT2C and histaminergic H1 receptors on the same schedule. Clozapine reliably increased responding for food, even when rats had ad libitum access to food. The effect of clozapine on responding for food was reproduced by combined (but not individual) antagonism of the serotonin 5-HT2C and histaminergic H1 receptors. CONCLUSION: These findings show that clozapine enhances the motivation to work for food, that this effect is stable over repeated testing, and is independent of hunger state of the animal. This effect may relate to a combined action of clozapine at the serotonin 5-HT2C and histaminergic H1 receptors.


Assuntos
Antipsicóticos/farmacologia , Clozapina/farmacologia , Comportamento Alimentar/fisiologia , Motivação/fisiologia , Receptor 5-HT2C de Serotonina/fisiologia , Receptores 5-HT1 de Serotonina/fisiologia , Animais , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Ingestão de Alimentos/psicologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/psicologia , Masculino , Motivação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Esquema de Reforço , Antagonistas da Serotonina/farmacologia , Ganho de Peso/efeitos dos fármacos , Ganho de Peso/fisiologia
9.
Neuron ; 105(6): 1094-1111.e10, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-31955944

RESUMO

Interoception, the sense of internal bodily signals, is essential for physiological homeostasis, cognition, and emotions. While human insular cortex (InsCtx) is implicated in interoception, the cellular and circuit mechanisms remain unclear. We imaged mouse InsCtx neurons during two physiological deficiency states: hunger and thirst. InsCtx ongoing activity patterns reliably tracked the gradual return to homeostasis but not changes in behavior. Accordingly, while artificial induction of hunger or thirst in sated mice via activation of specific hypothalamic neurons (AgRP or SFOGLUT) restored cue-evoked food- or water-seeking, InsCtx ongoing activity continued to reflect physiological satiety. During natural hunger or thirst, food or water cues rapidly and transiently shifted InsCtx population activity to the future satiety-related pattern. During artificial hunger or thirst, food or water cues further shifted activity beyond the current satiety-related pattern. Together with circuit-mapping experiments, these findings suggest that InsCtx integrates visceral-sensory signals of current physiological state with hypothalamus-gated amygdala inputs that signal upcoming ingestion of food or water to compute a prediction of future physiological state.


Assuntos
Córtex Cerebral/fisiologia , Fome/fisiologia , Interocepção/fisiologia , Sede/fisiologia , Proteína Relacionada com Agouti/metabolismo , Animais , Clozapina/análogos & derivados , Clozapina/farmacologia , Sinais (Psicologia) , Feminino , Hipotálamo/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Vias Neurais/fisiologia , Imagem Óptica , Optogenética , Órgão Subfornical/fisiologia
11.
Nat Neurosci ; 22(12): 1986-1999, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719672

RESUMO

The importance of neuronal ensembles, termed engram cells, in storing and retrieving memory is increasingly being appreciated, but less is known about how these engram cells operate within neural circuits. Here we tagged engram cells in the ventral CA1 region of the hippocampus (vCA1) and the core of the nucleus accumbens (AcbC) during cocaine conditioned place preference (CPP) training and show that the vCA1 engram projects preferentially to the AcbC and that the engram circuit from the vCA1 to the AcbC mediates memory recall. Direct activation of the AcbC engram while suppressing the vCA1 engram is sufficient for cocaine CPP. The AcbC engram primarily consists of D1 medium spiny neurons, but not D2 medium spiny neurons. The preferential synaptic strengthening of the vCA1→AcbC engram circuit evoked by cocaine conditioning mediates the retrieval of cocaine CPP memory. Our data suggest that the vCA1 engram stores specific contextual information, while the AcbC D1 engram and its downstream network store both cocaine reward and associated contextual information, providing a potential mechanism by which cocaine CPP memory is stored.


Assuntos
Região CA1 Hipocampal/fisiologia , Cocaína/farmacologia , Condicionamento Psicológico/fisiologia , Rememoração Mental/fisiologia , Núcleo Accumbens/fisiologia , Animais , Comportamento Animal/fisiologia , Clozapina/análogos & derivados , Clozapina/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Camundongos Transgênicos , Vias Neurais/fisiologia , Optogenética , Receptores Dopaminérgicos/fisiologia
12.
J Clin Psychopharmacol ; 39(6): 591-596, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31688397

RESUMO

PURPOSE: Given that switching to clozapine is an important treatment option for tardive movement syndrome (TMS), its effect and clinical correlates have not been fully explored yet. This study investigated the improvement of TMS after switching to clozapine and factors associated with the response in a naturalistic outpatient setting. METHODS: Subjects were 35 patients with schizophrenia or bipolar disorder receiving only clozapine as an antipsychotic drug for more than 12 months. Their prior antipsychotics were switched to clozapine after the onset of tardive dyskinesia and/or tardive dystonia. Tardive movement syndrome and clinical characteristics were assessed through direct examination and review of hospital records. FINDINGS: Offending antipsychotics administered at the time of TMS onset were second-generation antipsychotics in 88.6% of patients. Tardive movement syndrome symptoms were remitted in 65.7% of patients after switching to clozapine. Younger age, younger age at onset of TMS, and lower baseline Abnormal Involuntary Movement Scale score were significantly associated with remission of TMS. Female sex and good antipsychotic effects of clozapine showed a trend of association with better response. IMPLICATIONS: Clozapine seems to be an excellent treatment option for TMS in the era of second-generation antipsychotics, especially for younger patients with mild tardive dyskinesia. Clinical trials comparing the effect of switching antipsychotics to clozapine with add-on therapy of new drugs targeting TMS are difficult to design in ordinary clinical settings. Therefore, more naturalistic observational studies are warranted to identify predictors of TMS response to clozapine.


Assuntos
Antipsicóticos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Clozapina/farmacologia , Discinesia Induzida por Medicamentos/prevenção & controle , Distonia/induzido quimicamente , Distonia/prevenção & controle , Avaliação de Resultados em Cuidados de Saúde , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Adulto , Fatores Etários , Idade de Início , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Clozapina/administração & dosagem , Substituição de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Índice de Gravidade de Doença , Fatores Sexuais
13.
Nat Neurosci ; 22(11): 1771-1781, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636449

RESUMO

Microglia dynamically survey the brain parenchyma. Microglial processes interact with neuronal elements; however, what role neuronal network activity plays in regulating microglial dynamics is not entirely clear. Most studies of microglial dynamics use either slice preparations or in vivo imaging in anesthetized mice. Here we demonstrate that microglia in awake mice have a relatively reduced process area and surveillance territory and that reduced neuronal activity under general anesthesia increases microglial process velocity, extension and territory surveillance. Similarly, reductions in local neuronal activity through sensory deprivation or optogenetic inhibition increase microglial process surveillance. Using pharmacological and chemogenetic approaches, we demonstrate that reduced norepinephrine signaling is necessary for these increases in microglial process surveillance. These findings indicate that under basal physiological conditions, noradrenergic tone in awake mice suppresses microglial process surveillance. Our results emphasize the importance of awake imaging for studying microglia-neuron interactions and demonstrate how neuronal activity influences microglial process dynamics.


Assuntos
Microglia/fisiologia , Neurônios/fisiologia , Norepinefrina/fisiologia , Córtex Somatossensorial/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Receptor 1 de Quimiocina CX3C/genética , Clozapina/análogos & derivados , Clozapina/farmacologia , Isoflurano/farmacologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microinjeções , Muscimol/farmacologia , Norepinefrina/farmacologia , Optogenética , Propanolaminas/farmacologia , Propranolol/farmacologia , Receptores Purinérgicos P2Y12/genética , Privação Sensorial/fisiologia , Córtex Somatossensorial/efeitos dos fármacos , Tetrodotoxina/farmacologia , Vigília
14.
Psychiatr Danub ; 31(Suppl 3): 574-578, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31488793

RESUMO

Bipolar disorder is associated with the highest risk of completed suicide of all mental disorders. The suicide mortality of people with bipolar disorder is approximately 25 times higher than the general population. No approved pharmacological strategies for suicidality in bipolar disorder have been introduced so far. There is evidence for anti-suicidal effect of clozapine in schizophrenia. Clozapine with its unique pharmacology, anti-aggressive and anti-impulsive properties is potentially an effective strategy for suicidality in bipolar disorder.


Assuntos
Transtorno Bipolar/psicologia , Clozapina/farmacologia , Clozapina/uso terapêutico , Suicídio/prevenção & controle , Suicídio/psicologia , Transtorno Bipolar/mortalidade , Transtorno Bipolar/terapia , Humanos
15.
Endocr Regul ; 53(2): 83-92, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517626

RESUMO

OBJECTIVE: Prolonged treatment with neuroleptics has been shown to induce FosB/ΔFosB expression in several brain regions including the medial prefrontal cortex, dorsomedial and dorsolateral striatum, ventrolateral and dorsolateral septum, nucleus accumbens shell and core, and the hypothalamic paraventricular nucleus (PVN). Some of these regions are known to be also stress responsive. This study was designed to determine whether repeated clozapine (CLZ) administration for 7 consecutive days to Wistar rats may modify FosB/ΔFosB expression in the above-mentioned brain areas induced by acute stress or novel stressor that followed 13-day chronic mild stress preconditioning. METHODS: Following experimental groups were used: unstressed animals treated with vehicle/ CLZ for 7 days; 7-day vehicle/CLZ-treated animals on the last day exposed to acute stress - forced swimming (FSW); and animals preconditioned with stress for 13 days treated from the 8th day with vehicle/CLZ and on the 14th day exposed to novel stress - FSW. RESULTS: In the unstressed animals CLZ markedly increased FosB/ΔFosB immunoreactivity in the ventrolateral septum and PVN. FSW elevated FosB/ΔFosB expression in the medial prefrontal cortex, striatum, and septum. CLZ markedly potentiated the effect of the FSW on FosB/ΔFosB expression in the PVN, but suppressed it in the dorsomedial striatum. Novel stress with stress preconditioning increased FosB/ΔFosB immunoreactivity in the prefrontal cortex, striatum, ventrolateral septum, and the PVN. In the nucleus accumbens the effect of the novel stressor was potentiated by CLZ. CONCLUSION: Our data indicate that CLZ may modulate the acute as well as novel stress effects on FosB/ΔFosB expression but its effect differs within the individual brain regions.


Assuntos
Clozapina/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Estresse Psicológico/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Masculino , Neurônios/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/patologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/patologia , Ratos , Ratos Wistar , Estresse Psicológico/complicações , Estresse Psicológico/patologia , Natação/psicologia
16.
Neurosci Res ; 147: 39-47, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446906

RESUMO

Perinatal virus infection is an environmental risk factor for neurodevelopmental disorders such as schizophrenia. We previously demonstrated that neonatal treatment with a viral mimetic, polyriboinosinic-polyribocytidilic acid (polyI:C), in mice leads to emotional and cognitive deficits in adolescence. Here, we investigated the effects of antipsychotics on polyI:C-induced behavioral abnormalities. We also performed a proteomic analysis in the hippocampus of polyI:C-treated adult mice using two-dimensional electrophoresis to understand the changes in protein expression following neonatal immune activation. Neonatal mice were subcutaneously injected with polyI:C for 5 days (postnatal day 2-6). At 10 weeks, sensorimotor gating, emotional and cognitive function were analyzed in behavioral tests. Clozapine improved PPI deficit and emotional and cognitive dysfunction in polyI:C-treated mice. However, haloperidol improved only PPI deficit. Proteomic analysis revealed that two candidate proteins were obtained in the hippocampus of polyI:C-treated mice, including aldehyde dehydrogenase family 1 member L1 (ALDH1L1) and collapsin response mediator protein 5 (CRMP5). These data suggest that the neonatal polyI:C-treated mouse model may be useful for evaluating antipsychotic activity of compounds. Moreover, changes in the protein expression of ALDH1L1 and CRMP5 support our previous findings that astrocyte-neuron interaction plays a role in the pathophysiology of neurodevelopmental disorders induced by neonatal immune activation.


Assuntos
Antipsicóticos/farmacologia , Poli I-C/farmacologia , Proteômica , Esquizofrenia/induzido quimicamente , Aldeído Desidrogenase 1/metabolismo , Animais , Animais Recém-Nascidos , Clozapina/farmacologia , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Feminino , Haloperidol/farmacologia , Hipocampo/efeitos dos fármacos , Hidrolases/metabolismo , Relações Interpessoais , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas do Tecido Nervoso , Gravidez , Inibição Pré-Pulso , Reconhecimento Psicológico , Filtro Sensorial/efeitos dos fármacos
17.
Transl Psychiatry ; 9(1): 181, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371697

RESUMO

Clozapine is an antipsychotic agent prescribed to psychotic patients exhibiting tolerance and/or resistance to the conventional antipsychotic medications that mainly drive monoamine antagonism. As the pharmacological fundamentals of its unique antipsychotic profile have been unrevealed, here, we attempted to obtain hints at this question. Here, we found that clozapine directly acts on ErbB kinases to downregulate epidermal growth factor (EGF)/neuregulin signaling. In cultured cell lines and cortical neurons, EGF-triggered ErbB1 phosphorylation was diminished by 30 µM clozapine, but not haloperidol, risperidone, or olanzapine. The neuregulin-1-triggered ErbB4 phosphorylation was attenuated by 10 µM clozapine and 30 µM haloperidol. We assumed that clozapine may directly interact with the ErbB tyrosine kinases and affect their enzyme activity. To test this assumption, we performed in vitro kinase assays using recombinant truncated ErbB kinases. Clozapine (3-30 µM) significantly decreased the enzyme activity of the truncated ErbB1, B2, and B4 kinases. Acute in vivo administration of clozapine (20 mg/kg) to adult rats significantly suppressed the basal phosphorylation levels of ErbB4 in the brain, although we failed to detect effects on basal ErbB1 phosphorylation. Altogether with the previous findings that quinazoline inhibitors for ErbB kinases harbor antipsychotic potential in animal models for schizophrenia, our present observations suggest the possibility that the micromolar concentrations of clozapine can attenuate the activity of ErbB receptor kinases, which might illustrate a part of its unique antipsychotic psychopharmacology.


Assuntos
Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Clozapina/farmacologia , Fator de Crescimento Epidérmico/metabolismo , Neurregulinas/metabolismo , Proteínas Oncogênicas v-erbB/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Encéfalo/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
18.
Acta Neuropsychiatr ; 31(6): 305-315, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31364522

RESUMO

OBJECTIVE: Despite its numerous side effects, clozapine is still the most effective antipsychotics making it an ideal reference substance to validate the efficacy of novel compounds for the treatment of schizophrenia. However, blood-brain barrier permeability for most new molecular entities is unknown, requiring central delivery. Thus, we performed a dose-finding study for chronic intracerebroventricular (icv) delivery of clozapine in mice. METHODS: Specifically, we implanted wild-type C57BL/6J mice with osmotic minipumps (Alzet) delivering clozapine at a rate of 0.15 µl/h at different concentrations (0, 3.5, 7 and 14 mg/ml, i.e. 0, 12.5, 25 and 50 µg/day). Mice were tested weekly in a modified SHIRPA paradigm, for locomotor activity in the open field and for prepulse inhibition (PPI) of the acoustic startle response (ASR) for a period of 3 weeks. RESULTS: None of the clozapine concentrations caused neurological deficits or evident gross behavioural alterations in the SHIRPA paradigm. In male mice, clozapine had no significant effect on locomotor activity or PPI of the ASR. In female mice, the 7 and 14 mg/ml dose of clozapine significantly affected both open field activity and PPI, while 3.5 mg/ml of clozapine increased PPI but had no effects on locomotor activity. CONCLUSION: Our findings indicate that 7 mg/ml may be the optimal dose for chronic icv delivery of clozapine in mice, allowing comparison to screen for novel antipsychotic compounds.


Assuntos
Clozapina/administração & dosagem , Clozapina/farmacologia , Relação Dose-Resposta a Droga , Animais , Feminino , Infusões Intraventriculares , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Inibição Pré-Pulso/efeitos dos fármacos , Caracteres Sexuais
19.
BMC Psychiatry ; 19(1): 220, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299940

RESUMO

BACKGROUND: Among patients with treatment-resistant schizophrenia (TRS), some exhibited further clozapine resistance (CR). This study aimed to investigate whether greater severity of treatment resistance in schizophrenia is associated with greater impairments in sustained attention. METHODS: Patients with a DSM-IV-defined schizophrenia were recruited from a psychiatric center in northern Taiwan (April 2010 to October 2010). Both TRS and CR were determined retrospectively from participants' medical records following the consensus guidelines. The patients were divided into three groups: 102 non-TRS, 48 TRS without CR, and 54 TRS with CR. They underwent both undegraded and degraded Continuous Performance Tests (CPT), and their performance scores (d') were standardized against a community sample to derive age-, sex-, and education-adjusted z scores. RESULTS: The TRS with CR group had significantly lower adjusted z scores of d' on both undegraded and degraded CPTs than the other two groups. Meanwhile, the differences between the TRS without CR group and the non-TRS group were not significant. Multivariable linear regression analyses with adjustment for covariates revealed a trend of gradient impairments on the degraded CPT from non-TRS to TRS without CR and to TRS with CR. The proportions of attentional deficits (an adjusted z score of ≤ - 2.5) on the degraded CPT also exhibited a significant trend, from 36.3% in the non-TRS group to 62.5% in the TRS without CR group and to 83.3% in the TRS with CR group. CONCLUSIONS: Greater severity of treatment resistance in schizophrenia was associated with greater impairments in sustained attention, indicating some common vulnerability.


Assuntos
Antipsicóticos/farmacologia , Atenção/efeitos dos fármacos , Clozapina/farmacologia , Resistência a Medicamentos , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Retrospectivos , Taiwan
20.
Pak J Pharm Sci ; 32(3 (Supplementary)): 1193-1199, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31303590

RESUMO

Cognitive behavior is associated with physiological processes that affect the working performance of an individual. Cognitive control is used to override self-serving impulses and behave in socially desirable manner. The objective of the study is to compare the effects of Choline with Fluoxetine and Clozapine for the modulation of cognitive behavior including learning, memory, locomotor, exploratory behavior and anxiety. The study was based on twenty four albino rats divided into four equal groups: (1) Control kept on normal saline (2) Fluoxetine (3) Clozapine (4) Choline. Morris Water Maze (WM) test was used for the psychological assessment based on neural mechanism involved in spatial learning and memory. Open field activity test evaluated locomotor and exploratory behavior. The behavior modulation in WM test and open field activity test was determined at 1st, 3rd, 5th and 7th week. Fluoxetine, Clozapine and Choline were used as drugs and administered to the rat groups mentioned earlier. The modulation of behavior in WM test and Open field activity test was recorded at 1st, 3rd, 5th and 7th week after administering the drugs. Impairment in learning behavior in Fluoxetine treated group was observed at 1st, 3rd, 5th and 7th week and in Clozapine group at 1st and 2nd week when compared to Control (Saline) group. Rise in latency time was observed in Fluoxetine treated group but was not significant. Clozapine and Choline had exhibited beneficial effects in memory retention and prevention of learning impairment. The findings have led to the conclusion that Choline and Clozapine improve the memory retention after continuous administration of 5 and 7 weeks. Moreover, Clozapine has different receptor specificity as compared to Choline. However, both improve the learning capability and enhance the memory in rats. Meanwhile, Fluoxetine did not show any considerable enhancement of memory.


Assuntos
Colina/farmacologia , Clozapina/farmacologia , Cognição/efeitos dos fármacos , Fluoxetina/farmacologia , Animais , Antipsicóticos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Ratos
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