RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Scrophularia buergeriana has been used for traditional medicine as an agent for reducing heat in the blood and for nourishing kidney 'Yin'. Therefore, S. buergeriana might be a potential treatment for mental illness, especially schizophrenia, which may be attenuated by supplying kidney Yin and reducing blood heat. In a pilot study, we found that S. buergeriana alleviated sensorimotor gating dysfunction induced by MK-801. AIM OF THE STUDY: In the present study, we attempted to reveal the active component(s) of S. buergeriana as a candidate for treating sensorimotor gating dysfunction, and we identified 4-methoxycinnamic acid. We explored whether 4-methoxycinnamic acid could affect schizophrenia-like behaviors induced by hypofunction of the glutamatergic neurotransmitter system. MATERIALS AND METHODS: Mice were treated with 4-methoxycinnamic acid (3, 10, or 30 mg/kg, i.g.) under MK-801-induced schizophrenia-like conditions. The effect of 4-methoxycinnamic acid on schizophrenia-like behaviors were explored using several behavioral tasks. We also used Western blotting to investigate which signaling pathway(s) is involved in the pharmacological activities of 4-methoxycinnamic acid. RESULTS: 4-Methoxycinnamic acid ameliorated MK-801-induced prepulse inhibition deficits, social interaction disorders and cognitive impairment by regulating the phosphorylation levels of PI3K, Akt and GSK-3ß signaling in the prefrontal cortex. And there were no adverse effects in terms of catalepsy and motor coordination impairments. CONCLUSION: Collectively, 4-methoxycinnamic acid would be a potential candidate for treating schizophrenia with fewer adverse effects, especially the negative symptoms and cognitive dysfunctions.
Assuntos
Cinamatos/uso terapêutico , Maleato de Dizocilpina/toxicidade , Esquizofrenia/induzido quimicamente , Animais , Comportamento Animal/efeitos dos fármacos , Western Blotting , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Cinamatos/química , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Masculino , Medicina Tradicional , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Esquizofrenia/tratamento farmacológico , Scrophularia/química , Transdução de Sinais/efeitos dos fármacosRESUMO
Increasing evidence supports schizophrenia may be a neurodevelopmental and neurodegenerative disorder. Fluoxetine, a selective serotonin reuptake inhibitor, has been reported to have neuroprotective effects and be effective in treating neurodegenerative disorders including schizophrenia. The objective of the present study was to evaluate the effect and underlying neuroprotective mechanism of fluoxetine on the sensorimotor gating deficit, a schizophrenia-like behavior in a neurodevelopmental schizophrenic mouse model induced by MK-801, an N-methyl-D-aspartate glutamate receptor antagonist. On postnatal day 7, mouse pups were treated with a total seven subcutaneous daily injections of MK-801 (1 mg/kg/day), followed by intraperitoneal injection of fluoxetine (5 or 10 mg/kg/day) starting on postnatal day 14 in the MK-801-injected mice for 4 weeks. The sensorimotor gating deficit in mice was measured by prepulse inhibition (PPI) behavioral test on postnatal day 43. After the behavioral test, the protein expression of brain-derived neurotrophic factor (BDNF) was measured by western blot or ELISA in the frontal cortex of mice. Our results showed fluoxetine attenuated PPI deficit and the decrease of cerebral BDNF expression in the MK-801-injected mice. These results suggest that fluoxetine can be used to treat sensorimotor gating deficit in a neurodevelopmental mouse model of schizophrenia, and the attenuating effect of fluoxetine on sensorimotor gating deficit may be related to fluoxetine's neuroprotective effect targeting on the modulation of cerebral BDNF.
Assuntos
Maleato de Dizocilpina/toxicidade , Antagonistas de Aminoácidos Excitatórios/toxicidade , Fluoxetina/farmacologia , Inibição Pré-Pulso/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estimulação Acústica/efeitos adversos , Estimulação Acústica/métodos , Animais , Animais Recém-Nascidos , Feminino , Camundongos , Camundongos Endogâmicos ICR , Inibição Pré-Pulso/fisiologia , Reflexo de Sobressalto/fisiologiaRESUMO
OBJECTIVES: This study was aimed to investigate the effect of aqueous cranberry extract (ACE) on MK-801-induced psychosis in mice. MATERIALS AND METHODS: MK-801-treated mice were administered ACE (1 and 2 g/kg, p.o.) for 14 days. Various behavioral parameters and neurochemical estimations such as dopamine (DA), 5-hydroxytryptamine (5-HT), norepinephrine (NE), gamma-aminobutyric acid (GABA), glutamate, and glycine as well as markers of oxidative stress such as nitrite levels were measured. RESULTS: Psychosis-induced mice showed a significant elevation of immobility time in forced swim test, locomotor activity, and reduction in time of permanency in rota-rod test, escape latency time in Cook's pole test while treatment with ACE showed a significant alteration in above-mentioned behavioral parameters in MK-801-induced psychosis. Moreover, MK-801-induced psychosis in the mice showed a significant increase in DA, 5-HT, and NA levels and decrease in GABA, glutamate, and glycine levels in the brain. In contrast, treatment with ACE at both doses remarkably altered the neurochemical parameters. In addition, ACE-treated mice showed a substantial reduction in acetylcholinesterase, D-amino acid oxidase enzyme activity, and nitrite levels which were elevated by the administration of MK-801. CONCLUSIONS: Treatment with ACE once for 14 days (1 and 2 g/kg) significantly ameliorated the behavioral symptoms in experimentally induced psychosis by virtue of neuromodulation and decreased oxidative stress.
Assuntos
Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Transtornos Psicóticos/tratamento farmacológico , Vaccinium macrocarpon/química , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Maleato de Dizocilpina/toxicidade , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Feminino , Locomoção/efeitos dos fármacos , Camundongos , Norepinefrina/metabolismo , Extratos Vegetais/administração & dosagem , Serotonina/metabolismoRESUMO
RATIONALE: Altered glutamate NMDA receptor function is implicated in schizophrenia, and gender differences have been demonstrated in this illness. OBJECTIVES: This study aimed to investigate the interaction of gonadal hormones with NMDA receptor-mediated locomotor hyperactivity and PPI disruption in mice. RESULTS: The effect of 0.25 mg/kg of MK-801 on locomotor activity was greater in male mice than in female mice. Gonadectomy (by surgical castration) significantly reduced MK-801-induced hyperlocomotion in male mice, but no effect of gonadectomy was seen in female mice or on amphetamine-induced locomotor hyperactivity. The effect of MK-801 on prepulse inhibition of startle (PPI) was similar in intact and castrated male mice and in ovariectomized (OVX) female mice. In contrast, there was no effect of MK-801 on PPI in intact female mice. Forebrain NMDA receptor density, as measured with [3H]MK-801 autoradiography, was significantly higher in male than in female mice but was not significantly altered by either castration or OVX. CONCLUSIONS: These results suggest that male sex hormones enhance the effect of NMDA receptor blockade on psychosis-like behaviour. This interaction was not seen in female mice and was independent of NMDA receptor density in the forebrain. Male sex hormones may be involved in psychosis by an interaction with NMDA receptor hypofunction.
Assuntos
Hormônios Esteroides Gonadais/metabolismo , Hipercinese/induzido quimicamente , Hipercinese/metabolismo , Receptores de N-Metil-D-Aspartato/fisiologia , Estimulação Acústica/métodos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Maleato de Dizocilpina/toxicidade , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Orquiectomia , Ovariectomia , Inibição Pré-Pulso/efeitos dos fármacos , Inibição Pré-Pulso/fisiologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologiaRESUMO
Although N-methyl-d-aspartate receptor antagonists-induced hypoglutamate rodent models are the most well-established models for preclinical studies of schizophrenia-related deficits, they also evoke a wide spectrum of psychotomimetic side effects. It is significant to increase the specificity of hypoglutamate rodent models. In this study, the recognition memory was evaluated in rats by object recognition test (ORT), sensorimotor gating was evaluated by prepulse inhibition of the startle reflex (PPI), and locomotor activity was measured using open field test. High-performance liquid chromatography was used to measure neurotransmitters content in the medial prefrontal cortex (mPFC) and thalamus (THA). Total Akt and phospho-Akt protein was measured by Western blots. Results showed that 0.3mg/kg of MK-801 was most effective in inducing locomotion. 0.3mg/kg of MK-801 was most effective in decreasing PPI. 0.03mg/kg of MK-801 was most effective in decreasing object memory while not affecting exploration manners in the training session. 0.03mg/kg of MK-801 significantly increased HVA and Glu content in the mPFC. 0.1mg/kg of MK-801 significantly decreased GABA content in the THA. 0.03mg/kg of MK-801 significantly decreased Akt phosphorylation in the mPFC, which was related to the ORT index. In conclusion, a dose of 0.03mg/kg MK-801 can establish a "pure" memory impairment model without contaminations of sensorimotor gating and locomotor activity. MK-801-induced cognitive deficits is associated with increased DA metabolites and glutamate content in the mPFC and decreased GABA content in the THA as well as decrease in Akt phosphorylation in the mPFC.
Assuntos
Modelos Animais de Doenças , Maleato de Dizocilpina/toxicidade , Antagonistas de Aminoácidos Excitatórios/toxicidade , Transtornos da Memória/induzido quimicamente , Aminoácidos/metabolismo , Animais , Relação Dose-Resposta a Droga , Locomoção/efeitos dos fármacos , Masculino , Neurotransmissores/metabolismo , Proteína Oncogênica v-akt/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Inibição Pré-Pulso/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Filtro Sensorial/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Tálamo/metabolismoRESUMO
Human growth hormone (GH) displays promising protective effects in the central nervous system after damage caused by various insults. Current evidence suggests that these effects may involve N-methyl-d-aspartate (NMDA) receptor function, a receptor that also is believed to play a role in opioid-induced neurotoxicity. The aims of the present study were to examine the acute toxic effects of methadone, an opioid receptor agonist and NMDA receptor antagonist, as well as to evaluate the protective properties of recombinant human GH (rhGH) on methadone-induced toxicity. Primary cortical cell cultures from embryonic day 17 rats were grown for 7days in vitro. Cells were treated with methadone for 24h and the 50% lethal dose was calculated and later used for protection studies with rhGH. Cellular toxicity was determined by measuring mitochondrial activity, lactate dehydrogenase release, and caspase activation. Furthermore, the mRNA expression levels of NMDA receptor subunits were investigated following methadone and rhGH treatment using quantitative PCR (qPCR) analysis. A significant protective effect was observed with rhGH treatment on methadone-induced mitochondrial dysfunction and in methadone-induced LDH release. Furthermore, methadone significantly increased caspase-3 and -7 activation but rhGH was unable to inhibit this effect. The mRNA expression of the NMDA receptor subunit GluN1, GluN2a, and GluN2b increased following methadone treatment, as assessed by qPCR, and rhGH treatment effectively normalized this expression to control levels. We have demonstrated that rhGH can rescue cells from methadone-induced toxicity by maintaining mitochondrial function, cellular integrity, and NMDA receptor complex expression.
Assuntos
Hormônio do Crescimento Humano/farmacologia , Metadona/toxicidade , Fármacos Neuroprotetores/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Caspase 3/metabolismo , Caspase 7/metabolismo , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Maleato de Dizocilpina/toxicidade , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , L-Lactato Desidrogenase/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Morfina/toxicidade , Naloxona/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologiaRESUMO
Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a very potent 5-HT7 receptor antagonist (Kiâ=â153âpM), with slightly lesser potency toward 5-HT6, 5-HT2A, and 5HT-2C receptors (Kiâ=â1.2-2.0ânM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Kiâ=â0.58ânM) and adrenergic α2A, α2B, and α2C (Kiâ=â0.41-3.6ânM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20âmg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer's disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis.
Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Modelos Animais de Doenças , Neuroprostanos/uso terapêutico , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/uso terapêutico , Animais , Doenças do Sistema Nervoso Central/sangue , Doenças do Sistema Nervoso Central/etiologia , Maleato de Dizocilpina/toxicidade , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Antagonistas de Aminoácidos Excitatórios/toxicidade , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Fatores de TempoRESUMO
INTRODUCTION: Compound X is a new proprietary antihypertensive agent that induces its pharmacodynamic effect at an approximate plasma Cmax.u of 0.6nmol/L (rat hypertension model). However, Compound X also shows potent off-target activity at PDE-10a (IC50~12nmol/L). Since PDE-10a is expressed predominantly in brain (striatum) and inhibition/knockout of PDE-10a have been reported to result in anti-psychotic effects, we have established the "induced hyperactivity" test for CNS de-risking of Compound X. METHODS: Male Wistar rats treated orally with vehicle or Compound X (single dose; 1-3-10mg/kg) were assessed for exploratory locomotor activity following induction of hyperactivity by d-amphetamine (2mg/kg) or the NMDA antagonist MK-801 (0.2mg/kg). The assay was validated with anti-psychotic drugs (haloperidol, clozapine). RESULTS: Induced hyperactivity was not antagonized by Compound X at doses relevant for its primary pharmacodynamic activity (0.1-0.3mg/kg, rat). Although sufficient plasma concentrations were reached with Compound X (Cmax.u up to ~8nmol/L at 10mg/kg) to show its PDE-10a activity, its low brain penetration (~10%) likely precluded any meaningful PDE-10a inhibition. In comparison, other blood pressure lowering agents such as prazosin (alpha-1 adrenoceptor antagonist) and isradipine (L-Type Ca(2+) channel blocker), but not the NO-donor ISDN, tended to attenuate induced hyperactivity in rats at high doses. CONCLUSION: The relevance of a potent in-vitro off-target hit (PDE-10a inhibition) by Compound X was attenuated by a robust in-vivo assay (rat induced hyperactivity test), hence lowering the potential liability profile of Compound X. Finally, this piece of investigative safety pharmacology work enabled early de-risking of Compound X based on its primary pharmacodynamic activity in a relevant rat model.
Assuntos
Anti-Hipertensivos/toxicidade , Hipercinese/induzido quimicamente , Hipercinese/psicologia , Animais , Anti-Hipertensivos/farmacocinética , Antipsicóticos/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/metabolismo , Estimulantes do Sistema Nervoso Central/toxicidade , Dextroanfetamina/toxicidade , Maleato de Dizocilpina/toxicidade , Avaliação Pré-Clínica de Medicamentos , Antagonistas de Aminoácidos Excitatórios/toxicidade , Comportamento Exploratório/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
NMDA receptor hypofunction could be involved, in addition to the positive, also to the negative symptoms and cognitive deficits found in schizophrenia patients. An increasing number of data has linked schizophrenia with neuroinflammatory conditions and glial cells, such as microglia and astrocytes, have been related to the pathogenesis of schizophrenia. Cannabidiol (CBD), a major non-psychotomimetic constituent of Cannabis sativa with anti-inflammatory and neuroprotective properties induces antipsychotic-like effects. The present study evaluated if repeated treatment with CBD (30 and 60 mg/kg) would attenuate the behavioral and glial changes observed in an animal model of schizophrenia based on the NMDA receptor hypofunction (chronic administration of MK-801, an NMDA receptor antagonist, for 28 days). The behavioral alterations were evaluated in the social interaction and novel object recognition (NOR) tests. These tests have been widely used to study changes related to negative symptoms and cognitive deficits of schizophrenia, respectively. We also evaluated changes in NeuN (a neuronal marker), Iba-1 (a microglia marker) and GFAP (an astrocyte marker) expression in the medial prefrontal cortex (mPFC), dorsal striatum, nucleus accumbens core and shell, and dorsal hippocampus by immunohistochemistry. CBD effects were compared to those induced by the atypical antipsychotic clozapine. Repeated MK-801 administration impaired performance in the social interaction and NOR tests. It also increased the number of GFAP-positive astrocytes in the mPFC and the percentage of Iba-1-positive microglia cells with a reactive phenotype in the mPFC and dorsal hippocampus without changing the number of Iba-1-positive cells. No change in the number of NeuN-positive cells was observed. Both the behavioral disruptions and the changes in expression of glial markers induced by MK-801 treatment were attenuated by repeated treatment with CBD or clozapine. These data reinforces the proposal that CBD may induce antipsychotic-like effects. Although the possible mechanism of action of these effects is still unknown, it may involve CBD anti-inflammatory and neuroprotective properties. Furthermore, our data support the view that inhibition of microglial activation may improve schizophrenia symptoms.
Assuntos
Antipsicóticos/uso terapêutico , Encéfalo/patologia , Canabidiol/uso terapêutico , Neuroglia/efeitos dos fármacos , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/patologia , Animais , Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Clozapina/uso terapêutico , Modelos Animais de Doenças , Maleato de Dizocilpina/toxicidade , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/toxicidade , Comportamento Exploratório/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Neuroglia/metabolismo , Fosfopiruvato Hidratase/metabolismo , Transtornos Psicóticos/etiologia , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
Head direction (HD) cells, found in the rodent Papez circuit, are thought to form the neural circuitry responsible for directional orientation. Because NMDA transmission has been implicated in spatial tasks requiring directional orientation, we sought to determine if the NMDA antagonist dizocilpine (MK-801) would disrupt the directional signal carried by the HD network. Anterior thalamic HD cells were isolated in female Long-Evans rats and initially monitored for baseline directional activity while the animals foraged in a familiar enclosure. The animals were then administered MK-801 at a dose of .05 mg/kg or 0.1 mg/kg, or isotonic saline, and cells were re-examined for changes in directional specificity and landmark control. While the cells showed no changes in directional specificity and landmark control following administration of saline or the lower dose of MK-801, the higher dose of MK-801 caused a dramatic attenuation of the directional signal, characterized by decreases in peak firing rates, signal to noise, and directional information content. While the greatly attenuated directional specificity of cells in the high dose condition usually remained stable relative to the landmarks within the recording enclosure, a few cells in this condition exhibited unstable preferred directions within and between recording sessions. Our results are discussed relative to the possibility that the findings explain the effects of MK-801 on the acquisition and performance of spatial tasks.
Assuntos
Maleato de Dizocilpina/toxicidade , Antagonistas de Aminoácidos Excitatórios/toxicidade , Neurônios/efeitos dos fármacos , Orientação/efeitos dos fármacos , Transtornos da Percepção/induzido quimicamente , Tálamo/citologia , Potenciais de Ação/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Movimento/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Ratos , Ratos Long-Evans , Comportamento Espacial/efeitos dos fármacosRESUMO
The design, synthesis and structure activity relationship studies of a series of compounds from benzo[d]imidazo[5,1-b]thiazole scaffold as phosphodiesterase 10A (PDE10A) inhibitors are discussed. Several potent analogs with heteroaromatic substitutions (9a-d) were identified. The anticipated binding mode of these analogs was confirmed by performing the in silico docking experiments. Later, the heteroaromatics were substituted with saturated heteroalkyl groups which provided a tool compound 9e with excellent PDE10A activity, PDE selectivity, CNS penetrability and with favorable pharmacokinetic profile in rats. Furthermore, the compound 9e was shown to be efficacious in the MK-801 induced psychosis model and in the CAR model of psychosis.
Assuntos
Imidazóis/química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/química , Tiazóis/química , Animais , Antipsicóticos/química , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Modelos Animais de Doenças , Maleato de Dizocilpina/toxicidade , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Feminino , Meia-Vida , Simulação de Acoplamento Molecular , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Transtornos Psicóticos/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/uso terapêuticoRESUMO
According to the aberrant-salience hypothesis, attribution of motivational salience is severely disrupted in patients with schizophrenia. To provide a translational approach for investigating underlying mechanisms, neural correlates of salience attribution were examined in normal mice and in a MK-801 model of schizophrenia. Electrophysiological responses to standard and deviant tones were assessed in the medial prefrontal cortex (mPFC) using an auditory oddball paradigm. Motivational salience was induced by aversive conditioning to the deviant tone. Analysis of the auditory evoked potential (AEP) showed selective modulation of the late frontal negativity (LFN) by motivational salience, which persisted throughout a 4-week delay. MK-801, an N-methyl-D-aspartic acid receptor antagonist, abolished this differential response to motivational salience in conditioned mice. In contrast, a pronounced LFN response was observed towards the deviant, ie, perceptually salient tone, in nonconditioned mice. The finding of a selective modulation of a late frontal slow wave suggests increased top-down processing and emotional evaluation of motivationally salient stimuli. In particular, the LFN is discussed as the mouse analog to the human stimulus preceding negativity, which reflects preparatory processes in anticipation of reward or punishment. MK-801 led to a disruption of the normal response in conditioned and nonconditioned mice, including an aberrantly increased LFN in nonconditioned mice. This pattern of 'false-negative' and 'false-positive' responses suggests a degradation of salience attribution, which points to mPFC responses to be relevant for translational research on cognitive alterations in schizophrenia.
Assuntos
Estimulação Acústica/métodos , Eletroencefalografia , Potenciais Evocados Auditivos/fisiologia , Motivação/fisiologia , Córtex Pré-Frontal/fisiologia , Esquizofrenia/fisiopatologia , Animais , Maleato de Dizocilpina/farmacologia , Maleato de Dizocilpina/toxicidade , Eletroencefalografia/métodos , Potenciais Evocados Auditivos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Motivação/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Distribuição Aleatória , Esquizofrenia/induzido quimicamenteRESUMO
Prepulse inhibition (PPI) refers to the decrease in motor startle response to salient sensory stimuli (pulses) when they are closely preceded in time by another more modest sensory stimulus (prepulse). PPI deficits can be induced by stimulation of dopamine receptors (e.g., amphetamine or apomorphine) or blockade of NMDA glutamate receptors (e.g., dizocilpine or PCP). Previously we found that antagonists of α(2)-noradrenergic and H(1)-histaminergic receptors significantly attenuate PPI impairments caused by amphetamine or dizocilpine. In the current study we assessed the effects of the antidepressant mirtazapine, which has combined antagonist effects at α(2)-noradrenergic, H(1)-histaminergic and 5-HT serotonergic receptors, on amphetamine- and dizocilpine-induced PPI deficits. In Experiment 1, rats were tested for PPI of the startle response to a tactile air-puff stimulus after auditory prepulses of three different intensities. Drug treatments consisted of combinations of amphetamine (0 and 1mg/kg) and mirtazapine (0, 0.5, 1, 2, and 5mg/kg), with all rats receiving all drug doses and combinations with different counterbalanced orders. In Experiment 2, a different group of rats was tested with drug treatments consisting of combinations of dizocilpine (0 and 0.05 mg/kg) and mirtazapine (0, 0.5, 1, 2, and 5 mg/kg). In Experiment 1 amphetamine (1 mg/kg) significantly reduced PPI whereas mirtazapine caused the opposite effect, with the highest dose of mirtazapine (5 mg/kg) effectively reversing the amphetamine-induced PPI deficit. In Experiment 2 dizocilpine (0.05 mg/kg) significantly reduced PPI, but mirtazapine did not have a significant effect on the inhibition of the startle response. These results indicate that the potential beneficial effects of combined α-adrenergic, 5-HT, and H(1) receptor blockade in counteracting PPI deficits may be associated to cases of sensorimotor gating disorders mediated by dopamine, but not necessarily to NMDA glutamate-induced PPI impairments.
Assuntos
Anfetamina/toxicidade , Antidepressivos/farmacologia , Maleato de Dizocilpina/toxicidade , Inibição Psicológica , Mianserina/análogos & derivados , Reflexo de Sobressalto/efeitos dos fármacos , Estimulação Acústica/efeitos adversos , Anfetamina/agonistas , Anfetamina/antagonistas & inibidores , Animais , Maleato de Dizocilpina/agonistas , Maleato de Dizocilpina/antagonistas & inibidores , Feminino , Mianserina/farmacologia , Mirtazapina , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/fisiologia , Filtro Sensorial/efeitos dos fármacos , Filtro Sensorial/fisiologiaRESUMO
T-817MA [1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}azetidin-3-ol maleate] is a newly synthesized neuroprotective agent for the treatment of psychiatric disorders characterized by cognitive disturbances, such as Alzheimer's disease. Cognitive impairment has also been suggested to be a cardinal feature of schizophrenia. We sought to determine whether T-817MA would ameliorate sensorimotor gating deficits and loss of parvalbumin (PV)-positive γ-aminobutyric acid (GABA) neurons in the brain of rats transiently exposed to MK-801, an N-methyl-d-aspartate receptor blocker, in the neonatal stage, as an animal model of schizophrenia. Prepulse inhibition (PPI) was examined in rats treated neonatally with MK-801 (postnatal day; PD 7-10, 0.2 mg/kg/day, s.c.) or vehicle at PD 35 and PD 63. The number of PV-positive GABAergic neurons in the medial prefrontal cortex (mPFC) and the hippocampus was measured after the behavioral assessments. T-817MA (10 or 20 mg/kg) or vehicle was administered for 14 days (on PD 49-62). Administration of T-817MA at 20 mg/kg, but not 10 mg/kg, ameliorated PPI deficits and completely reversed the decrease in the number of PV-positive GABAergic neurons in rats given MK-801. These results indicate that T-817MA may provide a novel therapeutic approach for the treatment of cognitive deficits of schizophrenia.
Assuntos
Encéfalo/patologia , Neurônios GABAérgicos/metabolismo , Transtornos Neurológicos da Marcha/tratamento farmacológico , Maleatos/uso terapêutico , Fatores de Crescimento Neural/uso terapêutico , Parvalbuminas/metabolismo , Tiofenos/uso terapêutico , Estimulação Acústica , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Maleato de Dizocilpina/toxicidade , Antagonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Neurônios GABAérgicos/efeitos dos fármacos , Transtornos Neurológicos da Marcha/induzido quimicamente , Transtornos Neurológicos da Marcha/patologia , Masculino , Inibição Neural/efeitos dos fármacos , Gravidez , Psicoacústica , Distribuição Aleatória , Ratos , Ratos Wistar , Reflexo de Sobressalto/efeitos dos fármacosRESUMO
C57BL/6J mice were introduced to a nine arm radial maze without prior habituation and trained in the acquisition of a working memory task in 16 sessions, one session per day. In this maze mice need to climb onto an upward inclined bridge in order to reach and cross onto an arm. They received in each session an i.p. injection of MK-801 (0.1 mg/kg) 30 min before training or immediately after training. MK-801 pre-treated mice made significantly more entries onto the bridges, fewer entries onto the arms and took significantly longer time to make a first arm visit compared to saline and MK-801 post-treated mice during the first 3 session blocks (4 sessions per block). These results indicate that MK-801 induced anxiety which was extended throughout the first 3 session blocks. MK-801 pre-treated mice made also significantly more errors and required more sessions to reach the criterion compared to saline and MK-801 post-treated mice. Administration of MK-801 after training did not affect the acquisition of the task. The present results indicate that MK-801 pre-treatment impaired the acquisition of a spatial task and this can be accounted for by its effect on the baseline level of anxiety which was elevated. The introduction of mice to the acquisition of the task without prior habituation demonstrates that a drug treatment can affect learning and memory by increasing and/or prolonging anxiety. Such effect may be confounded with learning and memory performance and not detected with pre-habituation training procedures, particularly when the number of sessions is determined a-priori.
Assuntos
Ansiedade/induzido quimicamente , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Habituação Psicofisiológica/fisiologia , Aprendizagem em Labirinto/fisiologia , Animais , Ansiedade/fisiopatologia , Maleato de Dizocilpina/toxicidade , Avaliação Pré-Clínica de Medicamentos , Antagonistas de Aminoácidos Excitatórios/toxicidade , Habituação Psicofisiológica/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Fatores de TempoRESUMO
Prenatal supplementation of rat dams with dietary choline has been shown to provide their offspring with neuroprotection against N-methyl-d-aspartate (NMDA) antagonist-mediated neurotoxicity. This study investigated whether postnatal dietary choline supplementation exposure for 30 and 60 days of rats starting in a pre-puberty age would also induce neuroprotection (without prenatal exposure). Male and female Sprague-Dawley rats (postnatal day 30 of age) were reared for 30 or 60 concurrent days on one of the four dietary levels of choline: 1) fully deficient choline, 2) 1/3 the normal level, 3) the normal level, or 4) seven times the normal level. After diet treatment, the rats received one injection of MK-801 (dizocilpine 3mg/kg) or saline control. Seventy-two hours later, the rats were anesthetized and transcardially perfused. Their brains were then postfixed for histology with Fluorojade-C (FJ-C) staining. Serial coronal sections were prepared from a rostrocaudal direction from 1.80 to 4.2mm posterior to the bregma to examine cell degeneration in the retrosplenial and piriform regions. MK-801, but not control saline, produced significant numbers of FJ-C positive neurons, indicating considerable neuronal degeneration. Dietary choline supplementation or deprivation in young animals reared for 30-60days did not alter NMDA antagonist-induced neurodegeneration in the retrosplenial region. An interesting finding is the absence of the piriform cortex involvement in young male rats and the complete absence of neurotoxicity in both hippocampus regions and DG. However, neurotoxicity in the piriform cortex of immature females treated for 60days appeared to be suppressed by low levels of dietary choline.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Colina/metabolismo , Maleato de Dizocilpina/toxicidade , Fármacos Neuroprotetores/metabolismo , Neurotoxinas/toxicidade , Animais , Animais Recém-Nascidos , Encéfalo/patologia , Colina/farmacologia , Citoproteção/efeitos dos fármacos , Citoproteção/fisiologia , Suplementos Nutricionais/normas , Modelos Animais de Doenças , Maleato de Dizocilpina/antagonistas & inibidores , Feminino , Masculino , Degeneração Neural/tratamento farmacológico , Degeneração Neural/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/antagonistas & inibidores , Ratos , Ratos Sprague-DawleyRESUMO
Neuropeptide S (NPS) and its cognate receptor were reported to mediate anxiolytic-like and arousal effects. NPS receptors are predominantly expressed in the brain, especially in limbic structures, including amygdala, olfactory nucleus, subiculum and retrosplenial cortex. In contrast, the NPS precursor is expressed in only a few brainstem nuclei where it is co-expressed with various excitatory transmitters, including glutamate. The current study investigates interactions of the NPS system with glutamatergic neurotransmission. It has been suggested that dysfunctions in glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors might be involved in the pathophysiology of schizophrenia since NMDA receptor antagonists, such as MK-801, have been shown to induce psychotic-like behavior in humans and animal models. Also, MK-801 is known to produce histological changes such as cytoplasmic vacuoles in retrosplenial cortex neurons where NPS receptors are highly expressed. In this study we show that NPS is able to alleviate neuropathological, neurochemical and behavioral changes produced by NMDA receptor antagonists. NPS treatment attenuated MK-801-induced vacuolization in the rat retrosplenial cortex in a dose-dependent manner that can be blocked by an NPS receptor-selective antagonist. NPS also suppressed MK-801-induced increases of extracellular acetylcholine levels in the retrosplenial cortex. In the prepulse inhibition (PPI) assay, animals pretreated with NPS recovered significantly from MK-801-induced disruption of PPI. Our study suggests that NPS may have protective effects against the neurotoxic and behavioral changes produced by NMDA receptor antagonists and that NPS receptor agonists may elicit antipsychotic effects.
Assuntos
Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Encéfalo , Neuropeptídeos/farmacologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/fisiopatologia , Estimulação Acústica/efeitos adversos , Análise de Variância , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Maleato de Dizocilpina/toxicidade , Antagonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Inibição Psicológica , Masculino , Camundongos , Camundongos Endogâmicos , Microdiálise/métodos , Neuropeptídeos/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Ratos , Ratos Sprague-DawleyRESUMO
1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous compound that is constantly present in the brain, and that exhibits neuroprotective activity. Our earlier study has suggested that 1MeTIQ may play a crucial physiological role in the mammalian brain as an endogenous regulator of dopaminergic activity. It is well known that central nervous system stimulants such as: amphetamine, cocaine, phencyclidine, and selective NMDA receptor antagonists, e.g., MK-801 produce neuropsychotoxicity (psychosis, addiction) that is indistinguishable from paranoid type schizophrenia. In rodents, phencyclidine and MK-801 are often used to evoke schizophrenia-like behavioral abnormalities which are inhibited by neuroleptics. The present study was designed to further investigate potential antipsychotic properties of 1MeTIQ by using both behavioral and neurochemical studies in the rat. We investigated the influence of 1MeTIQ (25 and 50 mg/kg ip) on locomotor hyperactivity, disruptions of prepulse inhibition (PPI), and working memory impairment induced by the NMDA receptor antagonist, MK-801 (0.2-0.3 mg/kg ip). In addition in the biochemical study, we analyzed the effect of 1MeTIQ on the changes in dopamine metabolism in different brain structures and in extraneuronal release of dopamine and glutamate in the rat frontal cortex, produced by MK-801. The concentration of dopamine (DA) and its metabolites: 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA), as well as the extraneuronal concentration of dopamine and glutamate were established by HPLC. MK-801 (0.25 mg/kg ip) evoked significant disruptions of PPI and working memory impairment, and co-administration of 1MeTIQ at two investigated doses of 25 and 50 mg/kg ip did not antagonize these effects. On the other hand hyperactivity evoked by MK-801 as well as a rise in dopamine metabolism in specific brain structures and glutamate release in the frontal cortex was completely antagonized by pretreatment with 1MeTIQ. If the hyperlocomotion elicited by acutely administered MK-801 is a valid model of at least some aspects of schizophrenia, these results indicate that 1MeTIQ will show efficacy in treating this condition. In conclusions, the present study suggests that 1MeTIQ, an endogenous neuroprotective compound, exhibits also antipsychotic-like efficacy in some animal tests, and may be useful in clinical practice as a psychosis-attenuating drug in schizophrenic patients. However, 1MeTIQ did not attenuate sensorimotor gating deficit or working memory impairment evoked by MK-801 which may be served as a model of negative symptoms of schizophrenia.
Assuntos
Maleato de Dizocilpina/toxicidade , Antagonistas de Dopamina/farmacologia , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Hipercinese , Córtex Pré-Frontal , Tetra-Hidroisoquinolinas/farmacologia , Estimulação Acústica/efeitos adversos , Análise de Variância , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Antagonistas de Dopamina/uso terapêutico , Relação Dose-Resposta a Droga , Interações Medicamentosas , Hipercinese/induzido quimicamente , Hipercinese/patologia , Inibição Psicológica , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/fisiopatologia , Microdiálise/métodos , Atividade Motora/efeitos dos fármacos , Neuroquímica/métodos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Ratos , Ratos Wistar , Reflexo de Sobressalto/efeitos dos fármacos , Tetra-Hidroisoquinolinas/uso terapêuticoRESUMO
Aripiprazole is an atypical antipsychotic that acts as a partial agonist at the dopamine D(2) receptor. It has been mainly investigated in dopamine-based models of schizophrenia, while its effects on glutamate-based paradigms have remained to be further characterized. Due to its unique mechanism of action, aripiprazole has also been considered as a replacement medication for psychostimulant abuse. Thus, in the present study we tested the hypothesis that aripiprazole would prevent the motor hyperactivity induced by psychostimulant and psychotomimetic drugs that act either by dopaminergic or glutamatergic mechanisms. Male Swiss mice received injections of aripiprazole (0.1-1 mg/kg) followed by drugs that enhance the dopamine-mediated neurotransmission, amphetamine (3 mg/kg) or cocaine (5 mg/kg), or by glutamate NMDA-receptor antagonists, ketamine (60 mg/kg) or MK-801 (0.4 mg/kg). Independent groups also received aripiprazole (0.1-1 mg/kg) or haloperidol (0.5 mg/kg) and were tested for catalepsy. All doses of aripiprazole were effective in preventing the motor stimulant effects of amphetamine and cocaine. Moreover, the higher dose also prevented the effects of ketamine and MK-801. The present study reports the effects of aripiprazole in dopaminergic and glutamatergic models predictive of antipsychotic activity, suggesting that both may be useful for screening novel partial agonists with antipsychotic activity. It also shows that aripiprazole may prevent the acute effects of psychostimulant drugs without significant motor impairment.