RESUMEN
Recent studies have reported that oxytocin ameliorates behavioral abnormalities in both animal models and individuals with autism spectrum disorders (ASD). However, the mechanisms underlying the ameliorating effects of oxytocin remain unclear. In this study, we examined the effects of intranasal oxytocin on impairments in social interaction and recognition memory in an ASD mouse model in which animals are prenatally exposed to valproic acid (VPA). We found that a single intranasal administration of oxytocin restored social interaction deficits for up to 2h in mice prenatally exposed to VPA, but there was no effect on recognition memory impairments. Additionally, administration of oxytocin across 2weeks improved prenatal VPA-induced social interaction deficits for at least 24h. In contrast, there were no effects on the time spent sniffing in control mice. Immunohistochemical analysis revealed that intranasal administration of oxytocin increased c-Fos expression in the paraventricular nuclei (PVN), prefrontal cortex, and somatosensory cortex, but not the hippocampal CA1 and CA3 regions of VPA-exposed mice, suggesting the former regions may underlie the effects of oxytocin. These findings suggest that oxytocin attenuates social interaction deficits through the activation of higher cortical areas and the PVN in an ASD mouse model.
Asunto(s)
Trastorno Autístico/inducido químicamente , Oxitocina/uso terapéutico , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/psicología , Reconocimiento en Psicología/efectos de los fármacos , Aprendizaje Social/efectos de los fármacos , Ácido Valproico/efectos adversos , Animales , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/patología , Trastorno Autístico/psicología , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Hipocampo/efectos de los fármacos , Relaciones Interpersonales , Masculino , Ratones , Ratones Endogámicos ICR , Oxitocina/farmacología , Corteza Prefrontal/efectos de los fármacos , Embarazo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Conducta SocialRESUMEN
RATIONALE: Rodents exposed prenatally to valproic acid (VPA) exhibit autism spectrum disorder (ASD)-like behavioral abnormalities. We recently found that prenatal VPA exposure causes hypofunction of the prefrontal dopaminergic system in mice. This suggests that the dopaminergic system may be a potential pharmacological target for treatment of behavioral abnormalities in ASD patients. OBJECTIVES: In the present study, we examined the effects of antipsychotic drugs, which affect the dopaminergic system, on the social interaction deficits, recognition memory impairment, and reduction in dendritic spine density in the VPA mouse model of ASD. RESULTS: Both acute and chronic administrations of the atypical antipsychotic drugs risperidone and aripiprazole increased prefrontal dopamine (DA) release, while the typical antipsychotic drug haloperidol did not. Chronic risperidone and aripiprazole, but not haloperidol, increased the expression of c-Fos in the prefrontal cortex, although they all increased c-Fos expression in the striatum. Chronic, but not acute, administrations of risperidone and aripiprazole improved the VPA-induced social interaction deficits and recognition memory impairment, as well as the reduction in dendritic spine density in the prefrontal cortex and hippocampus. In contrast, chronic administration of haloperidol did not ameliorate VPA-induced abnormalities in behaviors and dendritic spine density. CONCLUSIONS: These findings indicate that chronic risperidone and aripiprazole treatments improve VPA-induced abnormalities in behaviors and prefrontal dendritic spine density, which may be mediated by repeated elevation of extracellular DA in the prefrontal cortex. Our results also imply that loss of prefrontal dendritic spines may be involved in the abnormal behaviors in the VPA mouse model of ASD.
Asunto(s)
Aripiprazol/farmacología , Trastorno del Espectro Autista/inducido químicamente , Espinas Dendríticas/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Risperidona/farmacología , Ácido Valproico , Animales , Trastorno del Espectro Autista/prevención & control , Trastorno del Espectro Autista/psicología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Femenino , Haloperidol/farmacología , Masculino , Ratones , Ratones Endogámicos ICR , Embarazo , Conducta Social , Ácido Valproico/toxicidadRESUMEN
BACKGROUND: MicroRNAs, small non-coding RNAs, are highly expressed in the mammalian brain, and the dysregulation of microRNA levels may be involved in neurodevelopmental disorders such as autism spectrum disorder (ASD). In the present study, we examined whether prenatal valproic acid (VPA) exposure affects levels of microRNAs, especially the brain specific and enriched microRNAs, in the mouse embryonic brain. RESULTS: Prenatal exposure to VPA at E12.5 immediately increased miR-132 levels, but not miR-9 or miR-124 levels, in the male embryonic brain. Prenatal exposure to VPA at E12.5 also increased miR-132 levels in the female embryonic brain. We further found that the prenatal exposure to VPA at E12.5 increased mRNA levels of Arc, c-Fos and brain-derived neurotrophic factor in both male and female embryonic brains, prior to miR-132 expression. In contrast, prenatal exposure to VPA at E14.5 did not affect miR-132 levels in either male or female embryonic brain. The prenatal VPA exposure at E12.5 also decreased mRNA levels of methyl-CpG-binding protein 2 and Rho GTPase-activating protein p250GAP, both of which are molecular targets of miR-132. Furthermore, RNA sequence analysis revealed that prenatal VPA exposure caused changes in several microRNA levels other than miR-132 in the embryonic whole brain. CONCLUSIONS: These findings suggest that the alterations in neuronal activity-dependent microRNAs levels, including an increased level of miR-132, in the embryonic period, at least in part, underlie the ASD-like behaviors and cortical pathology produced by prenatal VPA exposure.
Asunto(s)
Encéfalo/metabolismo , Embrión de Mamíferos/metabolismo , Exposición Materna/efectos adversos , MicroARNs/metabolismo , Ácido Valproico/efectos adversos , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos ICR , Ácido Valproico/farmacologíaRESUMEN
We recently demonstrated that prenatal exposure to valproic acid (VPA) at embryonic day 12.5 causes autism spectrum disorder (ASD)-like phenotypes such as hypolocomotion, anxiety-like behavior, social deficits and cognitive impairment in mice and that it decreases dendritic spine density in the hippocampal CA1 region. Previous studies show that some abnormal behaviors are improved by environmental enrichment in ASD rodent models, but it is not known whether environmental enrichment improves cognitive impairment. In the present study, we examined the effects of early environmental enrichment on behavioral abnormalities and neuromorphological changes in prenatal VPA-treated mice. We also examined the role of dendritic spine formation and synaptic protein expression in the hippocampus. Mice were housed for 4 weeks from 4 weeks of age under either a standard or enriched environment. Enriched housing was found to increase hippocampal brain-derived neurotrophic factor mRNA levels in both control and VPA-exposed mice. Furthermore, in VPA-treated mice, the environmental enrichment improved anxiety-like behavior, social deficits and cognitive impairment, but not hypolocomotion. Prenatal VPA treatment caused loss of dendritic spines in the hippocampal CA1 region and decreases in mRNA levels of postsynaptic density protein-95 and SH3 and multiple ankyrin repeat domains 2 in the hippocampus. These hippocampal changes were improved by the enriched housing. These findings suggest that the environmental enrichment improved most ASD-like behaviors including cognitive impairment in the VPA-treated mice by enhancing dendritic spine function.
Asunto(s)
Anticonvulsivantes/toxicidad , Trastorno Autístico/inducido químicamente , Trastorno Autístico/complicaciones , Ambiente , Trastornos Mentales/etiología , Trastornos Mentales/enfermería , Ácido Valproico/toxicidad , Animales , Encéfalo/citología , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/patología , Espinas Dendríticas/ultraestructura , Modelos Animales de Enfermedad , Homólogo 4 de la Proteína Discs Large/genética , Homólogo 4 de la Proteína Discs Large/metabolismo , Conducta Exploratoria/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Relaciones Interpersonales , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos Mentales/patología , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/fisiopatologíaRESUMEN
Subcellular resolution imaging of the whole brain and subsequent image analysis are prerequisites for understanding anatomical and functional brain networks. Here, we have developed a very high-speed serial-sectioning imaging system named FAST (block-face serial microscopy tomography), which acquires high-resolution images of a whole mouse brain in a speed range comparable to that of light-sheet fluorescence microscopy. FAST enables complete visualization of the brain at a resolution sufficient to resolve all cells and their subcellular structures. FAST renders unbiased quantitative group comparisons of normal and disease model brain cells for the whole brain at a high spatial resolution. Furthermore, FAST is highly scalable to non-human primate brains and human postmortem brain tissues, and can visualize neuronal projections in a whole adult marmoset brain. Thus, FAST provides new opportunities for global approaches that will allow for a better understanding of brain systems in multiple animal models and in human diseases.
Asunto(s)
Encéfalo/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/métodos , Imagenología Tridimensional/métodos , Microscopía Fluorescente/métodos , Neuroimagen/métodos , Tomografía/métodos , Anciano de 80 o más Años , Animales , Encéfalo/anatomía & histología , Callithrix , Femenino , Humanos , Masculino , Ratones , Microscopía/métodos , NeuritasRESUMEN
The selective serotonin (5-HT) reuptake inhibitors (SSRIs) are generally used for the treatment of major depressive disorders, and the 5-HT1A and σ1 receptors are considered to be targets for treatment of psychiatric disorders. Some SSRIs such as fluvoxamine have agonistic activity towards for the σ1 receptor, but it is not known whether the effect on the receptor plays a key role in the pharmacological effects. We have recently demonstrated that fluvoxamine shows an anti-anhedonic effect in picrotoxin-induced model of anxiety/depression, while the SSRI paroxetine, which have little affinity for the σ1 receptor, does not. We also suggest that the anti-anhedonic effect of fluvoxamine is mediated by combined activation of the 5-HT1A and σ1 receptors and it is associated with activation of prefrontal dopaminergic system. In these studies, picrotoxin-treated mice and adrenalectomized/castrated mice were used as decreased GABAA receptor function and neurosteroid-deficient models, respectively. These findings suggest that the functional interaction between the 5-HT1A and σ1 receptors activates prefrontal dopaminergic system under the conditions of decreased brain GABAA receptor function and the neurochemical effect is linked to the behavioral effect. This review summarizes the pharmacological role of the 5-HT1A and σ1 receptors, focusing on the functional interaction between these receptors, and the role of prefrontal dopaminergic system in depressive-like behaviors.
Asunto(s)
Receptor de Serotonina 5-HT1A/metabolismo , Receptores sigma/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Dopamina/metabolismo , Humanos , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/metabolismo , Psicofarmacología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Receptor Sigma-1RESUMEN
Background: Isolation-reared mice show social encounter-induced hyperactivity with activation of prefrontal serotonergic and dopaminergic systems, but it is not known whether this stress response is observed in other pathological conditions. Here we examined whether the social encounter stimulation induces abnormal behavior during withdrawal in chronic methamphetamine-treated mice. Methods: To induce methamphetamine-induced behavioral sensitization, male mice were injected with methamphetamine (1 mg/kg) once daily for 7 days. Results: The encounter with an intruder elicited hyperactivity 24 h after the last injection of methamphetamine in methamphetamine-sensitized mice. This response was observed even as long as 2 weeks after withdrawal of methamphetamine. The encounter increased c-Fos expression in the prefrontal cortex, dorsal raphe nucleus and ventral tegmental area in methamphetamine-sensitized mice, while it did not in control mice. Furthermore, the encounter increased extracellular serotonin (5-HT) and dopamine, but not noradrenaline, levels in the prefrontal cortex in methamphetamine-sensitized mice. Local injection of 5,7-dihydroxytryptamine and 6-hydroxydopamine into the prefrontal cortex attenuated encounter-induced hyperactivity in methamphetamine-sensitized mice and it markedly decreased prefrontal 5-HT and dopamine levels, respectively. Pharmacological analysis showed that the encounter-induced hyperactivity is mediated by dopamine D1 receptors and 5-HT2A receptors and attenuated by anxiolytics and antidepressants such as diazepam, osemozotan and selective 5-HT reuptake inhibitors. The effect of paroxetine was blocked by the 5-HT3 receptor antagonist azasetron. Conclusions: The present study shows that psychological stress elicits hyperactivity with activation of prefrontal 5-HT and dopamine systems in methamphetamine-dependent mice and suggests that the abnormal behavior is associated with anxiety and depression.
Asunto(s)
Estimulantes del Sistema Nervioso Central/toxicidad , Dopamina/metabolismo , Hipercinesia/inducido químicamente , Metanfetamina/toxicidad , Corteza Prefrontal/metabolismo , Serotonina/metabolismo , 5,7-Dihidroxitriptamina/toxicidad , Animales , Desipramina/uso terapéutico , Dopaminérgicos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Hipercinesia/tratamiento farmacológico , Locomoción/efectos de los fármacos , Masculino , Ratones , Microdiálisis , Oxidopamina/toxicidad , Corteza Prefrontal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Serotoninérgicos/farmacología , Conducta Social , Factores de TiempoRESUMEN
Recent rodent studies have shown that nanoparticles are distributed to breast milk, and more-detailed safety information regarding nanoparticle consumption by lactating mothers is required. Here, we used mice to investigate the safety of nanoparticle use during lactation. When Ag and Au nanoparticles were intravenously administered to lactating mice, the nanoparticles were distributed to breast milk without producing apparent damage to the mammary gland, and the amount of Ag nanoparticles distributed to breast milk increased with decreasing particle size. Orally administered Ag nanoparticles were also distributed to breast milk and subsequently to the brains of breast-fed pups. Ten-nanometer Ag nanoparticles were retained longer in the pups' brains than in their livers and lungs. Nevertheless, no significant behavioral changes were observed in offspring breast-fed by dams that had received orally administered 10 nm Ag nanoparticles. These data provide basic information for evaluating the safety of nanoparticle use during lactation.
Asunto(s)
Conducta Animal , Lactancia , Nanopartículas del Metal/análisis , Plata , Animales , Encéfalo , Femenino , Hígado , Ratones , Leche , Distribución TisularRESUMEN
Chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), which is a second receptor for prostaglandin (PG) D2, is involved in inflammatory responses in peripheral tissue; however, its role in cognitive function remains unclear. Here, we demonstrate that CRTH2 is involved in cognitive function using a well-established animal model of cognitive dysfunction induced by MK-801, an N-methyl-d-aspartate receptor antagonist. Genetic deletion and pharmacological inhibition of CRTH2 suppressed MK-801-induced cognitive dysfunction. Pharmacological inhibition of cyclooxygenase-1, a rate-limiting enzyme in PG synthesis, also suppressed MK-801-induced cognitive dysfunction. Moreover, an MK-801-induced increase in c-Fos expression in the paraventricular nucleus (PVN) was abolished in the CRTH2-deficient mice. Together, these results suggest that PGD2-CRTH2 signaling is involved in both MK-801-induced cognitive dysfunction and neuronal activity regulation in the PVN. Furthermore, genetic association studies suggest that CRTH2 is weakly associated with cognitive function in humans. Our study provides evidence that PGD2-CRTH2 signaling is involved in cognitive function and may represent a potential therapeutic target for cognitive dysfunction in patients with psychiatric disorders.
Asunto(s)
Disfunción Cognitiva/metabolismo , Maleato de Dizocilpina/farmacología , Prostaglandina D2/metabolismo , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Animales , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/fisiopatología , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos BALB C , Ratones Noqueados , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
RATIONALE: We previously reported that the fluvoxamine-induced increase in prefrontal dopamine levels is enhanced by adrenalectomy/castration (which results in circulating neurosteroid deficiency), via combined activation of serotonin1A (5-HT1A) and σ1 receptors. However, the mechanistic details of the interaction between 5-HT1A and σ1 receptors are unknown. OBJECTIVES: Because most neurosteroids have affinity for γ-aminobutyric acid (GABA)A receptors, in the present study, we examined the involvement of GABAA receptors in this process. RESULTS: Adrenalectomy/castration decreased pentobarbital-induced sleeping time in mice, suggesting that it reduced GABAA receptor function. The GABAA receptor antagonist picrotoxin (1 mg/kg) enhanced the fluvoxamine-induced increase in prefrontal dopamine, but not noradrenaline or serotonin, levels in mice, suggesting that picrotoxin mimicked the effect of adrenalectomy/castration. Picrotoxin also potentiated the increase in prefrontal dopamine levels mediated by co-administration of the 5-HT1A receptor agonist osemozotan and the σ1 receptor agonist (+)-SKF-10,047, while it did not affect the co-administration-induced changes in noradrenaline and serotonin levels. Conversely, the GABAA receptor agonist diazepam (1 mg/kg) blocked the effect of adrenalectomy/castration on the fluvoxamine-induced increase in prefrontal dopamine levels. Co-administration of osemozotan and (+)-SKF-10,047 did not affect the expression of the neuronal activity marker c-Fos in the prefrontal cortex, ventral tegmental area, and nucleus accumbens in control mice, while it increased the c-Fos expression only in the prefrontal cortex and ventral tegmental area in picrotoxin-treated mice. CONCLUSIONS: These results suggest that the GABAA receptor plays a key role in mediating the synergistic effects of 5-HT1A and σ1 receptor activation on prefrontal dopamine neurotransmission.
Asunto(s)
Corteza Prefrontal/efectos de los fármacos , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de GABA-A/metabolismo , Receptores sigma/metabolismo , Adrenalectomía , Animales , Antipsicóticos/farmacología , Castración , Diazepam/farmacología , Dioxanos/farmacología , Dioxoles/farmacología , Dopamina/metabolismo , Fluvoxamina/farmacología , Antagonistas del GABA/farmacología , Moduladores del GABA/farmacología , Antagonistas de Receptores de GABA-A/farmacología , Masculino , Ratones , Norepinefrina/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Orquiectomía , Fenazocina/análogos & derivados , Fenazocina/farmacología , Picrotoxina/farmacología , Corteza Prefrontal/metabolismo , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores de GABA/metabolismo , Serotonina/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Transmisión Sináptica/efectos de los fármacos , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Receptor Sigma-1RESUMEN
Valproic acid (VPA) is a multi-target drug and an inhibitor of histone deacetylase (HDAC). We have previously demonstrated that prenatal exposure to VPA at embryonic day 12.5 (E12.5), but not at E14.5, causes autism-like behavioral abnormalities in male mouse offspring. We have also found that prenatal VPA exposure causes transient histone hyperacetylation in the embryonic brain, followed by decreased neuronal cell numbers in the prefrontal and somatosensory cortices after birth. In the present study, we examined whether prenatal HDAC inhibition affects neuronal maturation in primary mouse cortical neurons. Pregnant mice were injected intraperitoneally with VPA (500 mg/kg) and the more selective HDAC inhibitor trichostatin A (TSA; 500 µg/kg) at E12.5 or E14.5, and primary neuronal cultures were prepared from the cerebral cortices of their embryos. Prenatal exposure to VPA at E12.5, but not at E14.5, decreased total number, total length, and complexity of neuronal dendrites at 14 days in vitro (DIV). The effects of VPA weakened at 21 DIV. Exposure to TSA at E12.5, but not at E14.5, also delayed maturation of cortical neurons. In addition, real-time quantitative PCR revealed that the prenatal exposure to TSA decreased neuroligin-1 (Nlgn1), Shank2, and Shank3 mRNA levels and increased contactin-associated protein-like 2 mRNA level. The delay in neuronal maturation was also observed in Nlgn1-knockdown cells, which were transfected with Nlgn1 siRNA. These findings suggest that prenatal HDAC inhibition causes changes in gene expression of autism-related molecules linked to a delay of neuronal maturation.
Asunto(s)
Trastorno Autístico/genética , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Neurogénesis/efectos de los fármacos , Neuronas/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/metabolismo , Animales , Trastorno Autístico/patología , Femenino , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Ratones , Neuronas/metabolismo , Embarazo , Ácido Valproico/farmacologíaRESUMEN
Since 1998, when the laboratory of Medicinal Pharmacology was established in the Graduate School of Pharmaceutical Sciences, Osaka University, I have been interested in psychopharmacological research topics. During this period, we identified a number of novel regulatory mechanisms that control the prefrontal dopamine system through functional interaction between serotonin1A and dopamine D2 receptors or between serotonin1A and σ1 receptors. Our findings suggest that strategies that enhance the prefrontal dopamine system may have therapeutic potential in the treatment of psychiatric disorders. We also found that environmental factors during development strongly impact the psychological state in adulthood. Furthermore, we clarified the pharmacological profiles of the acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine, providing novel insights into their mechanisms of action. Finally, we developed the female encounter test, a novel method for evaluating motivation in mice. This simple method should help advance future psychopharmacological research. In this review, we summarize the major findings obtained from our recent studies in mice.
Asunto(s)
Dopamina/fisiología , Descubrimiento de Drogas , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/etiología , Ratones/psicología , Psicofarmacología , Investigación , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/etiología , Animales , Inhibidores de la Colinesterasa , Modelos Animales de Enfermedad , Donepezilo , Descubrimiento de Drogas/tendencias , Ambiente , Femenino , Galantamina , Indanos , Masculino , Terapia Molecular Dirigida , Motivación , Piperidinas , Psicofarmacología/tendencias , Ratas , Receptor de Serotonina 5-HT1A/fisiología , Receptor de Serotonina 5-HT1D/fisiología , Receptores de Dopamina D2/fisiología , RivastigminaRESUMEN
RATIONALE: The acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine are used for the treatment of Alzheimer's disease. We previously demonstrated that donepezil and galantamine differentially affect isolation rearing-induced prepulse inhibition (PPI) deficits and that this might be due to differential effects on brain muscarinic acetylcholine (mACh) receptor function in mice. OBJECTIVES: We examined the effects of rivastigmine on isolation rearing-induced PPI deficits, brain ACh levels, and mACh receptor function in mice. METHODS: Acoustic startle responses were measured in a startle chamber. Microdialysis was performed, and the levels of dopamine and ACh in the prefrontal cortex were measured. RESULTS: Rivastigmine (0.3 mg/kg) improved PPI deficits, and this improvement was antagonized by the mACh receptor antagonist telenzepine but not by the nicotinic ACh receptor antagonist mecamylamine. Rivastigmine increased extracellular ACh levels by approximately 2-3-fold, less than the increase produced by galantamine. Rivastigmine enhanced the effect of the mACh receptor agonist N-desmethylclozapine on prefrontal dopamine release, a marker of mACh receptor function, and this increase was blocked by telenzepine. In contrast, galantamine did not affect N-desmethylclozapine-induced dopamine release. Furthermore, rivastigmine did not affect cortical dopamine release induced by the serotonin1A receptor agonist osemozotan, suggesting that the effect of rivastigmine has specificity for mACh receptors. CONCLUSIONS: Taken together with our previous finding that marked increases in ACh levels are required for the PPI deficit improvement induced by galantamine, our present results suggest that rivastigmine improves isolation rearing-induced PPI deficits by increasing ACh levels and by concomitantly enhancing mACh receptor function.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Receptores Muscarínicos/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacos , Rivastigmina/farmacología , Aislamiento Social/psicología , Acetilcolina/metabolismo , Estimulación Acústica , Animales , Química Encefálica/efectos de los fármacos , Dopamina/metabolismo , Masculino , Mecamilamina/farmacología , Ratones , Antagonistas Muscarínicos/farmacología , Antagonistas Nicotínicos/farmacología , Pirenzepina/análogos & derivados , Pirenzepina/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacosRESUMEN
Rodents exposed prenatally to valproic acid (VPA) show autism-related behavioral abnormalities. We recently found that prenatal VPA exposure causes a reduction of dopaminergic activity in the prefrontal cortex of male, but not female, mice. This suggests that reduced prefrontal dopaminergic activity is associated with behavioral abnormalities in VPA-treated mice. In the present study, we examined whether the attention deficit/hyperactivity disorder drugs methylphenidate and atomoxetine (which increase dopamine release in the prefrontal cortex, but not striatum, in mice) could alleviate the behavioral abnormalities and changes in dendritic spine morphology induced by prenatal VPA exposure. We found that methylphenidate and atomoxetine increased prefrontal dopamine and noradrenaline release in VPA-treated mice. Acute treatment with methylphenidate or atomoxetine did not alleviate the social interaction deficits or recognition memory impairment in VPA-treated mice, while chronic treatment for 2 weeks did. Methylphenidate or atomoxetine for 2 weeks also improved the prenatal VPA-induced decrease in dendritic spine density in the prefrontal cortex. The effects of these drugs on behaviors and dendritic spine morphology were antagonized by concomitant treatment with the dopamine-D1 receptor antagonist SCH39166 or the dopamine-D2 receptor antagonist raclopride, but not by the α2 -adrenoceptor antagonist idazoxan. These findings suggest that chronic treatment with methylphenidate or atomoxetine improves abnormal behaviors and diminishes the reduction in spine density in VPA-treated mice via a prefrontal dopaminergic system-dependent mechanism. Autism Res 2016, 9: 926-939. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
Asunto(s)
Clorhidrato de Atomoxetina/farmacología , Trastorno Autístico/inducido químicamente , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Relaciones Interpersonales , Metilfenidato/farmacología , Animales , Trastorno Autístico/fisiopatología , Conducta Animal/fisiología , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/fisiología , Dopamina/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Norepinefrina/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiopatología , Embarazo , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiología , Ácido Valproico/toxicidadRESUMEN
Previous studies have shown that inhibitors of the Na(+)/Ca(2+) exchanger (NCX) attenuate seizure activity in drug-induced epilepsy models, but the role of NCX in epilepsy is not fully understood. The present study examined the effects of pentylenetetrazole (PTZ)-induced kindling on the mRNA expression of NCX isoforms (NCX1, NCX2 and NCX3) in mouse brain. Chronic administration of PTZ at 40mg/kg resulted in kindling seizure development. It caused decreases in the mRNA levels of NCX1 and NCX2, but not NCX3, in the hippocampus. Changes in NCX isoform expression levels were not observed in the prefrontal cortex or striatum. Acute PTZ at 40mg/kg, which caused little seizure activity, also decreased NCX2, but not NCX1 mRNA levels in the hippocampus. These results suggest that down-regulation of hippocampal NCX1 expression is associated with PTZ-induced kindling seizure development.
Asunto(s)
Hipocampo/metabolismo , Proteínas de Homeodominio/metabolismo , Excitación Neurológica/metabolismo , Convulsiones/metabolismo , Animales , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo/fisiología , Masculino , Ratones Endogámicos ICR , Pentilenotetrazol , Corteza Prefrontal/metabolismo , Isoformas de ARN , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Thrombin acts on the endothelium by activating protease-activated receptors (PARs). The endothelial thrombin-PAR system becomes deregulated during pathological conditions resulting in loss of barrier function and a pro-inflammatory and pro-angiogenic endothelial phenotype. We reported recently that the ion transporter Na(+)/Ca(2+) exchanger (NCX) operating in the Ca(2+)-influx (reverse) mode promoted ERK1/2 activation and angiogenesis in vascular endothelial growth factor-stimulated primary human vascular endothelial cells. Here, we investigated whether Ca(2+) influx through NCX was involved in ERK1/2 activation, angiogenesis, and endothelial barrier dysfunction in response to thrombin. Reverse-mode NCX inhibitors and RNAi-mediated NCX1 knockdown attenuated ERK1/2 phosphorylation in response to thrombin or an agonist of PAR-1, the main endothelial thrombin receptor. Conversely, promoting reverse-mode NCX by suppressing Na(+)-K(+)-ATPase activity enhanced ERK1/2 activation. Reverse-mode NCX inhibitors and NCX1 siRNA suppressed thrombin-induced primary human vascular endothelial cell angiogenesis, quantified as proliferation and tubular differentiation. Reverse-mode NCX inhibitors or NCX1 knockdown preserved barrier integrity upon thrombin stimulation in vitro. Moreover, the reverse-mode NCX inhibitor SEA0400 suppressed Evans' blue albumin extravasation to the lung and kidneys and attenuated edema formation and ERK1/2 activation in the lungs of mice challenged with a peptide activator of PAR-1. Mechanistically, thrombin-induced ERK1/2 activation required NADPH oxidase 2-mediated reactive oxygen species (ROS) production, and reverse-mode NCX inhibitors and NCX1 siRNA suppressed thrombin-induced ROS production. We propose that reverse-mode NCX is a novel mechanism contributing to thrombin-induced angiogenesis and hyperpermeability by mediating ERK1/2 activation in a ROS-dependent manner. Targeting reverse-mode NCX could be beneficial in pathological conditions involving unregulated thrombin signaling.
Asunto(s)
Calcio/metabolismo , Glicoproteínas de Membrana/metabolismo , NADPH Oxidasas/metabolismo , Neovascularización Fisiológica/genética , Especies Reactivas de Oxígeno/metabolismo , Intercambiador de Sodio-Calcio/genética , Compuestos de Anilina/administración & dosificación , Animales , Endotelio/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Sistema de Señalización de MAP Quinasas/genética , Glicoproteínas de Membrana/genética , Ratones , NADPH Oxidasa 2 , NADPH Oxidasas/genética , Neovascularización Fisiológica/efectos de los fármacos , Permeabilidad/efectos de los fármacos , Éteres Fenílicos/administración & dosificación , ARN Interferente Pequeño/genética , Receptor PAR-1/genética , Receptor PAR-1/metabolismo , Transducción de Señal/efectos de los fármacos , Intercambiador de Sodio-Calcio/biosíntesis , Intercambiador de Sodio-Calcio/metabolismo , Trombina/administración & dosificaciónRESUMEN
BACKGROUND: Reduced motivation is an important marker of psychiatric disorders, including depression. We describe the female encounter test, a novel method of evaluating reward-seeking behavior in mice. METHODS: The test apparatus consists of three open chambers, formed with partitions that allow the animal to move freely from one chamber to another. A test male mouse is habituated in the apparatus, and subsequently a female and male mouse are introduced into a wire-mesh box in the left and right chamber, respectively. The time the test male mouse spends in the female or male area is measured for 10 min. RESULTS: All six strains of mice tested showed a significant preference for female encounters. The preference was observed in 7-30-week-old mice. The preference was blocked by castration of the resident male test mouse, and was not affected by the phase of the menstrual cycle of the female intruder. The preference was impaired in mouse models of depression, including social isolation-reared, corticosterone-treated, and lipopolysaccharide-treated mice. The impairment was alleviated by fluvoxamine in isolation-reared and lipopolysaccharide-treated mice, and it was improved by the metabotropic glutamate 2/3 receptor antagonist LY341495 in corticosterone-treated mice. Encounter with a female, but not male, mouse increased c-Fos expression in the nucleus accumbens shell of test male mice. Furthermore, both the preference and encounter-induced increases in c-Fos expression were blocked by dopamine D1 and D2 receptor antagonists. CONCLUSIONS: These findings indicate that motivation in adult male mice can be easily evaluated by quantitating female encounters.
Asunto(s)
Ratones/psicología , Motivación , Pruebas Psicológicas , Recompensa , Conducta Social , Aminoácidos/farmacología , Animales , Antidepresivos de Segunda Generación/farmacología , Castración , Conducta de Elección/efectos de los fármacos , Conducta de Elección/fisiología , Corticosterona , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/fisiopatología , Modelos Animales de Enfermedad , Diseño de Equipo , Ciclo Estral , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Fluvoxamina/farmacología , Lipopolisacáridos , Masculino , Ratones/fisiología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Aislamiento Social , Xantenos/farmacologíaRESUMEN
We have recently found that isolation-reared mice show hyperactivity during an encounter with an intruder. However, it is not known whether encounter-induced hyperactivity may model some aspects of psychiatric disorders. The present study examined the pharmacological profile of encounter-induced hyperactivity in isolation-reared mice. Encounter-induced hyperactivity was reduced by acute administration of various antidepressants including the tricyclic antidepressant desipramine (10 mg/kg), the selective serotonin (5-HT) reuptake inhibitors fluvoxamine (10 mg/kg) and paroxetine (10 mg/kg), the 5-HT/noradrenaline reuptake inhibitors venlafaxine (10 mg/kg) and duloxetine (10 mg/kg), the antipsychotic drug risperidone (0.01 mg/kg), the 5-HT2 antagonist ritanserin (1 mg/kg), and the glucocorticoid receptor antagonist RU-43044 (30 mg/kg). The α2 adrenoceptor agonist clonidine (0.03 mg/kg) and the 5-HT4 receptor agonist BIMU8 (30 mg/kg) also reduced encounter-induced hyperactivity. The effect of desipramine was blocked by the α2 adrenoceptor antagonist idazoxan (0.3 mg/kg). The effect of fluvoxamine was blocked by the 5-HT4 receptor antagonist GR125487 (3 mg/kg), but not the 5-HT1A receptor antagonist WAY100635 (1 mg/kg), the 5-HT3 receptor antagonist azasetron (3 mg/kg), or the 5-HT6 receptor antagonist SB399885 (3 mg/kg). The effect of venlafaxine was blocked by the simultaneous administration of idazoxan (0.3 mg/kg) and GR125487 (3 mg/kg), but not by either compound alone. These findings suggest that encounter-induced hyperactivity in isolation-reared mice is a robust model for testing the pharmacological profile of antidepressants, although the range of antidepressants tested is limited and some non-antidepressants are also effective. The present study also shows a key role of α2 and 5-HT4 receptors in the antidepressant effect in this model.