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1.
Environ Health Prev Med ; 26(1): 34, 2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33706700

RESUMEN

BACKGROUND: Arsenic is a developmental neurotoxicant. It means that its neurotoxic effect could occur in offspring by maternal arsenic exposure. Our previous study showed that developmental arsenic exposure impaired social behavior and serotonergic system in C3H adult male mice. These effects might affect the next generation with no direct exposure to arsenic. This study aimed to detect the social behavior and related gene expression changes in F2 male mice born to gestationally arsenite-exposed F1 mice. METHODS: Pregnant C3H/HeN mice (F0) were given free access to tap water (control mice) or tap water containing 85 ppm sodium arsenite from days 8 to 18 of gestation. Arsenite was not given to F1 or F2 mice. The F2 mice were generated by mating among control F1 males and females, and arsenite-F1 males and females at the age of 10 weeks. At 41 weeks and 74 weeks of age respectively, F2 males were used for the assessment of social behavior by a three-chamber social behavior apparatus. Histological features of the prefrontal cortex were studied by ordinary light microscope. Social behavior-related gene expressions were determined in the prefrontal cortex by real time RT-PCR method. RESULTS: The arsenite-F2 male mice showed significantly poor sociability and social novelty preference in both 41-week-old group and 74-week-old group. There was no significant histological difference between the control mice and the arsenite-F2 mice. Regarding gene expression, serotonin receptor 5B (5-HT 5B) mRNA expression was significantly decreased (p < 0.05) in the arsenite-F2 male mice compared to the control F2 male mice in both groups. Brain-derived neurotrophic factor (BDNF) and dopamine receptor D1a (Drd1a) gene expressions were significantly decreased (p < 0.05) only in the arsenite-F2 male mice of the 74-week-old group. Heme oxygenase-1 (HO-1) gene expression was significantly increased (p < 0.001) in the arsenite-F2 male mice of both groups, but plasma 8-hydroxy-2'-deoxyguanosine (8-OHdG) and cyclooxygenase-2 (COX-2) gene expression were not significantly different. Interleukin-1ß (IL-1ß) mRNA expression was significantly increased only in 41-week-old arsenite-F2 mice. CONCLUSIONS: These findings suggest that maternal arsenic exposure affects social behavior in F2 male mice via serotonergic system in the prefrontal cortex. In this study, COX-2 were not increased although oxidative stress marker (HO-1) was increased significantly in arsnite-F2 male mice.


Asunto(s)
Arsénico/toxicidad , Arsenitos/toxicidad , Contaminantes Ambientales/toxicidad , Expresión Génica/efectos de los fármacos , Exposición Materna/efectos adversos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Conducta Social , Compuestos de Sodio/toxicidad , Animales , Conducta Animal/efectos de los fármacos , Femenino , Marcadores Genéticos , Masculino , Ratones , Ratones Endogámicos C3H , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Corteza Prefrontal/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/psicología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Serotonina/genética , Serotonina/metabolismo
2.
Nat Commun ; 12(1): 1398, 2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-33658519

RESUMEN

We previously identified a causal link between a rare patient mutation in DISC1 (disrupted-in-schizophrenia 1) and synaptic deficits in cortical neurons differentiated from isogenic patient-derived induced pluripotent stem cells (iPSCs). Here we find that transcripts related to phosphodiesterase 4 (PDE4) signaling are significantly elevated in human cortical neurons differentiated from iPSCs with the DISC1 mutation and that inhibition of PDE4 or activation of the cAMP signaling pathway functionally rescues synaptic deficits. We further generated a knock-in mouse line harboring the same patient mutation in the Disc1 gene. Heterozygous Disc1 mutant mice exhibit elevated levels of PDE4s and synaptic abnormalities in the brain, and social and cognitive behavioral deficits. Pharmacological inhibition of the PDE4 signaling pathway rescues these synaptic, social and cognitive behavioral abnormalities. Our study shows that patient-derived isogenic iPSC and humanized mouse disease models are integral and complementary for translational studies with a better understanding of underlying molecular mechanisms.


Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Proteínas del Tejido Nervioso/genética , Inhibidores de Fosfodiesterasa 4/farmacología , Esquizofrenia/genética , Animales , Conducta Animal/efectos de los fármacos , Corteza Cerebral/fisiología , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Humanos , Masculino , Ratones Mutantes , Mutación , Neuronas/efectos de los fármacos , Rolipram/farmacología , Esquizofrenia/patología , Sinapsis/efectos de los fármacos , Sinapsis/fisiología
3.
Int J Nanomedicine ; 16: 1423-1434, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33654394

RESUMEN

Background: Interleukin-1ß (IL-1)-treated mesenchymal stem cells (MSCs) and IL-1-MSCs-conditioned medium (CM) exert anti-inflammatory roles. Astrocytes are essential for the modulation of synaptic activity and neuronal homeostasis in the brain. Exosomes are the critical mediators in intercellular communication. However, the mechanism underlying the anti-inflammatory effect of IL-1-treated MSCs remains unknown. Methods: In this study, exosomes (IL-1-Exo) were isolated from IL-1-treated MSCs. In addition, lipopolysaccharide (LPS)-treated hippocampal astrocytes and status epilepticus (SE) mice were treated with IL-1-Exo. Inflammatory activity, astrogliosis, and cognitive performance were measured to determine the effect of IL-1-Exo on inflammation. Results: The results revealed that IL-1-Exo significantly inhibited LPS-induced astrogliosis and inflammatory responses of astrocytes. Also, IL-1-Exo reversed the LPS-induced effect on calcium signaling. The Nrf2 signaling pathway was associated with the effect of IL-1-Exo in LPS-treated astrocytes. Furthermore, IL-1-Exo reduced the inflammatory response and improved the cognitive performance of SE mice. Conclusion: The results suggest that IL-1-Exo inhibited LPS-induced inflammatory responses in astrocytes and SE mice and that the effect of IL-1-Exo was primarily mediated through the Nrf-2 signaling pathway. This study provides a new understanding of the molecular mechanism of inflammation-associated brain diseases and an avenue to develop nanotherapeutic agents for the treatment of inflammatory conditions in the brain.


Asunto(s)
Astrocitos/patología , Exosomas/metabolismo , Hipocampo/patología , Inflamación/terapia , Interleucina-1beta/farmacología , Células Madre Mesenquimatosas/citología , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal , Animales , Animales Recién Nacidos , Antiinflamatorios/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Conducta Animal/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Exosomas/efectos de los fármacos , Exosomas/ultraestructura , Humanos , Inflamación/patología , Lipopolisacáridos , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Transducción de Señal/efectos de los fármacos , Estado Epiléptico/patología
4.
Ecotoxicol Environ Saf ; 212: 111999, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33550078

RESUMEN

Tramadol is a widely used analgesic with additional antidepressant and anxiolytic effects. This compound has been reported in continental waters reaching concentrations of µg/L as a consequence of its inefficient removal in sewage treatment plants and increasing use over time. In this study, European chubs (Squalius cephalus) were exposed to 1 µg/L of tramadol in water for 42 days with a subsequent 14 days of depuration. Our results revealed that chubs exposed to this analgesic underwent changes in their behaviour as compared to the control group. The behavioural outcome was also influenced by the individual concentration of tramadol in brain tissue. In particular, experimental fish presented anxiolytic-like effects, characterized by less bold and less social individuals. Exposed animals were less frequently out of the shelter and moved a shorter distance, indicating that they explored the new environment less during the boldness test. In the novel object recognition experiment, although they distinguished the new item, they examined it less and displayed a reduced activity. Shoal cohesion was disrupted as observed in an increased distance between individuals. After the depuration phase, this alteration remained whereas the boldness effect disappeared. Moreover, the degree of behavioural changes was correlated with the concentration of the substance in brain. According to our findings, chronic presence of tramadol in the environment can impact the fitness of exposed aquatic fauna by altering evolutionary crucial behaviours.


Asunto(s)
Conducta Animal/efectos de los fármacos , Cyprinidae/fisiología , Tramadol/toxicidad , Contaminantes Químicos del Agua/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Agua Dulce/química , Tramadol/metabolismo , Contaminantes Químicos del Agua/metabolismo
5.
Ecotoxicol Environ Saf ; 212: 112008, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33578129

RESUMEN

Pollutants can have severe detrimental effects on insects, even at sublethal doses, damaging developmental and cognitive processes involved in crucial behaviours. Agrochemicals have been identified as important causes of pollinator declines, but the impacts of other anthropogenic compounds, such as metallic trace elements in soils and waters, have received considerably less attention. Here, we exposed colonies of the European honey bee Apis mellifera to chronic field-realistic concentrations of lead in food and demonstrated that consumption of this trace element impaired bee cognition and morphological development. Honey bees exposed to the highest of these low concentrations had reduced olfactory learning performances. These honey bees also developed smaller heads, which may have constrained their cognitive functions as we show a general relationship between head size and learning performance. Our results demonstrate that lead pollutants, even at trace levels, can have dramatic effects on honey bee cognitive abilities, potentially altering key colony functions and the pollination service.


Asunto(s)
Abejas/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Plomo/toxicidad , Aprendizaje Inverso/efectos de los fármacos , Animales , Abejas/fisiología , Cefalometría , Cognición/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Cabeza/anatomía & histología , Polinización
6.
Nat Commun ; 12(1): 1142, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33602941

RESUMEN

Negative symptoms in schizophrenia strongly contribute to poor functional outcomes, however its pathogenesis is still unclear. Here, we found that histamine H1 receptor (H1R) expression in basal forebrain (BF) cholinergic neurons was decreased in patients with schizophrenia having negative symptoms. Deletion of H1R gene in cholinergic neurons in mice resulted in functional deficiency of cholinergic projections from the BF to the prefrontal cortex and in the formation of sensorimotor gating deficit, social impairment and anhedonia-like behavior. These behavioral deficits can be rescued by re-expressing H1R or by chemogenetic activation of cholinergic neurons in the BF. Direct chemogenetic inhibition of BF cholinergic neurons produced such behavioral deficits and also increased the susceptibility to hyperlocomotion. Our results suggest that the H1R deficiency in BF cholinergic neurons is critical for sensorimotor gating deficit, social impairments and anhedonia-like behavior. This finding may help to understand the genetic and biochemical bases of negative symptoms in schizophrenia.


Asunto(s)
Neuronas Colinérgicas/metabolismo , Receptores Histamínicos H1/metabolismo , Filtrado Sensorial , Conducta Social , Anhedonia/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Colina O-Acetiltransferasa/metabolismo , Disfunción Cognitiva/complicaciones , Maleato de Dizocilpina/farmacología , Femenino , Integrasas/metabolismo , Locomoción/efectos de los fármacos , Masculino , Ratones , Ratones Transgénicos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/patología , Esquizofrenia/patología
7.
Toxicol Lett ; 342: 95-103, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33609686

RESUMEN

Neonicotinoids, which act as agonists of the nicotinic acetylcholine receptors of insects, are widely used pesticides worldwide. Although epidemiological studies revealed that the detection amounts of neonicotinoids in urine are higher in the elderly population than other age-groups, there is no available information regarding the risks of neonicotinoids to older mammals. This study was aimed to investigate aging-related differences in the behavioral effects of the neonicotinoid pesticide clothianidin (CLO). We acutely administered a sub-NOAEL level (5 mg/kg) of CLO to adult (12-week-old) and aging (90-week-old) mice and conducted four behavioral tests focusing on the emotional behavior. In addition, we measured the concentrations of CLO and its metabolites in blood, brain and urine. There were age-related changes in most parameters in all behavioral tests, and CLO significantly decreased the locomotor activity in the open field test and elevated plus-maze test in the aging group, but not in the adult group. The concentrations of most CLO and its metabolites were significantly higher in the blood and brain and were slightly lower in the urine in the aging group compared to the adult group. These findings should contribute to our understanding of age-related differences in the adverse effects of neonicotinoids in mammals.


Asunto(s)
Conducta Animal/efectos de los fármacos , Guanidinas/toxicidad , Insecticidas/toxicidad , Neonicotinoides/toxicidad , Tiazoles/toxicidad , Envejecimiento , Animales , Relación Dosis-Respuesta a Droga , Guanidinas/administración & dosificación , Insecticidas/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Neonicotinoides/administración & dosificación , Tiazoles/administración & dosificación
8.
Anesth Analg ; 132(4): e50-e55, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33560660

RESUMEN

Many general anesthetics potentiate gamma-aminobutyric acid (GABA) A receptors but their neuroanatomic sites of action are less clear. GABAergic neurons in the rostromedial tegmental nucleus (RMTg) send inhibitory projections to multiple arousal-promoting nuclei, but the role of these neurons in modulating consciousness is unknown. In this study, designer receptors exclusively activated by designer drugs (DREADDs) were targeted to RMTg GABAergic neurons of Vgat-ires-Cre mice. DREADDs expression was found in the RMTg and other brainstem regions. Activation of these neurons decreased movement and exploratory behavior, impaired motor coordination, induced electroencephalogram (EEG) oscillations resembling nonrapid eye movement (NREM) sleep without loss of righting and reduced the dose requirement for sevoflurane-induced unconsciousness. These results suggest that GABAergic neurons in the RMTg and other brainstem regions promote sedation and facilitate sevoflurane-induced unconsciousness.


Asunto(s)
Anestésicos por Inhalación/farmacología , Conducta Animal/efectos de los fármacos , Tronco Encefálico/efectos de los fármacos , Estado de Conciencia/efectos de los fármacos , Neuronas GABAérgicas/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Sevoflurano/farmacología , Sueño/efectos de los fármacos , Animales , Tronco Encefálico/metabolismo , Ondas Encefálicas/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Femenino , Neuronas GABAérgicas/metabolismo , Masculino , Ratones Transgénicos , Actividad Motora/efectos de los fármacos
9.
Ecotoxicol Environ Saf ; 210: 111868, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33421720

RESUMEN

Psychiatric drugs are among the leading medications prescribed for humans, with their presence in aquatic environments raising concerns relating to potentially harmful effects on non-target organisms. Nortriptyline (NTP) is a selective serotonin-norepinephrine reuptake inhibitor antidepressant, widely used in clinics and found in environmental water matrices. In this study, we evaluated the toxic effects of NTP on zebrafish (Danio rerio) embryos and early larval stages. Developmental and mortality analyses were performed on zebrafish exposed to NTP for 168 h at concentrations ranging from 500 to 46,900 µg/L. Locomotor behaviour and acetylcholinesterase (AChE) activity were evaluated by exposing embryos/larvae to lower NTP concentrations (0.006-500 µg/L). The median lethal NTP concentration after 168 h exposure was 2190 µg/L. Although we did not identify significant developmental changes in the treated groups, lack of equilibrium was already visible in surviving larvae exposed to ≥ 500 µg/L NTP. The behavioural analyses showed that NTP was capable of modifying zebrafish larvae swimming behaviour, even at extremely low (0.006 and 0.088 µg/L) environmentally relevant concentrations. We consistently observed a significant reduction in AChE activity in the animals exposed to 500 µg/L NTP. Our results highlight acute toxic effects of NTP on the early-life stages of zebrafish. Most importantly, exposure to environmentally relevant NTP concentrations may affect zebrafish larvae locomotor behaviour, which in turn could reduce the fitness of the species. More studies involving chronic exposure and sensitive endpoints are warranted to better understand the effect of NTP in a more realistic exposure scenario.


Asunto(s)
Inhibidores de Captación Adrenérgica/toxicidad , Antidepresivos Tricíclicos/toxicidad , Nortriptilina/toxicidad , Inhibidores de la Captación de Serotonina/toxicidad , Contaminantes Químicos del Agua/toxicidad , Pez Cebra , Acetilcolinesterasa/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Embrión no Mamífero/efectos de los fármacos , Larva/efectos de los fármacos , Locomoción/efectos de los fármacos
10.
Psychopharmacology (Berl) ; 238(3): 899-911, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33404737

RESUMEN

RATIONALE: The majority of preclinical studies assessing treatments for alcohol use disorder use singly housed animals. Because social factors affect ethanol intake, studies investigating such treatments in group-housed animals are needed. OBJECTIVES: We investigated the effects of repeated oxytocin treatment on ethanol intake in socially housed male and female C57BL/6J mice. METHODS: We used the novel "Herdsman" system implementing radiotracking technology to measure individual ethanol intake in group-housed animals. Mice were housed in same-sex groups of 4 per cage and exposed to 3 and 6% ethanol solutions. After baseline drinking was established, half of the animals in each cage received repeated intraperitoneal injections of 3 mg/kg oxytocin. RESULTS: During baseline, females consumed more ethanol than males partly due to greater number of ethanol drinks taken by females. We also observed a gradual development of two peaks of ethanol consumption during the dark phase of the circadian cycle. The effects of oxytocin treatment were short-acting and varied across treatment days. Oxytocin significantly decreased ethanol intake on three out the four treatment days. On the fourth treatment day, oxytocin decreased ethanol intake and water intake. CONCLUSION: The greater intake of ethanol in female mice is associated with the number of drinks taken. Oxytocin treatments not only cause an acute decrease in ethanol consumption, but can also change in efficacy over time. While the oxytocin system remains a promising therapeutic target for alcoholism, studies investigating longer periods of repeated oxytocin treatment and those using additional oxytocin receptor agonists are warranted.


Asunto(s)
Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Alcoholismo/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Etanol/administración & dosificación , Oxitocina/farmacología , Animales , Conducta de Elección/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Inyecciones Intraperitoneales , Masculino , Ratones , Ratones Endogámicos C57BL , Oxitocina/administración & dosificación , Factores Sexuales , Factores de Tiempo
11.
Psychopharmacology (Berl) ; 238(3): 877-886, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33404738

RESUMEN

BACKGROUND: Memory deficit is a common cognitive comorbid in patients with neuropathic pain that need better treatment. Recent research revealed that nanocurcumin has an antinociceptive action and a protective effect against memory disorders, suggesting its possible effectiveness for the treatment of neuropathic pain and its comorbidity. METHODS: Adult male albino Wistar rats (n = 32) were randomly divided into four experimental groups: CCI+ nanocurcumin, CCI + vehicle, sham + nanocurcumin, and sham + vehicle. Neuropathic pain induced by a chronic constriction injury of the sciatic nerve. Nanocurcumin or vehicle was injected intraperitoneally for 10 days. Behavioral assessment achieved to evaluate pain threshold in the von Frey test and radiant heat test, also spatial learning and memory examined by the Morris water maze (MWM) test. To explore the possible relation, IL-1ß, and TNF-α levels of the hippocampus measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our data showed that CCI caused neuropathic pain-related behaviors and spatial learning and memory disorders in rats. Chronic treatment with nanocurcumin significantly increased pain threshold (P < 0.001; F = 27.63, F = 20.58), improved spatial memory (P < 0.01; F = 47.37), and decreased the hippocampal levels of IL-1ß (P < 0.001; F = 33.57) and TNF-α (P < 0.01; F = 7.25) in CCI rats. CONCLUSION: Chronic nanocurcumin can ameliorate pain-related behavior, improve spatial learning and memory deficits, and is associated with the reduction of IL-1ß and TNF-α levels in the hippocampus in CCI rats. Nanocurcumin may be potentially providing a therapeutic alternative for the treatment of neuropathic pain and its memory impairment comorbidity.


Asunto(s)
Analgésicos/uso terapéutico , Curcumina/uso terapéutico , Hipocampo/efectos de los fármacos , Interleucina-1beta/metabolismo , Neuralgia/tratamiento farmacológico , Memoria Espacial/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Analgésicos/administración & dosificación , Analgésicos/química , Animales , Conducta Animal/efectos de los fármacos , Constricción , Curcumina/administración & dosificación , Curcumina/química , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Masculino , Trastornos de la Memoria/complicaciones , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Nanopartículas/administración & dosificación , Nanopartículas/química , Neuralgia/complicaciones , Neuralgia/metabolismo , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas Wistar , Nervio Ciático/efectos de los fármacos , Nervio Ciático/lesiones
12.
Toxicol Lett ; 340: 23-32, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33421551

RESUMEN

Acrylamide (ACR) is a neurotoxin with moderate acute toxicity. Significant level of ACR exists in diet and drinking water. Occupational exposure causes motor function impairment, but the underlying mechanisms remain poorly defined. This study aims to explore whether microtubule-associated protein tau phosphorylation, excessive activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway and BDNF decline are involved in cerebellar neuron lesions and motor dysfunction after subchronic ACR exposure. The present results displayed that ACR caused gait abnormality and hind foot splay in rats. The HE and Nissl staining results revealed that ACR exposure aggravated cerebellar neuron lesions especially in purkinje cell layer. ACR markedly increased tau phosphorylation at Ser262 and Ser396/404 and inhibited the level of phosphorylation of glycogen synthase kinase 3ß (P-GSK3ß) at Ser9. The PERK-eukaryotic initiation factor-2α (eIF2α)-activating transcription factor 4 (ATF4) pathway was activated to promote CHOP expression and then to accelerate neuron lesions. Furthermore, ACR significantly decreased P-CREB at Ser133 and BDNF expression, which might be related to the inhibition of upstream signals from extracellular signal-related kinase (ERK) and protein kinase B (Akt). This work helps to elucidate the underlying mechanisms of ACR-induced neurotoxicity and present a potential target for prevention against the neurotoxicity.


Asunto(s)
Acrilamida/administración & dosificación , Acrilamida/toxicidad , Conducta Animal/efectos de los fármacos , Cerebelo/efectos de los fármacos , Animales , Esquema de Medicación , Regulación de la Expresión Génica/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Actividad Motora/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/fisiología , Fosforilación , Ratas , Ratas Sprague-Dawley
13.
Psychopharmacology (Berl) ; 238(2): 551-557, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33410990

RESUMEN

RATIONALE: The emergence of the consumption of highly potent synthetic cannabinoid receptor agonists (spice drugs) that produce important neurological symptoms has prompted the research on the consequences of acute and chronic use of these new psychoactive substances. Most studies on cannabinoid dependence have been performed in male animals, and there is a need of studies using female subjects. OBJECTIVES: In the present study, we evaluated only in female animals the role of dopamine D1 receptors in the behavioral responses induced by acute and repeated stimulation of cannabinoid CB1 receptors, including the development of physical dependence, since cannabinoid CB1 receptors are co-localized with dopamine D1 receptors on GABAergic neurons projecting to the substantia nigra. METHODS: To this end, female dopamine D1 receptor-deficient mice and wild-type littermates were treated with HU-210, a potent synthetic cannabinoid agonist. RESULTS: Mutant mice displayed an enhanced response to acute motor and hypothermic effects to HU-210 when compared with wild-type females. The administration of SR141716A precipitated behavioral signs of withdrawal in mice treated subchronically with HU-210. Severity of cannabinoid withdrawal syndrome was potentiated in dopamine D1-deficient female mice. Indeed, 4 of 6 abstinence signs were increased in mutant mice. CONCLUSIONS: These results support for a role of dopamine D1 receptors in the acute, chronic, and withdrawal actions of spice drugs.


Asunto(s)
Agonistas de Receptores de Cannabinoides/farmacología , Antagonistas de Receptores de Cannabinoides/farmacología , Dronabinol/análogos & derivados , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptores de Dopamina D1/genética , Rimonabant/farmacología , Síndrome de Abstinencia a Sustancias/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Dronabinol/farmacología , Femenino , Masculino , Ratones , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Receptor Cannabinoide CB1/agonistas , Receptores de Dopamina D2/metabolismo , Síndrome de Abstinencia a Sustancias/psicología
14.
Life Sci ; 269: 119078, 2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33460662

RESUMEN

AIMS: Cognitive decline is one of the most challenging issues for cancer survivors undergoing doxorubicin (DOX) based chemotherapy. Oxidative stress and inflammation primarily through tumor necrosis factor-alpha (TNF-α) are considered the key contributors to DOX-induced chemobrain. Berberine (BBR) has attracted much interest because of its anti-oxidative, anti-inflammatory and anti-apoptotic actions. This study aimed to evaluate the potential neuroprotective effect of BBR in DOX-induced neurodegeneration and cognitive deficits. MATERIALS AND METHODS: Chemobrain was induced by DOX i.p. injection at the dose of 2 mg/kg, once/week, for four consecutive weeks. Rats were treated with BBR (100 mg/kg, p.o.) for 5 days/week for four consecutive weeks. KEY FINDINGS: BBR significantly attenuated behavioral defects in DOX-induced cognitive impairment. Besides, BBR reversed histopathological abnormalities. Mechanistically, it reversed DOX-induced neuroinflammation by attenuating NF-κB gene and protein expression in addition to diminishing expression of pro-inflammatory mediators (TNF-α and IL-1ß), as well as apoptotic related factors (Bax, Bcl2 and Bax/Bcl2 ratio). Additionally, BBR activated the anti-oxidative defense via upregulating the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and manganese superoxide dismutase (MnSOD). BBR improved synaptic plasticity through cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF). These effects were related through the modulation of Sirtuin1 (SIRT1) expression. SIGNIFICANCE: BBR is highlighted to induce neuroprotection against DOX-induced cognitive decline through modulating brain growth factors and imposing an anti-inflammatory, anti-apoptotic and anti-oxidative effects.


Asunto(s)
Conducta Animal/efectos de los fármacos , Berberina/farmacología , Doxorrubicina/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Animales , Antibióticos Antineoplásicos/toxicidad , /metabolismo , Inflamación/etiología , Inflamación/metabolismo , Inflamación/patología , Mediadores de Inflamación/metabolismo , Masculino , Ratas , Transducción de Señal
15.
Ecotoxicol Environ Saf ; 211: 111938, 2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33476844

RESUMEN

Melamine cyanuric acid (MCA) is a flame retardant linked by hydrogen bonds between melamine and cyanuric acid. MCA is used in an excellent series of phosphorus and nitrogen flame retardants. MCA can harm the kidney, liver, testis, and spleen cells. However, the effects of MCA on the emotions and behaviour of adolescent mice have not yet been investigated. In this article, male mice were exposed to MCA at 10, 20, and 40 mg/kg for four weeks. MCA exposure resulted in enhanced mouse locomotor and nocturnal activity. We also observed anxiety-like and depression-like behaviours. Moreover, after MCA exposure, the serum concentrations of thyroid-related hormones were changed, and the mRNA levels were affected. In short, MCA exposure can cause behavioural and emotion disorders.


Asunto(s)
Conducta Animal/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Triazinas/toxicidad , Animales , Retardadores de Llama , Riñón , Masculino , Ratones , Bazo , Testículo
16.
Aquat Toxicol ; 231: 105734, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33385846

RESUMEN

Several studies have suggested eugenol as a suitable anaesthetic for fish. However, it has also been regarded as a toxic and aversive substance to several aquatic organisms, including fish. This study sought to assess the eugenol-induced behavioural alterations and its seizurogenic potential to fish. Moreover, a distinctive methodology for an in vivo evaluation of the brain activity was also presented. Prior to the evaluation of eugenol-induced responses, fish were exposed to pentylenetetrazole (PTZ), to characterize any seizure-like patterns. Antagonizing responses to PTZ were assessed in fish receiving diazepam (BDZ) and subsequently exposed to PTZ. Tambaqui fish juveniles, Colossoma macropomum (15.8 ± 2.8 g) were used as models and assayed as follows: (i) fish exposed to PTZ (15 mM) and (ii) fish receiving a dose of BDZ (10 mg Kg-1) and later exposed to PTZ (15 mM) (BDZ-PTZ group). Thereafter, fish were evaluated throughout (iii) eugenol exposure at 65 µL L-1 (ethanolic solution) and recovery. Control fish and a vehicle control group (ethanol at 585 µL L-1) were also established. PTZ baths elicited body immobilization preceded by hyperactivity in a stereotyped seizure-like behaviour with increased EEG wave amplitude and frequency. PTZ effects in the brain were attenuated by a pre-administration of BDZ. Upon eugenol exposure, tambaqui had an intense neuronal excitability, showing a clonus-like seizure behaviour, also corroborated by the EEG patterns, which were consistent with a seizure-like response. Responses of eugenol-exposed fish resembled those of the PZT-exposed animals, with epileptiform discharges. EMG was in line with the EEG modulation, showing increased tracing oscillations and higher mean amplitudes in PTZ-exposed fish whereas in BDZ-PTZ group muscle contraction was less frequent and powerful. Fish exposed to eugenol showed initially some muscle activity followed by a loss of muscle tonus over time. In summary, our results showed that upon eugenol exposure, although a time-dependent body immobilization was attained, fish presented an intense neuronal excitability comparable to that evoked by PTZ. Eugenol failed to promote depression of the CNS and therefore may be not suitable to be used for general anaesthesia of C. macropomum. As eugenol could be implicated in seizurogenesis and be potentially toxic to the fish brain, protocols suggesting the broad use of eugenol for short-term anaesthesia or euthanasia of fish should be carefully revised, as it raises important concerns in terms of ethics and fish welfare.


Asunto(s)
Characiformes/fisiología , Eugenol/toxicidad , Inmovilización , Neuronas/patología , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Electrodos , Electroencefalografía , Electromiografía , Fenómenos Electrofisiológicos , Masculino , Músculos/efectos de los fármacos , Neuronas/efectos de los fármacos , Pentilenotetrazol/toxicidad , Contaminantes Químicos del Agua/toxicidad
17.
Int J Mol Sci ; 22(2)2021 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-33477830

RESUMEN

The forced swim stress test (FST) is widely used for screening pharmacological or non-pharmacological strategies with potential antidepressant activities. Recent data have suggested that repeated FST for five consecutive days (i.e., 5d-RFSS) could be used to generate a robust depressive-like phenotype in mice. However, the face, construct, and predictive validities of 5d-RFSS have been recently challenged. This study took advantage of recent findings showing that mice vulnerability to anxiety is enhanced when animals are stressed during the dark phase, to provide new insight into the relevance of this model. Our results showed a progressive increase in time of immobility in 5d-RFSS mice relative to control non-stressed animals (sham). Three weeks later, we noticed that 5d-RFSS mice injected with the vehicle compound (Veh) still exhibited a high level of immobility in the FST whereas this behavior was reversed by the antidepressant drug amitriptyline (AMI). However, 5d-RFSS/Veh and 5d-RFSS mice/AMI mice showed normal performances in the open field, the novelty suppressed feeding and the tail suspension tests. Despite this lack of generalized behavioral deficits, an impairment of different parameters characterizing the hypothalamic-pituitary-adrenal (HPA) axis reactivity was evidenced in 5d-RFSS mice/Veh but not in 5d-RFSS mice/AMI. Despite anomalies in the HPA axis, the activity of the central serotonergic system remained unaffected in 5d-RFSS mice relative to controls. From our results, it is suggested that learned immobility does not replicate the broad spectrum of depressive symptoms observed in other chronic models of depression such as the unpredictable chronic mild stress (UCMS) model, the chronic social defeat stress (CSDS) model or chronic corticosterone (CORT) exposure but its influence on the HPA axis is remarkable. Further experiments are warranted to makes this model suitable for modelling depression and therefore refine its translational applicability.


Asunto(s)
Ansiedad/tratamiento farmacológico , Corticosterona/farmacología , Trastorno Depresivo/tratamiento farmacológico , Estrés Psicológico/tratamiento farmacológico , Animales , Antidepresivos/farmacología , Ansiedad/fisiopatología , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/patología , Conducta Animal/efectos de los fármacos , Trastorno Depresivo/patología , Modelos Animales de Enfermedad , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/patología , Ratones , Fenotipo , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/patología , Estrés Psicológico/patología , Natación
18.
Psychopharmacology (Berl) ; 238(4): 1087-1098, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33442771

RESUMEN

RATIONALE: Antipsychotics help alleviate the positive symptoms associated with schizophrenia; however, their debilitating side effects have spurred the search for better treatment options. Novel compounds can be screened for antipsychotic potential in neuronal cell cultures and following acute N-methyl-D-aspartate (NMDA) receptor blockade with non-competitive antagonists such as MK-801 in rodent behavioral models. Given the known interactions between NMDA receptors and type 1 cannabinoid receptors (CB1R), compounds that modulate CB1Rs may have therapeutic potential for schizophrenia. OBJECTIVES: This study assessed whether the CB1R positive allosteric modulator GAT211, when compared to ∆9-tetrahydrocannabinol (THC), has potential to reduce psychiatric behavioral phenotypes following acute MK-801 treatment in rats, and block hyperdopaminergic signalling associated with those behaviors. METHODS: The effects of GAT211 and THC on cellular signaling were compared in Neuro2a cells, and behavioral effects of GAT211 and THC on altered locomotor activity and prepulse inhibition of the acoustic startle response caused by acute MK-801 treatment were assessed in male, Long Evans rats. RESULTS: GAT211 limited dopamine D2 receptor-mediated extracellular regulated kinase (ERK) phosphorylation in Neuro2a cells, whereas THC did not. As expected, acute MK-801 (0.15 mg/kg) produced a significant increase in locomotor activity and impaired PPI. GAT211 treatment alone (0.3-3.0 mg/kg) dose-dependently reduced locomotor activity and the acoustic startle response. GAT211 (3.0 mg/kg) also prevented hyperlocomotion caused by MK-801 but did not significantly affect PPI impairments. CONCLUSION: Taken together, these findings support continued preclinical research regarding the usefulness of CB1R positive allosteric modulators as antipsychotics.


Asunto(s)
Antipsicóticos/farmacología , Indoles/farmacología , Receptor Cannabinoide CB1/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Línea Celular , Maleato de Dizocilpina , Relación Dosis-Respuesta a Droga , Dronabinol/farmacología , Antagonistas de Aminoácidos Excitadores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Fosforilación , Inhibición Prepulso/efectos de los fármacos , Psicosis Inducidas por Sustancias/tratamiento farmacológico , Psicosis Inducidas por Sustancias/psicología , Ratas , Ratas Long-Evans
19.
Psychopharmacology (Berl) ; 238(4): 1111-1120, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33511450

RESUMEN

RATIONALE: Elevated whole-blood serotonin (5-HT) is a robust biomarker in ~ 30% of patients with autism spectrum disorders, in which repetitive behavior is a core symptom. Furthermore, elevated whole-blood 5-HT has also been described in patients with pediatric obsessive-compulsive disorder. The 5-HT1B receptor is associated with repetitive behaviors seen in both disorders. Chronic blockade of serotonin transporter (SERT) reduces 5-HT1B receptor levels in the orbitofrontal cortex (OFC) and attenuates the sensorimotor deficits and hyperactivity seen with the 5-HT1B agonist RU24969. We hypothesized that enhanced SERT function would increase 5-HT1B receptor levels in OFC and enhance sensorimotor deficits and hyperactivity induced by RU24969. OBJECTIVES: We examined the impact of the SERT Ala56 mutation, which leads to enhanced SERT function, on 5-HT1B receptor binding and 5-HT1B-mediated sensorimotor deficits. METHODS: Specific binding to 5-HT1B receptors was measured in OFC and striatum of naïve SERT Ala56 or wild-type mice. The impact of the 5-HT1A/1B receptor agonist RU24969 on prepulse inhibition (PPI) of startle, hyperactivity, and expression of cFos was examined. RESULTS: While enhanced SERT function increased 5-HT1B receptor levels in OFC of Ala56 mice, RU24969-induced PPI deficits and hyperlocomotion were not different between genotypes. Baseline levels of cFos expression were not different between groups. RU24969 increased cFos expression in OFC of wild-types and decreased cFos in the striatum. CONCLUSIONS: While reducing 5-HT1B receptors may attenuate sensorimotor gating deficits, increased 5-HT1B levels in SERT Ala56 mice do not necessarily exacerbate these deficits, potentially due to compensations during neural circuit development in this model system.


Asunto(s)
Conducta Animal/efectos de los fármacos , Receptor de Serotonina 5-HT1B/efectos de los fármacos , Receptor de Serotonina 5-HT1B/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Sustitución de Aminoácidos , Animales , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/fisiología , Genotipo , Hipercinesia/genética , Hipercinesia/psicología , Indoles/farmacología , Masculino , Ratones , Mutación/genética , Inhibición Prepulso/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Proteínas Proto-Oncogénicas c-fos/genética , Filtrado Sensorial/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT1/farmacología
20.
Ecotoxicol Environ Saf ; 208: 111700, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396031

RESUMEN

Sertraline (SER) is one of the most frequently detected antidepressant drugs in aquatic environments. However, knowledge regarding SER-induced behavioral alterations in fish is insufficient, as well as the mechanisms underlying SER-induced toxicity. The present study aimed to determine behavioral and molecular responses in larval fish following SER exposure with a focus on its mode of action. Zebrafish embryos (~6 h-post-fertilization, hpf) were exposed to one of three concentrations of SER (1, 10, 100 µg/L) for 6 days, respectively. Evaluated parameters included development, behavior, transcripts related to serotonin signaling, serotonin levels, and acetylcholinesterase activity. Accelerated hatching of zebrafish embryos was observed for those fish exposed to 100 µg/L SER at 54 hpf. Locomotor activity (e.g. distance moved and mobile cumulative duration) was significantly reduced in larval zebrafish following exposure to 10 and 100 µg/L SER. Conversely, larval fish showed increased dark-avoidance after exposure to 1-100 µg/L SER. Of the measured transcripts related to serotonin signaling, only serotonin transporter (serta) and serotonin receptor 2c (5-ht2c) mRNA levels were increased in fish in response to 10 µg/L SER treatment. However, serotonin levels were unaltered in larvae exposed to SER. There were no differences among groups in acetylcholinesterase activity at any concentration tested. Taking together, the results evidenced that exposure to SER alters behavioral responses in early-staged zebrafish, which may be related to the abnormal expression of 5-ht2c. This study elucidates molecular responses to SER and characterizes targets that may be sensitive to antidepressant pharmaceuticals in larval fish.


Asunto(s)
Antidepresivos/toxicidad , Conducta Animal/efectos de los fármacos , Sertralina/toxicidad , Contaminantes Químicos del Agua/toxicidad , Pez Cebra/fisiología , Animales , Antidepresivos/análisis , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/fisiología , Locomoción/efectos de los fármacos , Serotonina/metabolismo , Sertralina/análisis , Transducción de Señal/efectos de los fármacos , Contaminantes Químicos del Agua/análisis , Pez Cebra/crecimiento & desarrollo , Pez Cebra/metabolismo
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