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1.
Front Pharmacol ; 11: 584057, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33041827

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19) has affected millions of people worldwide. Critically ill COVID-19 patients develop viral septic syndrome, including inflammatory damage, immune dysfunction, and coagulation disorder. In this study, we investigated ShenFuHuang formula (SFH), a traditional Chinese medicine, which has been widely used as complementary therapy for clinical treatment of COVID-19 in Wuhan, to understand its pharmacological properties. Results of systems pharmacology identified 49 active compounds of SFH and their 69 potential targets, including GSK3ß, ESR1, PPARG, PTGS2, AKR1B10, and MAPK14. Network analysis illustrated that the targets of SFH may be involved in viral disease, bacterial infection/mycosis, and metabolic disease. Moreover, signaling pathway analysis showed that Toll-like receptors, MAPK, PPAR, VEGF, NOD-like receptor, and NF-kappa B signaling pathways are highly connected with the potential targets of SFH. We further employed multiple zebrafish models to confirm the pharmacological effects of SFH. Results showed that SFH treatment significantly inhibited the inflammatory damage by reducing the generation of neutrophils in Poly (I:C)-induced viral infection model. Moreover, SFH treatment could improve the phagocytosis of macrophages and enhance the expression of immune genes in an immune deficiency model. Furthermore, SFH treatment exhibited promising anti-thrombosis effect in a thrombus model. This study provided additional evidence of SFH formula for treating COVID-19 patients with septic syndrome using multiple-scale estimation.

2.
Eur J Gastroenterol Hepatol ; 32(9): 1256-1262, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32732809

RESUMO

Lupus enteritis and Crohn's disease are two common immune diseases involving the gastrointestinal tract. There are many similar clinical manifestations, therefore it is very difficult to distinguish between them. The digestive system is involved anywhere from 8 to 40% of patients with systemic lupus erythematosus (SLE) and up to 53% of these go on to develop lupus enteritis. In patients with Crohn's disease, 6-40% were presented with oral mucosa ulceration, nodular erythema of skin, arthritis, eye disease and other extraintestinal manifestations. The concomitant of Crohn's disease and SLE is extremely rare; however, here we described a case of concomitant Crohn's disease and SLE characterized by recurrent intestinal obstruction. A systematic literature review of lupus concomitant with Crohn's disease was then conducted.

3.
Front Pharmacol ; 11: 579, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32457609

RESUMO

Sepsis commonly leads to acute and long-term cognitive and affective impairments which are associated with increased mortality in patients. Neuroinflammation characterized by excessive cytokine release and immune cell activation underlies the behavioral changes associated with sepsis. We previously reported that the administration of a traditional Chinese herbal Qiang Xin 1 (QX1) formula improves survival in septic mice. This study was performed to better understand the effects and the mechanisms of QX1 formula treatment on behavioral changes in a preclinical septic model induced by cecal ligation and puncture. Oral administration of QX1 formula significantly improved survival, alleviated overall cognitive impairment and emotional dysfunction as assessed by the Morris water maze, novel object recognition testing, elevated plus maze and open field testing in septic mice. QX1 formula administration dramatically inhibited short and long-term excessive pro-inflammatory cytokine production both peripherally and centrally, and was accompanied by diminished microglial activation in septic mice. Biological processes including synaptic transmission, microglia cell activation, cytokine production, microglia cell polarization, as well as inflammatory responses related to signaling pathways including the MAPK signaling pathway and the NF-κB signaling pathway were altered prominently by QX1 formula treatment in the hippocampus of septic mice. In addition, QX1 formula administration decreased the expression of the M1 phenotype microglia gene markers such as Cd32, Socs3, and Cd68, while up-regulated M2 phenotype marker genes including Myc, Arg-1, and Cd206 as revealed by microarray analysis and Real-time PCR. In conclusion, QX1 formula administration attenuates cognitive deficits, emotional dysfunction, and reduces neuroinflammatory responses to improve survival in septic mice. Diminished microglial activation and altered microglial polarization are involved in the neuroprotective mechanism of QX1 formula.

4.
J Psychopharmacol ; 34(4): 478-489, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31909693

RESUMO

BACKGROUND: Identifying neural substrates that are differentially affected by drugs of abuse and natural rewards is key to finding a target for an efficacious treatment for substance abuse. Melanin-concentrating hormone is a polypeptide with an inhibitory effect on the mesolimbic dopamine system. Here we test the hypothesis that melanin-concentrating hormone in the lateral hypothalamus and nucleus accumbens shell is differentially involved in the regulation of morphine and food-rewarded behaviors. METHODS: Male Sprague-Dawley rats were trained with morphine (5.0 mg/kg, subcutaneously) or food pellets (standard chow, 10-14 g) to induce a conditioned place preference, immediately followed by extinction training. Melanin-concentrating hormone (1.0 µg/side) or saline was infused into the nucleus accumbens shell or lateral hypothalamus before the reinstatement primed by morphine or food, and locomotor activity was simultaneously monitored. As the comparison, melanin-concentrating hormone was also microinjected into the nucleus accumbens shell or lateral hypothalamus before the expression of food or morphine-induced conditioned place preference. RESULTS: Microinfusion of melanin-concentrating hormone into the nucleus accumbens shell (but not into the lateral hypothalamus) prevented the reinstatement of morphine conditioned place preference but had no effect on the reinstatement of food conditioned place preference. In contrast, microinfusion of melanin-concentrating hormone into the lateral hypothalamus (but not in the nucleus accumbens shell) inhibited the reinstatement of food conditioned place preference but had no effect on the reinstatement of morphine conditioned place preference. CONCLUSIONS: These results suggest a clear double dissociation of melanin-concentrating hormone in morphine/food rewarding behaviors and melanin-concentrating hormone in the nucleus accumbens shell. Melanin-concentrating hormone could be a potential target for therapeutic intervention for morphine abuse without affecting natural rewards.

5.
Stress ; 23(4): 393-404, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31814486

RESUMO

Though the relationship between traumatic stress and social behavior, which has been explored for years, is dynamic and largely estimated between dyads, little is known about the causal effects of traumatic stress exposure on the time-dependent dynamic alterations in the social behaviors on a large-group level. We thus investigated the effect of a single prolonged stress (SPS) exposure, a classical animal model that recapitulates posttraumatic stress disorder (PTSD)-like symptoms in rodents, on the spatiotemporal, social behavior changes within a large group of cohabiting rats. One-half of thirty-two Sprague-Dawley rats were assigned to the experimental group and subjected to SPS treatment administered two weeks after baseline social behavior recording; the other half served as the controls. Each group of rats (n = 16) was housed in one of two large custom-made cylinders. We used an automatic tracking system to record the behavioral indices of social behavior of the rats before SPS exposure, on the SPS exposure day, during a 7-day-long quiescent period after SPS treatment, as well as during subsequent behavioral test days. In addition to SPS-induced PTSD-like behaviors, SPS induced a time-dependent, oscillating change in active/passive social behaviors that lasted for 3 weeks. SPS treatment decreased active social behaviors (especially affiliative behaviors) but increased passive social behaviors (e.g. huddling) immediately following stress exposure. Increased active social interactions were observed during the early phase after SPS treatment; while increased passive social behaviors were observed during the late phase after SPS treatment. These dynamic changes were repeatedly observed when the rats underwent subsequent stressful behavioral tests and challenges. SPS induced a long-term, time-dependent oscillating change in indices of the social behavior. These changes may serve as an adaptive mechanism, and their manifestations critically depended on the time course following the traumatic stress exposure.

6.
Front Immunol ; 10: 1930, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474996

RESUMO

Sepsis is a life-threatening condition that often occurs in the intensive care unit. The excessive activation of the host's immune system at early stages contributes to multiple organ damage. Mitogen-activated protein kinase phosphatase-1 (MKP1) exerts an important effect on the inflammatory process. In our recent bioinformatic analysis, we confirmed that the inhibition of protein tyrosine phosphatase-1B (PTP1B) significantly promoted the expression of MKP1 in murine macrophages. However, the underlying mechanism and its effect on macrophage polarization remain unclear. In this study, we show that the suppression of PTP1B induced upregulation of MKP1 in M1 macrophages. A RayBiotech mouse inflammation antibody assay further revealed that MKP1-knockdown promoted pro-inflammatory cytokine (IL-1ß, IL12p70, IL-17, IL-21, IL-23, and TNF-α) secretion but suppressed anti-proinflammatory cytokine (IL-10) production in M2 macrophages. Phospho-proteomics analysis further identified ERK1/2 and p38 as downstream molecules of MKP1. Moreover, we found that the inhibition of PTP1B lowered the expression of miR-26a, showing a negative correlation with MKP1 protein expression. Thus, we concluded that the inhibition of PTP1B contributes to M2 macrophage polarization via reducing mir-26a and afterwards enhancing MKP1 expression in murine macrophages.


Assuntos
Fosfatase 1 de Especificidade Dupla/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , MicroRNAs/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/imunologia , Animais , Citocinas/imunologia , Citocinas/metabolismo , Fosfatase 1 de Especificidade Dupla/genética , Fosfatase 1 de Especificidade Dupla/metabolismo , Humanos , Interleucina-10/imunologia , Interleucina-10/metabolismo , Ativação de Macrófagos/genética , Macrófagos/classificação , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Células RAW 264.7 , Interferência de RNA , Transdução de Sinais/genética , Transdução de Sinais/imunologia
7.
Psychopharmacology (Berl) ; 236(11): 3197-3208, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31297566

RESUMO

BACKGROUND: Negative affective states, e.g., anhedonia, may be linked to the long-lasting motivational processes associated with relapse. Here, this study investigated whether, and how, anhedonic states are influenced by stressful events that contribute to craving and relapse. METHODS: All male rats were pretreated with a binge-like morphine paradigm for five days. After 12 to 16 days of withdrawal, rats were subjected to a one-hour free consumption test or three operant tasks with increasing cost/benefit ratio, i.e., fixed ratio 1 (FR1), progressive ratio (PR), and PR-punishment procedure of reinforcement, with sucrose solutions of three concentrations (4%, 15%, and 60%) as rewards. The consumption and operant responses under FR1 and PR procedures were measured following exposure to acute foot-shock stress (intermittent foot shock, 0.5 mA × 0.5 s × 10 min; mean intershock interval, 40 s), and the operant responses for 60% sucrose solution under PR-punishment procedure was measured following a forced-swim stress (5 minutes). RESULT: Foot-shock stress increased water consumption in a subpopulation of rats and decreased consumption of sucrose solutions, while it did not influence the operant responses for sucrose solutions under either FR1 or PR procedure. The forced-swim stress reduced operant responses for 60% sucrose solution under PR-punishment procedure, but did not influence responding for 60% sucrose solution under PR procedure. In addition, the forced-swim stress also elevated anxiety level of rats in an open area test. CONCLUSIONS: Acute stress induced hedonic but not motivational deficit for sucrose reward in protracted drug-abstinent animals. Additional negative emotional states besides anhedonia were evoked by acute stress.


Assuntos
Morfina/administração & dosagem , Morfina/efeitos adversos , Motivação/fisiologia , Estresse Psicológico/psicologia , Síndrome de Abstinência a Substâncias/psicologia , Sacarose/administração & dosagem , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Masculino , Motivação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Autoadministração , Fatores de Tempo
8.
J Vis Exp ; (144)2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30855583

RESUMO

The present protocol describes a novel conflict task as a model of inhibitory control in rats. In this model, a natural rewarding stimulus (sexual stimulus) that represents a high-value reward, and the aversive stimuli (pins), are concurrently presented. The male rats have to climb or jump over the obstacle full of pins to approach and investigate the sexual partner. If the animal persists in their approaching behavior regardless of the aversive stimuli, it is considered as a maladaptive or risky reward-seeking behavior. The conflict task permits the evaluation of deficit in inhibitory control resulting from exposure to abused drug, such as morphine, or a stressful event. The main advantage of this model is that it provides a simple and quick way to discover the deficit in inhibitory control after exposure to opiate drugs or other stressful events. In addition to opiates, this behavioral model would also be useful for quickly discovering the inhibitory control deficits induced by other addictive drugs. However, the limitation is that the male rats' performance may be subject to exercising effects with repeated testing under this conflict task. In the future, one can hope that the individuals with the compulsive phenotype of reward-seeking behavior after exposure to opiates will be identified based on modifying this conflict model.


Assuntos
Comportamento Animal/fisiologia , Conflito Psicológico , Recompensa , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , Modelos Psicológicos , Morfina/farmacologia , Ratos
9.
Chin J Integr Med ; 24(4): 278-283, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29264841

RESUMO

OBJECTIVE: To observe the effect of norcantharidin (NCTD) on collagen-induced arthritis (CIA) rats. METHODS: Sixty Sprague-Dawley(SD) rats were randomly divided into 6 groups (n=10): normal group, CIA model group(model group), NCTD low-dose group [1.35 mg/(kg•d)], NCTD middle-dose group [2.7 mg/(kg•d)], NCTD high-dose group [5.4 mg/(kg•d)] and methotrexate (MTX) group [1.8 mg/(kg/w)]. Anesthetized rats were sacrificed by luxation of cervical vertebra after 4 weeks of administration. The arthritis scores were evaluated twice a week. The pathological changes in the ankle joints of rats were observed by hematoxylin-eosin (H&E) staining. The serum levels of interleukin (IL) 1ß, IL-6, tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), IL-17 and transform growth factor (TGF) ß were detected by enzyme linked immunosorbent assay (ELISA). The mRNA expression of retinoid-related orphan nuclear receptorγt (RORγt) and forkhead box P3 (Foxp3) in peripheral blood lymphocytes were confirmed by real-time polymerase chain reaction. RESULTS: MTX and high-dose NCTD not only decreased the arthritis scores but also alleviated the pathological changes in CIA rats' ankle joints compared with the model group (P<0.05 or P<0.01). All doses of NCTD significantly inhibited the serum levels of IL-6, IL-17 and TNF-α in CIA rats (P<0.05). Only middle- and high-dose of NCTD prominently decreased serum IL-1ß and TGF-ß levels of CIA rats (P<0.05). However, NCTD has no effect on vascular endothelial growth factor (VEGF) level in CIA rats. The Foxp3 mRNA expression in all NCTD groups were increased significantly than in the model group (P<0.05). The mRNA expression of RORγt in NCTD high-dose group was decreased apparently in comparison with the model group (P<0.05). CONCLUSIONS: NCTD showed therapeutic effect on CIA rats by inhibition of cytokines and regulation of Th17/Treg cells.


Assuntos
Artrite Experimental/tratamento farmacológico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Animais , Artrite Experimental/sangue , Artrite Experimental/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Citocinas/sangue , Fatores de Transcrição Forkhead/metabolismo , Articulações/efeitos dos fármacos , Articulações/patologia , Masculino , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley
10.
Psychopharmacology (Berl) ; 234(11): 1693-1702, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28280885

RESUMO

RATIONALE: Negative affective states, e.g., anhedonia, are suggested to be involved in the long-lasting motivational processes associated with relapse. Here, we investigated whether anhedonic behaviors could be elicited by an acute stress after protracted abstinence from morphine. OBJECTIVES: The behavioral responses to natural stimuli following exposure to an acute stress were examined after 14 days of withdrawal from morphine. Male rats were pretreated with either a binge-like morphine regimen or daily saline injections for 5 days. The motivation for two natural stimuli, i.e., a social stimulus (male rat) and a sexual stimulus (estrous female rat), was measured, following exposure to an acute stress (intermittent foot shock, 0.5 mA * 0.5 s * 10 min; mean inter-shock interval 40 s), under three conditions: free approach and effort- and conflict-based approaches. RESULTS: Foot-shock-induced stress did not influence free-approach behavior (sniffing time) towards the social or sexual stimulus. However, in the effort-based approach task, the stressed morphine-withdrawn rats demonstrated an attenuated motivation to climb over a partition to approach the social stimulus while the stressed saline-pretreated rats showed an increased motivation to approach the social stimulus. When an aversive stimulus (pins) was introduced in order to induce an approach-avoidance conflict, both drug-withdrawn and drug-naïve groups exhibited a bimodal distribution of approach behavior towards the sexual stimulus after the stress was introduced, i.e., the majority of rats had low risky appetitive behaviors but a minority of them showed rather highly "risky" approach behavior. CONCLUSIONS: The acute stress induces differential motivational deficits for social and sexual rewards in protracted drug-abstinent rats.


Assuntos
Comportamento Apetitivo/fisiologia , Relações Interpessoais , Morfina/administração & dosagem , Comportamento Sexual Animal/fisiologia , Estresse Psicológico/psicologia , Síndrome de Abstinência a Substâncias/psicologia , Animais , Comportamento Apetitivo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Masculino , Dependência de Morfina/psicologia , Ratos , Comportamento Sexual Animal/efeitos dos fármacos , Fatores de Tempo
11.
Psychopharmacology (Berl) ; 234(8): 1277-1292, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28229178

RESUMO

RATIONALE: The negative affective state, e.g., anhedonia, emerges after abstinence from abused drugs may be linked to the motivational processes of drug craving and relapse. Although anhedonia diminishes over time with drug abstinence, it is not yet rather explicit whether anhedonia exists or not following protracted withdrawal. OBJECTIVES: The behavioral responses to natural rewards were examined after 2 to 3 weeks withdrawal from morphine. Male rats were pretreated with either a binge-like morphine paradigm or daily saline injection for 5 days. The consummatory and motivational behaviors for three natural rewards (sucrose solutions 4, 15, and 60%, social stimulus: male rat, and sexual stimulus: estrous female rat) were examined under varied testing conditions. RESULTS: The morphine-withdrawn rats significantly increased their intake of 15% sucrose solution during the 1-h consumption test and their operant responding for 15% sucrose solution under a progressive ratio (PR) schedule of reinforcement. When obtaining a reinforcer was associated with a 0.5 mA foot shock under a PR-punishment schedule, the morphine-withdrawn rats showed a higher performance for 60% sucrose solution. Meanwhile, the morphine-withdrawn rats displayed a higher motivation to sexual stimulus during the free-approach test and more approaching behaviors towards sexual stimulus in a conflict-based approach test (concurrent presence of reward and aversive stimulus). CONCLUSIONS: No anhedonia-like behavior but sensitized behaviors for natural rewards were found after long-term morphine withdrawal. Notably, the morphine-withdrawn rats displayed persistent motivated behaviors for high-value rewards (60% sucrose and sexual stimulus) in the conflict tests suggesting impairments in inhibitory control in morphine-treated rats.


Assuntos
Anedonia/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Dependência de Morfina/psicologia , Motivação/efeitos dos fármacos , Recompensa , Síndrome de Abstinência a Substâncias/psicologia , Animais , Comportamento Alimentar/efeitos dos fármacos , Feminino , Masculino , Morfina/efeitos adversos , Ratos , Ratos Sprague-Dawley , Sacarose/farmacologia
12.
PLoS One ; 10(8): e0133327, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26247203

RESUMO

Nicotinic acetylcholine receptors (nAChRs) play an important role in regulating appetite and have been shown to do so by influencing neural activity in the hypothalamus. To shed light on the hypothalamic circuits governing acetylcholine's (ACh) regulation of appetite this study investigated the influence of hypothalamic nAChRs expressing the α4 subunit. We found that antagonizing the α4ß2 nAChR locally in the lateral hypothalamus with di-hydro-ß-erythroidine (DHßE), an α4 nAChR antagonist with moderate affinity, caused an increase in food intake following free access to food after a 12 hour fast, compared to saline-infused animals. Immunocytochemical analysis revealed that orexin/hypocretin (HO), oxytocin, and tyrosine hydroxylase (TH)-containing neurons in the A13 and A12 of the hypothalamus expressed the nAChR α4 subunit in varying amounts (34%, 42%, 50%, and 51%, respectively) whereas melanin concentrating hormone (MCH) neurons did not, suggesting that DHßE-mediated increases in food intake may be due to a direct activation of specific hypothalamic circuits. Systemic DHßE (2 mg/kg) administration similarly increased food intake following a 12 hour fast. In these animals a subpopulation of orexin/hypocretin neurons showed elevated activity compared to control animals and MCH neuronal activity was overall lower as measured by expression of the immediate early gene marker for neuronal activity cFos. However, oxytocin neurons in the paraventricular hypothalamus and TH-containing neurons in the A13 and A12 did not show differential activity patterns. These results indicate that various neurochemically distinct hypothalamic populations are under the influence of α4ß2 nAChRs and that cholinergic inputs to the lateral hypothalamus can affect satiety signals through activation of local α4ß2 nAChR-mediated transmission.


Assuntos
Ingestão de Alimentos/fisiologia , Hipotálamo/metabolismo , Atividade Motora/fisiologia , Neurônios/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Di-Hidro-beta-Eritroidina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Neurônios/efeitos dos fármacos , Antagonistas Nicotínicos/farmacologia , Orexinas/metabolismo , Ocitocina/metabolismo , Ratos , Ratos Wistar , Tirosina 3-Mono-Oxigenase/metabolismo
13.
Pharmacol Biochem Behav ; 133: 43-50, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25818040

RESUMO

The return of fear is an important issue in anxiety disorder research. Each time a fear memory is reactivated, it may further strengthen overactivation of the fear circuit, which may contribute to long-term maintenance of the fear memory. Recent evidence indicates that glucocorticoids may help attenuate pathological fear, but its role in the return of fear is unclear. In the present study, systemic corticosterone (CORT; 25mg/kg) administration 1h after fear conditioning did not impair the consolidation process but significantly suppressed the return of fear evoked by a subthreshold conditioning (SC) procedure and elevated platform (EP) stress. Compared with the SC-induced return of fear, acute stress-induced return was state-dependent. In addition, post-training CORT treatment increased the adrenocorticotropic response after EP stress, which indicates that the drug-induced suppression of the return of fear may possibly derive from its regulation effect of the hypothalamic-pituitary-adrenal axis reactivity to stress. These results suggest that post-training CORT administration may help inhibit the return of fear evoked by EP or SC stress. The possible mechanisms involved in the high-dose CORT-induced suppression of the SC- and EP-induced return of fear are discussed.


Assuntos
Condicionamento Clássico/efeitos dos fármacos , Corticosterona/farmacologia , Medo/efeitos dos fármacos , Estresse Psicológico/psicologia , Hormônio Adrenocorticotrópico/sangue , Animais , Corticosterona/sangue , Extinção Psicológica/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
14.
Pharmacol Biochem Behav ; 124: 188-95, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24933336

RESUMO

Exposure therapy is widely used to treat anxiety disorders, including posttraumatic stress disorder (PTSD). However, preventing the return of fear is still a major challenge after this behavioral treatment. An increasing number of studies suggest that high-dose glucocorticoid treatment immediately after trauma can alleviate the symptoms of PTSD in humans. Unknown is whether high-dose glucocorticoid treatment following fear conditioning suppresses the return of fear. In the present study, a typical fear renewal paradigm (AAB) was used, in which the fear response to an auditory cue can be restored in a novel context (context B) when both training and extinction occur in the same context (context A). We trained rats for auditory fear conditioning and administered corticosterone (CORT; 5 and 25mg/kg, i.p.) or vehicle with different delays (1 and 24h). Forty-eight hours after drug injection, extinction was conducted with no drug in the training context, followed by a test of tone-induced freezing behavior in the same (AAA) or a shifted (AAB) context. Both immediate and delayed administration of high-dose CORT after fear conditioning reduced fear renewal. To examine the anxiolytic effect of CORT, independent rats were trained for cued or contextual fear conditioning, followed by an injection of CORT (5 and 25mg/kg, i.p.) or vehicle at a 1 or 24h delay. One week later, anxiety-like behavior was assessed in the elevated plus maze (EPM) before and after fear expression. We found that high-dose CORT decreased anxiety-like behavior without changing tone- or context-induced freezing. These findings indicate that a single high-dose CORT administration given after fear conditioning may selectively suppress fear renewal by reducing anxiety-like behavior and not by altering the consolidation, retrieval, or extinction of fear memory.


Assuntos
Ansiedade , Condicionamento Clássico , Corticosterona/administração & dosagem , Medo , Animais , Comportamento Animal , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Sprague-Dawley
15.
Front Behav Neurosci ; 8: 23, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24550799

RESUMO

The anhedonia-like behaviors following about 1-week withdrawal from morphine were examined in the present study. Male rats were pretreated with either a binge-like morphine paradigm or daily saline injection for 5 days. Three types of natural reward were used, food reward (2.5, 4, 15, 30, 40, and 60% sucrose solutions), social reward (male rat) and sexual reward (estrous female rat). For each type of natural stimulus, consummatory behavior and motivational behaviors under varied testing conditions were investigated. The results showed that the morphine-treated rats significantly reduced their consumption of 2.5% sucrose solution during the 1-h consumption testing and their operant responding for 15, 30, and 40% sucrose solutions under a fixed ratio 1 (FR1) schedule. However, performance under a progressive ratio (PR) schedule increased in morphine-treated rats reinforced with 60% sucrose solution, but not in those reinforced with sucrose concentrations lower than 60%. Pretreatment with morphine significantly decreased the male rats' ejaculation frequency (EF) during the 1-h copulation testing, and impaired the maintenance of appetitive motivations to sexual and social stimuli under a free-approach condition. Moreover, the morphine-treated rats demonstrated a diminished motivation to approach social stimulus in the effort-based appetitive behavior test but showed a remarkable increase in motivation to approach sexual stimulus in the risky appetitive behavior test. These results demonstrated some complex motivated behaviors following about 1 week of morphine withdrawal: (1) The anhedonia-like behavior was consistently found in animals withdrawn from morphine. However, for a given reward, there was often a dissociation of the consummatory behaviors from the motivational behaviors, and whether the consummatory or the motivational anhedonia-like behaviors could be discovered heavily depended on the type and magnitude of the reward and the type of testing task; (2) These anhedonia-like behaviors coexisted with a craving for the high-incentive reward which was evidenced by the increased PR performance for the 60% sucrose solution and the heightened risky appetitive behavior for the sexual stimulus. The craving for the high-incentive reward alongside with the impaired inhibitory control in drug-withdrawn subjects might form one of psychological mechanisms underlying drug relapse after withdrawal.

16.
Psych J ; 3(3): 201-13, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26271938

RESUMO

Fear extinction decreases conditioned fear responses that normally occur when a conditioned stimulus (CS) is repeatedly presented in the absence of an aversive unconditioned stimulus (US), which is the behavioral basis of exposure therapy for posttraumatic stress disorder (PTSD). However, knowledge about the neurobiology of extinction is insufficient. The present study investigated changes in the protein expression of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the dorsal hippocampus (DH)and ventral hippocampus (VH), induced by extinction and return of conditioned fear responses to an auditory signal. Western blot analysis indicated that shock stress enhanced the expression of MRs in only the DH, whereas extinction selectively increased the expression of MRs in the VH. The infusion of MRs antagonist spironolactone in the VH indicated that MRs in the VH did not affect the retrieval of fear and extinction memories, but facilitated the formation of extinction memory. However, no changes in GRs in either the DH or VH were observed in each phase of auditory fear conditioning. These results suggest that MRs in the DH and VH have differential functions in the extinction of auditory fear conditioning. MRs in the DH appear to be related to only stressful experiences, whereas MRs in the VH are involved in extinction formation. The enhancement of MRs in the VH might be necessary to improve PTSD.

18.
Eur J Pharmacol ; 702(1-3): 294-301, 2013 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-23396226

RESUMO

Escalation of drug consumption is involved in the transition from drug use to addiction. Our previous study demonstrated that neuronal activation in ventral tegmental area (VTA) and substantia nigra (SN) was associated with behavioral sensitization induced by increasing doses of morphine. Here we sought to characterize the molecular mechanism underlying this behavioral sensitization. We compared mitogen-activated protein kinase (MAPK) signaling following pretreatment with either increasing doses or fixed doses of morphine before and after behavioral sensitization. We found phospho-MAPK markedly increased in ventral striatum and decreased in dorsal striatum after either pretreatment group, but no further change after sensitization induced by 10mg/kg morphine challenge. Furthermore, we also evaluated the level of phospho-glutamate receptor 1 at serine 845 (pSer845-GluA1) and 831 (pSer831-GluA1) sites in ventral striatum and dorsal striatum. The results showed a significant increase in pSer845-GluA1/GluA1 ratio in ventral striatum but not dorsal striatum after pretreatment with increasing doses of morphine but not after fixed-dose or saline pretreatment. Importantly, pSer845-GluA1/GluA1 ratio was increased exclusively in dorsal striatum and not ventral striatum following acute morphine challenge specifically paired with increasing-dose pretreatment and not fixed-dose or saline. These findings indicate that behavioral sensitization-induced by chronic pretreatment with increasing doses of morphine might be more closely associated with the dynamic GluA1 activity in the striatum rather than the modulation of MAPK signaling. These findings also indicate that GluA1 phosphorylation may occur independent of MAPK activation.


Assuntos
Analgésicos Opioides/administração & dosagem , Corpo Estriado/efeitos dos fármacos , Morfina/administração & dosagem , Receptores de AMPA/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/metabolismo , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Atividade Motora/efeitos dos fármacos , Fosforilação , Ratos , Ratos Sprague-Dawley
19.
Psych J ; 2(1): 1-10, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26272859

RESUMO

Accumulating evidence suggests that stress-dose corticosteroids impair fear memory in animals and humans. Corticosteroid treatment after critical illness is seen as a potential psychotropic medication by which to prevent posttraumatic stress disorder. However, individual difference in the responsiveness to stress (i.e., stress reactivity) is a factor that modulates the efficacy of corticosteroids. To understand the contribution of fear reactivity to the effect of post-stress corticosterone, male Sprague-Dawley rats were subjected to classical tone-cued fear conditioning and separated into high and low reactivity (HR and LR, respectively) responder groups based on their levels of freezing during conditioning. The HR rats showed significantly higher fear responses than the LR rats during conditioning as assessed by freezing behavior. At two intervals, 30 min and 48 hr later, the HR rats still displayed more pronounced conditioned responses to cued stimuli compared with the LR rats. Moreover, in contrast to the LR rats, the enhanced fear response in the HR rats was difficult to attenuate by post-training high-dose corticosterone. These results suggest that fear reactivity results in stronger fear memory, and that it is difficult to disrupt this strong fear memory in the HR phenotype using monotherapy. However, the strong fear memory in the HR rats was impaired by concurrent intramedial prefrontal cortex infusion of a high dose of the dopamine D1 receptor antagonist SCH 23390 and systemic administration of corticosterone. SCH 23390 and corticosterone alone did not decrease freezing levels in the HR rats. The fear impairment induced by SCH 23390 combined with corticosterone was not attributable to the effect of these drugs on locomotor activity. This effect was not found with administration of the D2 antagonist eticlopride combined with corticosterone. Our findings demonstrate that the conditioned fear memory in individuals with high stress reactivity is difficult to disrupt using monotherapy, but that combined pharmacotherapy may be useful for treating intervention-resistant fear.

20.
Chin Med J (Engl) ; 125(12): 2235-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22884160

RESUMO

A 16-year-old female patient with systemic lupus erythematosus (SLE) presented with abdominal pain and oliguria, after one month of hospital treatment with methylprednisolone and cyclophosphamide. Computed tomography of the abdomen revealed the calcification of bilateral superior segmental ureteral wall. Computed tomography urography revealed stenosis of bilateral ureters. This calcification may be associated with lupus-induced inflammatory reaction of ureteral endomembrane. By receiving the ureteral catheters, her abdominal pain and oliguria had been completely resolved. After discharge, she underwent the surgery of cutaneous ureterostomy in the local hospital. During two years follow-up, her condition is stable without any symptom of the urinary system.


Assuntos
Calcinose/diagnóstico , Lúpus Eritematoso Sistêmico/complicações , Ureter/patologia , Adolescente , Calcinose/etiologia , Feminino , Humanos
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