RESUMO
INTRODUCTION: Mesenteric lymph nodes (MLNs) are central in immune anatomy. MLNs are associated with the composition of gut microbiota, affecting the central system and immune system. Gut microbiota was found to differ among individuals of different social hierarchies. Nowadays, excision of MLNs is more frequently involved in gastrointestinal surgery; however, the potential side effects of excision of MLNs on social dominance are still unknown. METHODS: MLNs were removed from male mice (7-8 weeks old). Four weeks after MLN removal, social dominance test was performed to investigate social dominance; hippocampal and serum interleukin (IL)-1ß, IL-10, and tumor necrosis factor-alpha (TNF-α) were investigated; and histopathology was used to evaluate local inflammation of the ileum. The composition of the gut microbiota was then examined to understand the possible mechanism, and finally intraperitoneal injection of IL-10 was used to validate the effect of IL-10 on social dominance. RESULTS: There was a decrease in social dominance in the operation group compared to the control group, as well as a decrease in serum and hippocampal IL-10 levels, but no difference in serum and hippocampal IL-1ß and TNF-α levels, and no local inflammation of the ileum after MLN removal. 16S rRNA sequencing analysis showed that the relative abundance of the class Clostridia was decreased in the operation group. This decrease was positively associated with serum IL-10 levels. Furthermore, intraperitoneal injection of IL-10 in a subset of mice increased social dominance. CONCLUSIONS: Our findings suggested that MLNs contributed to maintaining social dominance, which might be associated with reduced IL-10 and the imbalance of specific flora in gut microbiota.
Assuntos
Microbioma Gastrointestinal , Interleucina-10 , Camundongos , Masculino , Animais , Fator de Necrose Tumoral alfa , RNA Ribossômico 16S/genética , Linfonodos , InflamaçãoRESUMO
Major depressive disorder (MDD) is one of the most debilitating and severe mental diseases globally. Increasing evidence has shown that epigenetics is critical for understanding brain function and brain disorders, including MDD. N-acetyltransferase 10 (NAT10), acting on histones, mRNA and other substrates, has been reported to be involved in epigenetic events, including histone acetylation and mRNA modifications. NAT10 is highly expressed in the brain. However, the potential effects of NAT10 on MDD are still unknown. Here, we exploited chronic mild stress (CMS) to induce anxiety- and depression-like behaviors in mice and found that the expression of NAT10 in the mouse hippocampus was upregulated after CMS treatment. Inhibition of NAT10 by pharmacological methods produced anxiolytic- and antidepressant-like effects. Neuron-specific overexpression of NAT10 in the hippocampus resulted in anxiety- and depression-like behaviors, accompanied by higher SIRT1 protein levels, and lower dendritic spine densities. Overall, it was found that elevation of NAT10 in hippocampal neurons is involved in the occurrence of anxiety- and depression-like behaviors, suggesting that NAT10 could be a potential new target for developing anxiolytics and antidepressants.
Assuntos
Depressão , Transtorno Depressivo Maior , Acetiltransferases/metabolismo , Acetiltransferases/farmacologia , Acetiltransferases/uso terapêutico , Animais , Antidepressivos/uso terapêutico , Ansiedade , Depressão/tratamento farmacológico , Depressão/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Hipocampo/metabolismo , Camundongos , Neurônios/metabolismo , RNA Mensageiro/metabolismo , Estresse Psicológico/metabolismoRESUMO
The inability to successfully adapt to stress produces pathological changes that can lead to depression. Molecular hydrogen has anti-oxidative and anti-inflammatory activities and neuroprotective effects. However, the potential role of molecular hydrogen in stress-related disorders is still poorly understood. The present study aims to investigate the effects of hydrogen gas on resilience to stress in mice. The results showed that repeated inhalation of hydrogen-oxygen mixed gas [67%:33% (V/V)] significantly decreased both the acute and chronic stress-induced depressive- and anxiety-like behaviors of mice, assessed by tail suspension test (TST), forced swimming test (FST), novelty suppressed feeding (NSF) test, and open field test (OFT). ELISA analyses showed that inhalation of hydrogen-oxygen mixed gas blocked CMS-induced increase in the serum levels of corticosterone, adrenocorticotropic hormone, interleukin-6, and tumor necrosis factor-α in mice exposed to chronic mild stress. Finally, inhalation of hydrogen gas in adolescence significantly increased the resilience to acute stress in early adulthood, which illustrates the long-lasting effects of hydrogen on stress resilience in mice. This was likely mediated by inhibiting the hypothalamic-pituitary-adrenal axis and inflammatory responses to stress. These results warrant further exploration for developing molecular hydrogen as a novel strategy to prevent the occurrence of stress-related disorders.
Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Gases/administração & dosagem , Hidrogênio/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Estresse Fisiológico/efeitos dos fármacos , Administração por Inalação , Animais , Comportamento Animal , Análise Química do Sangue , CamundongosRESUMO
Neuropeptides play important roles in modulating the rewarding value of abused drugs. Trefoil factor 3 (TFF3) was recently reported to modulate withdrawal syndrome of morphine, but the effects of TFF3 on the cocaine-induced behavioral changes are still elusive. In the present study, cocaine-induced hyperlocomotion and conditioned place preference (CPP) rat paradigms were provided to investigate the role of TFF3 in the reward response to cocaine. High-performance liquid chromatography (HPLC) analysis was used to analyse the dopamine concentration. The results showed that systemic TFF3 administration (0.1 mg/kg i.p.) significantly augmented cocaine- induced hyperlocomotion and CPP formation, without any effects on locomotor activity and aversive or rewarding effects per se. TFF3 significantly augmented the increment of the dopamine concentration in the NAc and the activity of the mTOR signalling pathway induced by acute cocaine exposure (10 mg/kg, i.p.) in the NAc shell, but not the core. The Intra-NAc shell infusion of rapamycin blocked TFF3-induced hyperactivity in cocaine-treatment rats. These findings indicated that TFF3 could potentiate behavioural response to cocaine, which may be associated with regulating dopamine concentration. Furthermore, the findings indicated that mTOR signalling pathway in the NAc shell is important for TFF3-induced enhancement on the cocaine-induced behavioral changes.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cocaína/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fator Trefoil-3/farmacologia , Animais , Cromatografia Líquida de Alta Pressão , Dopamina/análise , Humanos , Locomoção/efeitos dos fármacos , Masculino , Núcleo Accumbens/metabolismo , Núcleo Accumbens/patologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacologia , Fator Trefoil-3/genética , Fator Trefoil-3/metabolismoRESUMO
Histone modifications have been implicated in learning and memory. Our previous transcriptome data showed that expression of sirtuins 6 (SIRT6), a member of Histone deacetylases (HDACs) family in the hippocampal cornu ammonis 1 (CA1) was decreased after contextual fear conditioning. However, the role of SIRT6 in the formation of memory is still elusive. In the present study, we found that contextual fear conditioning inhibited translational expression of SIRT6 in the CA1. Microinfusion of lentiviral vector-expressing SIRT6 into theCA1 region selectively enhanced the expression of SIRT6 and impaired the formation of long-term contextual fear memory without affecting short-term fear memory. The overexpression of SIRT6 in the CA1 had no effect on anxiety-like behaviors or locomotor activity. Also, we also found that SIRT6 overexpression significantly inhibited the expression of insulin-like factor 2 (IGF2) and amounts of proteins and/or phosphoproteins (e.g. Akt, pAkt, mTOR and p-mTOR) related to the IGF2 signal pathway in the CA1. These results demonstrate that the overexpression of SIRT6 in the CA1 impaired the formation of long-term fear memory, and SIRT6 in the CA1 may negatively modulate the formation of contextual fear memory via inhibiting the IGF signaling pathway.
Assuntos
Região CA1 Hipocampal/metabolismo , Medo , Expressão Gênica , Memória de Longo Prazo , Sirtuínas/genética , Animais , Ansiedade , Comportamento Animal , Condicionamento Psicológico , Perfilação da Expressão Gênica , Técnicas de Transferência de Genes , Masculino , Atividade Motora , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais , Sirtuínas/metabolismo , Somatomedinas/metabolismo , Transdução GenéticaRESUMO
Drug addiction is considered an aberrant form of learning, and drug-associated memories evoked by the presence of associated stimuli (drug context or drug-related cues) contribute to recurrent craving and reinstatement. Epigenetic changes mediated by DNA methyltransferase (DNMT) have been implicated in the reconsolidation of fear memory. Here, we investigated the role of DNMT activity in the reconsolidation of cocaine-associated memories. Rats were trained over 10 days to intravenously self-administer cocaine by nosepokes. Each injection was paired with a light/tone conditioned stimulus (CS). After acquisition of stable self-administration behaviour, rats underwent nosepoke extinction (10 d) followed by cue-induced reactivation and subsequent cue-induced and cocaine-priming + cue-induced reinstatement tests or subsequently tested to assess the strength of the cocaine-associated cue as a conditioned reinforcer to drive cocaine seeking behaviour. Bilateral intra-basolateral amygdala (BLA) infusion of the DNMT inhibitor5-azacytidine (5-AZA, 1 µg per side) immediately following reactivation decreased subsequent reinstatement induced by cues or cocaine priming as well as cue-maintained cocaine-seeking behaviour. In contrast, delayed intra-BLA infusion of 5-AZA 6 h after reactivation or 5-AZA infusion without reactivation had no effect on subsequent cue-induced reinstatement. These findings indicate that memory reconsolidation for a cocaine-paired stimulus depends critically on DNMT activity in the BLA.
Assuntos
Complexo Nuclear Basolateral da Amígdala/enzimologia , Cocaína/farmacologia , DNA (Citosina-5-)-Metiltransferases/metabolismo , Memória/efeitos dos fármacos , Animais , Azacitidina/farmacologia , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Masculino , Ratos Sprague-Dawley , Reforço PsicológicoRESUMO
We recently reported that a conditioned stimulus (CS) memory retrieval-extinction procedure decreases reinstatement of cocaine and heroin seeking in rats and heroin craving in humans. Here we show that non-contingent cocaine or methylphenidate injections (UCS retrieval) 1 h before the extinction sessions decreases cocaine-priming-induced reinstatement, spontaneous recovery, and renewal of cocaine seeking in rats. Unlike the CS-based memory retrieval-extinction procedure, the UCS memory retrieval manipulation decreases renewal and reinstatement of cocaine seeking in the presence of cocaine cues that were not present during extinction training and also decreases cocaine seeking when the procedure commences after 28 days of abstinence. The inhibitory effect of the UCS retrieval manipulation on cocaine-priming-induced reinstatement is mediated by regulation of AMPA-receptor endocytosis in the basolateral amygdala. The UCS memory retrieval-extinction procedure has superior relapse prevention characteristics than the CS memory retrieval-extinction procedure and could be a promising method for decreasing relapse in human addicts.
Assuntos
Complexo Nuclear Basolateral da Amígdala/metabolismo , Comportamento Animal/fisiologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Cocaína/administração & dosagem , Comportamento de Procura de Droga/fisiologia , Extinção Psicológica/fisiologia , Inibição Psicológica , Rememoração Mental/fisiologia , Metilfenidato/administração & dosagem , Receptores de AMPA/metabolismo , Animais , Condicionamento Psicológico/fisiologia , Sinais (Psicologia) , Endocitose/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Recidiva , AutoadministraçãoRESUMO
Fear extinction forms a new memory but does not erase the original fear memory. Exposure to novelty facilitates transfer of short-term extinction memory to long-lasting memory. However, the underlying cellular and molecular mechanisms are still unclear. Using a classical contextual fear-conditioning model, we investigated the effect of novelty on long-lasting extinction memory in rats. We found that exposure to a novel environment but not familiar environment 1 h before or after extinction enhanced extinction long-term memory (LTM) and reduced fear reinstatement. However, exploring novelty 6 h before or after extinction had no such effect. Infusion of the ß-adrenergic receptor (ßAR) inhibitor propranolol and glucocorticoid receptor (GR) inhibitor RU486 into the CA1 area of the dorsal hippocampus before novelty exposure blocked the effect of novelty on extinction memory. Propranolol prevented activation of the hippocampal PKA-CREB pathway, and RU486 prevented activation of the hippocampal extracellular signal-regulated kinase 1/2 (Erk1/2)-CREB pathway induced by novelty exposure. These results indicate that the hippocampal ßAR-PKA-CREB and GR-Erk1/2-CREB pathways mediate the extinction-enhancing effect of novelty exposure. Infusion of RU486 or the Erk1/2 inhibitor U0126, but not propranolol or the PKA inhibitor Rp-cAMPS, into the CA1 before extinction disrupted the formation of extinction LTM, suggesting that hippocampal GR and Erk1/2 but not ßAR or PKA play critical roles in this process. These results indicate that novelty promotes extinction memory via hippocampal ßAR- and GR-dependent pathways, and Erk1/2 may serve as a behavioral tag of extinction.
Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Hipocampo/fisiologia , Receptores Adrenérgicos beta/fisiologia , Receptores de Glucocorticoides/fisiologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/antagonistas & inibidoresRESUMO
Maladaptive memories elicited by exposure to environmental stimuli associated with drugs of abuse are often responsible for relapse among addicts. Interference with the reconsolidation of drug memory can inhibit drug seeking. Previous studies have indicated that the dephosphorylation of the eukaryotic initiation factor 2 α-subunit (eIF2α) plays an important role in synaptic plasticity and long-term memory consolidation, but its role in the reconsolidation of drug memory remains unknown. The amygdala is required for the reconsolidation of a destabilized drug memory after retrieval of drug-paired stimuli. Here, we used conditioned place preference (CPP) and self-administration procedures to determine whether amygdala eIF2α dephosphorylation is required for the reconsolidation of morphine and cocaine memories in rats. We found that the levels of eIF2α phosphorylation (Ser51) and activating transcription factor 4 (ATF4) were decreased after reexposure to a previously morphine- or cocaine-paired context (i.e., a memory retrieval procedure) in the basolateral amygdala (BLA) but not in the central amygdala. Intra-BLA infusions of Sal003, a selective inhibitor of eIF2α dephosphorylation, immediately after memory retrieval disrupted the reconsolidation of morphine- or cocaine-induced CPP, leading to a long-lasting suppression of drug-paired stimulus-induced craving. Advanced knockdown of ATF4 expression in the BLA by lentivirus-mediated short-hairpin RNA blocked the disruption of the reconsolidation of morphine-induced CPP induced by Sal003 treatment. Furthermore, inhibition of eIF2α dephosphorylation in the BLA immediately after light/tone stimulus retrieval decreased subsequent cue-induced heroin-seeking behavior in the self-administration procedure. These results demonstrate that eIF2α dephosphorylation in the BLA mediates the memory reconsolidation of drug-paired stimuli.
Assuntos
Tonsila do Cerebelo/metabolismo , Sinais (Psicologia) , Comportamento de Procura de Droga/fisiologia , Fator de Iniciação 2 em Eucariotos/metabolismo , Memória/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Cocaína/administração & dosagem , Comportamento de Procura de Droga/efeitos dos fármacos , Heroína/administração & dosagem , Masculino , Memória/efeitos dos fármacos , Morfina/administração & dosagem , Fosforilação/fisiologia , Ratos , Ratos Sprague-Dawley , AutoadministraçãoRESUMO
RATIONALE: The persistence of physical dependence and craving in addicts is considered to contribute to relapse. Increasing evidence indicates that neuropeptide systems are associated with several phases of drug addiction, but little is known about whether the neuropeptide trefoil factor affects withdrawal symptoms. OBJECTIVES: This study aims to investigate the potential effects of the neuropeptide trefoil factor 3 (TFF3) on naloxone-precipitated withdrawal symptoms in morphine-dependent mice. RESULTS: Mice received increasing doses of morphine over 3 days. On day 4, the mice were injected with TFF3 (1.0 mg/kg, i.p.) 30 min after the last dose of morphine. Thirty minutes after TFF3 treatment, naloxone (1 mg/kg, i.p.) was injected, and body weight, jumping behavior, wet-dog shakes, and locomotor activity were assessed 30 min later. Naloxone caused significant weight loss and increased jumping behavior and wet-dog shakes in morphine-dependent mice. TFF3 (1.0 mg/kg) reversed these behavioral symptoms caused by morphine withdrawal, suggesting that TFF3 might ameliorate physical dependence associated with opiate addiction. Furthermore, TFF3 pretreatment significantly reduced morphine withdrawal-induced increases in plasma corticosterone and adrenocorticotropic hormone levels. The glucocorticoid receptor agonist RU486 blocked the behavioral effects of TFF3 on morphine withdrawal symptoms. Finally, Fos expression in the medial prefrontal cortex which was decreased during morphine withdrawal was increased by TFF3 pretreatment. CONCLUSION: These findings indicate that TFF3 might be a potential therapeutic candidate for opiate addiction by regulating glucocorticoid secretion and neuronal activation in the prefrontal cortex.
Assuntos
Comportamento Animal/efeitos dos fármacos , Morfina/farmacologia , Naloxona/farmacologia , Entorpecentes/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Peptídeos/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Animais , Comportamento Animal/fisiologia , Masculino , Camundongos , Transtornos Relacionados ao Uso de Opioides/metabolismo , Peptídeos/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Fator Trefoil-2RESUMO
Fear extinction has been extensively studied, but little is known about the molecular processes that underlie the persistence of extinction long-term memory (LTM). We found that microinfusion of norepinephrine (NE) into the CA1 area of the dorsal hippocampus during the early phase (0 h) after extinction enhanced extinction LTM at 2 and 14 days after extinction. Intra-CA1 infusion of NE during the late phase (12 h) after extinction selectively promoted extinction LTM at 14 days after extinction that was blocked by the ß-receptor antagonist propranolol, protein kinase A (PKA) inhibitor Rp-cAMPS, and protein synthesis inhibitors anisomycin and emetine. The phosphorylation levels of PKA, cyclic adenosine monophosphate response element-binding protein (CREB), GluR1, and the membrane GluR1 level were increased by NE during the late phase after extinction that was also blocked by propranolol and Rp-cAMPS. These results suggest that the enhancement of extinction LTM persistence induced by NE requires the activation of the ß-receptor/PKA/CREB signaling pathway and membrane GluR1 trafficking. Moreover, extinction increased the phosphorylation levels of Erk1/2, CREB, and GluR1, and the membrane GluR1 level during the late phase, and anisomycin/emetine alone disrupted the persistence of extinction LTM, indicating that the persistence of extinction LTM requires late-phase protein synthesis in the CA1. Propranolol and Rp-cAMPS did not completely disrupt the persistence of extinction LTM, suggesting that another ß-receptor/PKA-independent mechanism underlies the persistence of extinction LTM. Altogether, our results showed that enhancing hippocampal noradrenergic activity during the late phase after extinction selectively promotes the persistence of extinction LTM.
Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Memória de Longo Prazo/efeitos dos fármacos , Norepinefrina/farmacologia , Receptores Adrenérgicos beta/metabolismo , Animais , Condicionamento Psicológico/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Fosforilação , Biossíntese de Proteínas/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Cocaine sensitization and reward are reported to be under the influence of diurnal rhythm. However, no previous studies have reported brain areas that play a role as modulators and underlie the mechanism of diurnal variations in cocaine reward. We examined (1) the diurnal rhythm of glycogen synthase kinase-3ß (GSK-3ß) activity in the suprachiasmatic nucleus (SCN) and reward-related brain areas in naive rats; (2) the effect of day and night on the acquisition of cocaine-induced conditioned place preference (CPP); (3) the influence of cocaine-induced CPP on GSK-3ß activity in the SCN and reward-related brain areas; and (4) the effect of the GSK-3ß inhibitor SB216763 microinjected bilaterally into the ventral tegmental area (VTA) on cocaine-induced CPP. A significant diurnal rhythm of GSK-3ß activity was found in the SCN and reward-related brain areas, with diurnal variations in cocaine-induced CPP. GSK-3ß activity in the SCN and reward-related brain areas exhibited marked diurnal variations in rats treated with saline. GSK-3ß activity in rats treated with cocaine exhibited distinct diurnal variations only in the prefrontal cortex and VTA. Cocaine decreased the expression of phosphorylated GSK-3ß (i.e. increased GSK-3ß activity) only in the VTA in rats trained and tested at ZT4 and ZT16. SB216763 microinjected into the VTA bilaterally eliminated the diurnal variations in cocaine-induced CPP, but did not affect the acquisition of cocaine-induced CPP. These findings suggest that the VTA may be a critical area involved in the diurnal variations in cocaine-induced CPP, and GSK-3ß may be a regulator of diurnal variations in cocaine-induced CPP.
Assuntos
Cocaína/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Quinase 3 da Glicogênio Sintase/fisiologia , Área Tegmentar Ventral/enzimologia , Animais , Ritmo Circadiano/efeitos dos fármacos , Indóis/farmacologia , Masculino , Maleimidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley , Recompensa , Núcleo Supraquiasmático/enzimologia , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
The effects of stress on emotional memory are distinct and depend on the stages of memory. Memory undergoes consolidation and reconsolidation after acquisition and retrieval, respectively. Stress facilitates the consolidation but disrupts the reconsolidation of emotional memory. Previous research on the effects of stress on memory have focused on long-term memory (LTM) formation (tested 24 h later), but the effects of stress on the persistence of LTM (tested at least 1 week later) are unclear. Recent findings indicated that the persistence of LTM requires late-phase protein synthesis in the dorsal hippocampus. The present study investigated the effect of stress (i.e., cold water stress) during the late phase after the acquisition and retrieval of contextual fear memory in rats. We found that stress and corticosterone administration during the late phase (12 h) after acquisition, referred to as late consolidation, selectively enhanced the persistence of LTM, whereas stress during the late phase (12 h) after retrieval, referred to as late reconsolidation, selectively disrupted the restabilized persistence of LTM. Moreover, the effects of stress on the persistence of LTM were blocked by the corticosterone synthesis inhibitor metyrapone, which was administered before stress, suggesting that the glucocorticoid system is involved in the effects of stress on the persistence of LTM. We conclude that stress within a restricted time window after acquisition or retrieval selectively affects the persistence of LTM and depends on the glucocorticoid system.
Assuntos
Memória de Longo Prazo , Estresse Fisiológico , Animais , Condicionamento Psicológico/efeitos dos fármacos , Corticosterona/administração & dosagem , Corticosterona/farmacologia , Medo/efeitos dos fármacos , Masculino , Memória de Longo Prazo/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Metirapona/farmacologia , Ratos , Ratos Sprague-Dawley , Estresse Fisiológico/efeitos dos fármacos , Fatores de TempoRESUMO
BACKGROUND: Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists exert fast-acting antidepressant effects, providing a promising way to develop a new classification of antidepressant that targets the glutamatergic system. In the present study, we examined the potential antidepressant action of 7-chlorokynurenic acid (7-CTKA), a glycine recognition site NMDA receptor antagonist, in a series of behavioural models of depression and determined the molecular mechanisms that underlie the behavioural actions of 7-CTKA. METHODS: We administered the forced swim test, novelty-suppressed feeding test, learned helplessness paradigm and chronic mild stress (CMS) paradigm in male rats to evaluate the possible rapid antidepressant-like actions of 7-CTKA. In addition, we assessed phospho-glycogen synthase kinase-3ß (p-GSK3ß) level, mammalian target of rapamycin (mTOR) function, and postsynaptic protein expression in the medial prefrontal cortex (mPFC) and hippocampus. RESULTS: Acute 7-CTKA administration produced rapid antidepressant-like actions in several behavioural tests. It increased p-GSK3ß, enhanced mTOR function and increased postsynaptic protein levels in the mPFC. Activation of GSK3ß by LY294002 completely blocked the antidepressant-like effects of 7-CTKA. Moreover, 7-CTKA did not produce rewarding properties or abuse potential. LIMITATIONS: It is possible that 7-CTKA modulates glutamatergic transmission, thereby causing enduring alterations of GSK3ß and mTOR signalling, although we did not provide direct evidence to support this possibility. Thus, the therapeutic involvement of synaptic adaptions engaged by 7-CTKA requires further study. CONCLUSION: Our findings demonstrate that acute 7-CTKA administration produced rapid antidepressant-like effects, indicating that the behavioural response to 7-CTKA is mediated by GSK3ß and mTOR signalling function in the mPFC.
Assuntos
Antidepressivos/farmacologia , Ácido Cinurênico/análogos & derivados , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Comportamento de Escolha/efeitos dos fármacos , Cromonas/administração & dosagem , Cromonas/farmacologia , Relação Dose-Resposta a Droga , Ativadores de Enzimas/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Desamparo Aprendido , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Resposta de Imobilidade Tônica/efeitos dos fármacos , Ácido Cinurênico/antagonistas & inibidores , Ácido Cinurênico/farmacologia , Masculino , Microinjeções , Morfolinas/administração & dosagem , Morfolinas/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Estresse Psicológico/psicologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
RATIONALE AND OBJECTIVES: Drug reinforcement and the reinstatement of drug seeking are associated with the pathological processing of drug-associated cue memories that can be disrupted by manipulating memory consolidation and reconsolidation. Ras-related C3 botulinum toxin substrate (Rac) is involved in memory processing by regulating actin dynamics and neural structure plasticity. The nucleus accumbens (NAc) and amygdala have been implicated in the consolidation and reconsolidation of emotional memories. Therefore, we hypothesized that Rac in the NAc and amygdala plays a role in the consolidation and reconsolidation of cocaine-associated cue memory. METHODS: Conditioned place preference (CPP) and microinjection of Rac inhibitor NSC23766 were used to determine the role of Rac in the NAc and amygdala in the consolidation and reconsolidation of cocaine-associated cue memory in rats. RESULTS: Microinjections of NSC23766 into the NAc core but not shell, basolateral (BLA), or central amygdala (CeA) after each cocaine-conditioning session inhibited the consolidation of cocaine-induced CPP. A microinjection of NSC23766 into the BLA but not CeA, NAc core, or NAc shell immediately after memory reactivation induced by exposure to a previously cocaine-paired context disrupted the reconsolidation of cocaine-induced CPP. The effect of memory disruption on cocaine reconsolidation was specific to reactivated memory, persisted at least 2 weeks, and was not reinstated by a cocaine-priming injection. CONCLUSIONS: Our findings indicate that Rac in the NAc core and BLA are required for the consolidation and reconsolidation of cocaine-associated cue memory, respectively.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Cocaína/toxicidade , Sinais (Psicologia) , Memória/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Proteínas rac de Ligação ao GTP/metabolismo , Aminoquinolinas/farmacologia , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiopatologia , Animais , Condicionamento Psicológico/efeitos dos fármacos , Microinjeções , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiopatologia , Pirimidinas/farmacologia , Ratos , Proteínas rac de Ligação ao GTP/antagonistas & inibidoresRESUMO
The inhibitor κB protein kinase/nuclear factor κB (IKK/NF-κB) signaling pathway is critical for synaptic plasticity. However, the role of IKK/NF-κB in drug withdrawal-associated conditioned place aversion (CPA) memory is unknown. Here, we showed that inhibition of IKK/NF-κB by sulphasalazine (SSZ; 10 mM, i.c.v.) selectively blocked the extinction but not acquisition or expression of morphine-induced CPA in rats. The blockade of CPA extinction induced by SSZ was abolished by sodium butyrate, an inhibitor of histone deacetylase. Thus, the IKK/NF-κB signaling pathway might play a critical role in the extinction of morphine-induced CPA in rats and might be a potential pharmacotherapy target for opiate addiction.
Assuntos
Aprendizagem da Esquiva , Condicionamento Clássico , Quinase I-kappa B/metabolismo , Memória , NF-kappa B/metabolismo , Transdução de Sinais , Animais , Injeções Intraventriculares , Morfina/efeitos adversos , Ratos , Ratos Sprague-Dawley , Síndrome de Abstinência a Substâncias , Sulfassalazina/administração & dosagemRESUMO
Depression is one of the most common and debilitating psychiatric illnesses around the world, but the current antidepressants used to treat depression have many limitations. Progressively more studies have shown that neuropeptide systems are potential novel therapeutic targets for depression. However, whether the neuropeptide trefoil factor 3 (TFF3) participates in the development of depression has not been examined. In the current experiments, we assessed the antidepressant effects of TFF3 using the forced swim test (FST), tail suspension test (TST), and chronic mild stress (CMS) paradigm. Furthermore, we determined the mechanism that underlies the antidepressant-like effects of TFF3 in the rat FST. TFF3 dose-dependently reduced immobility time in both FST and TST. CMS elevated plasma TFF3 and decreased basolateral amygdala (BLA) TFF3 levels in rats, and acute TFF3 (0.1 mg/kg, i.p.) treatment reversed the depressive-like behaviors induced by CMS. Furthermore, TFF3 (0.1 mg/kg, i.p.) significantly increased Fos expression in the BLA, medial prefrontal cortex, and hypothalamus in rats subjected to the FST. Intra-BLA infusions of TFF3 (1 ng/side) exerted rapid antidepressant-like effects in the rat FST. Additionally, acute systemic TFF3 administration increased the level of phosphorylated-Akt (p-Akt) in the BLA. Finally, intra-BLA infusions of LY294002 (5 mM/side), a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, significantly blocked the antidepressant-like effect of TFF3. Our results demonstrated that TFF3 exerts antidepressant-like effects that might be mediated by the PI3K/Akt signaling pathway in the BLA. These findings suggest a novel neuropeptide system target in the development of new antidepressants.
Assuntos
Tonsila do Cerebelo/fisiopatologia , Antidepressivos , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Proteína Oncogênica v-akt/fisiologia , Peptídeos/farmacologia , Fosfatidilinositol 3-Quinases/fisiologia , Transdução de Sinais/efeitos dos fármacos , Doença Aguda , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Western Blotting , Doença Crônica , Depressão/etiologia , Ensaio de Imunoadsorção Enzimática , Elevação dos Membros Posteriores/psicologia , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microinjeções , Atividade Motora/efeitos dos fármacos , Proteína Oncogênica v-akt/antagonistas & inibidores , Peptídeos/administração & dosagem , Inibidores de Fosfoinositídeo-3 Quinase , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Estresse Psicológico/psicologia , Natação/psicologia , Fator Trefoil-3RESUMO
Drug use and relapse involve learned associations between drug-associated environmental cues and drug effects. Extinction procedures in the clinic can suppress conditioned responses to drug cues, but the extinguished responses typically reemerge after exposure to the drug itself (reinstatement), the drug-associated environment (renewal), or the passage of time (spontaneous recovery). We describe a memory retrieval-extinction procedure that decreases conditioned drug effects and drug seeking in rat models of relapse, and drug craving in abstinent heroin addicts. In rats, daily retrieval of drug-associated memories 10 minutes or 1 hour but not 6 hours before extinction sessions attenuated drug-induced reinstatement, spontaneous recovery, and renewal of conditioned drug effects and drug seeking. In heroin addicts, retrieval of drug-associated memories 10 minutes before extinction sessions attenuated cue-induced heroin craving 1, 30, and 180 days later. The memory retrieval-extinction procedure is a promising nonpharmacological method for decreasing drug craving and relapse during abstinence.
Assuntos
Comportamento Aditivo/prevenção & controle , Transtornos Relacionados ao Uso de Cocaína/psicologia , Extinção Psicológica , Dependência de Heroína/psicologia , Memória , Tonsila do Cerebelo/enzimologia , Animais , Cocaína/administração & dosagem , Transtornos Relacionados ao Uso de Cocaína/terapia , Condicionamento Clássico , Condicionamento Operante , Sinais (Psicologia) , Heroína/administração & dosagem , Dependência de Heroína/terapia , Humanos , Masculino , Rememoração Mental , Modelos Animais , Córtex Pré-Frontal/enzimologia , Proteína Quinase C/metabolismo , Ratos , Ratos Sprague-Dawley , Recidiva , Autoadministração , Fatores de TempoRESUMO
Anxiety disorders, characterized by anxiety and fearfulness, are found to be able to cause abnormal emotional responses' associated with memories of negative events, which implicate pressure on society with an increasingly large burden. Better treatment has been of concern to the community. Venlafaxine (VEN), a nonclassical antidepressant agent, is applied in the treatment of social phobia, major depression (MD) and general anxiety disorder (GAD) and, to a certain extent, posttraumatic stress disorder (PTSD), which improves working memory and spatial memory as well as ameliorates emotion by affecting specified brain regions. In this study, we committed to seek a new way for using VEN on treatment of anxiety disorders. To investigate the effect of VEN on extinction of auditory-cue conditioned fear, conditioned rats received a treatment with VEN before extinction training and tests for freezing level of within-session and between-session extinction. To investigate the effect of VEN on reinstatement, all conditioned rats received a treatment with VEN over a period for 21 days. After a rest for 7 days, two tests for freezing level were conducted. We found that: (1) VEN (40mg/kg) treatment at 30min prior to extinction training significantly facilitated the between-session extinction, but not the within-session extinction; (2) chronic administration with VEN (40mg/kg) prevented the return of extinguished auditory-cue fear. These data elucidate the critical role of VEN in auditory-cue fear memory, suggesting that VEN may be an ideal choice for the exposure-based drug treatment and maintenance treatment in patients with GAD, SAD and PTSD.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , Transtornos de Ansiedade/tratamento farmacológico , Condicionamento Psicológico/efeitos dos fármacos , Cicloexanóis/farmacologia , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Estimulação Acústica/efeitos adversos , Animais , Sinais (Psicologia) , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Cloridrato de VenlafaxinaRESUMO
Depression is one of the most pervasive and debilitating psychiatric diseases, and the molecular mechanisms underlying the pathophysiology of depression have not been elucidated. Cyclin-dependent kinase 5 (Cdk5) has been implicated in synaptic plasticity underlying learning, memory, and neuropsychiatric disorders. However, whether Cdk5 participates in the development of depressive diseases has not been examined. Using the chronic mild stress (CMS) procedure, we examined the effects of Cdk5/p35 activity in the hippocampus on depressive-like behaviour in rats. We found that CMS increased Cdk5 activity in the hippocampus, accompanied by translocation of neuronal-specific activator p35 from the cytosol to the membrane in the dentate gyrus (DG) subregion. Inhibition of Cdk5 in DG but not in the cornu ammonis 1 (CA1) or CA3 hippocampal subregions inhibited the development of depressive-like symptoms. Overexpression of p35 in DG blocked the antidepressant-like effect of venlafaxine in the CMS model. Moreover, the antidepressants venlafaxine and mirtazapine, but not the antipsychotic aripiprazole, reduced Cdk5 activity through the redistribution of p35 from the membrane to the cytosol in DG. Our results showed that the development of depressive-like behaviour is associated with increased Cdk5 activity in the hippocampus and that the Cdk5/p35 complex plays a key role in the regulation of depressive-like behaviour and antidepressant actions.