RESUMO
Recent studies found that non-coding RNAs (ncRNAs) played crucial roles in drug addiction through epigenetic regulation of gene expression and underlying drug-induced neuroadaptations. In this study, we characterized lncRNA transcriptome profiles in the nucleus accumbens (NAc) of mice exhibiting morphine-conditioned place preference (CPP) and explored the prospective roles of novel differentially expressed lncRNA, lncLingo2 and its derived miR-876-5p in the acquisition of opioids-associated behaviours. We found that the lncLingo2 was downregulated within the NAc core (NAcC) but not in the NAc shell (NAcS). This downregulation was found to be associated with the development of morphine CPP and heroin intravenous self-administration (IVSA). As Mfold software revealed that the secondary structures of lncLingo2 contained the sequence of pre-miR-876, transfection of LV-lncLingo2 into HEK293 cells significantly upregulated miR-876 expression and the changes of mature miR-876 are positively correlated with lncLingo2 expression in NAcC of morphine CPP trained mice. Delivering miR-876-5p mimics into NAcC also inhibited the acquisition of morphine CPP. Furthermore, bioinformatics analysis and dual-luciferase assay confirmed that miR-876-5p binds to its target gene, Kcnn3, selectively and regulates morphine CPP training-induced alteration of Kcnn3 expression. Lastly, the electrophysiological analysis indicated that the currents of small conductance calcium-activated potassium (SK) channel was increased, which led to low neuronal excitability in NAcC after CPP training, and these changes were reversed by lncLingo2 overexpression. Collectively, lncLingo2 may function as a precursor of miR-876-5p in NAcC, hence modulating the development of opioid-associated behaviours in mice, which may serve as an underlying biomarker and therapeutic target of opioid addiction.
Assuntos
MicroRNAs , RNA Longo não Codificante , Humanos , Camundongos , Animais , Analgésicos Opioides/farmacologia , Analgésicos Opioides/metabolismo , Epigênese Genética , Células HEK293 , Morfina/farmacologia , Morfina/metabolismo , Núcleo Accumbens/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismoRESUMO
Adolescent alcohol drinking, primarily in the form of binge-drinking episodes, is a serious public health concern. Binge drinking in laboratory animals has been modeled by a procedure involving chronic intermittent ethanol (CIE) administration, as compared with chronic intermittent water (CIW). The prolonged effects of adolescent binge alcohol exposure in adults, such as high risk of developing alcohol use disorder, are severe but available treatments in the clinic are limited. One reason is the lack of sufficient understanding about the associated neuronal alterations. The involvement of the insular cortex, particularly the anterior agranular insula (AAI), has emerged as a critical region to explain neuronal mechanisms of substance abuse. This study was designed to evaluate the functional output of the AAI by measuring the intrinsic excitability of pyramidal neurons from male rats 2 or 21 days after adolescent or adult CIE treatment. Decreases in intrinsic excitability in AAI pyramidal neurons were detected 21 days, relative to 2 days, after adolescent CIE. Interestingly, the decreased intrinsic excitability in the AAI pyramidal neurons was observed 2 days after adult CIE, compared to adult CIW, but no difference was found between 2 versus 21 days after adult CIE. These data indicate that, although the AAI is influenced within a limited period after adult but not adolescent CIE, neuronal alterations in AAI are affected during the prolonged period of withdrawal from adolescent but not adult CIE. This may explain the prolonged vulnerability to mental disorders of subjects with an alcohol binge history during their adolescent stage.
Assuntos
Consumo Excessivo de Bebidas Alcoólicas/fisiopatologia , Etanol/toxicidade , Córtex Insular/efeitos dos fármacos , Fatores Etários , Animais , Etanol/administração & dosagem , Córtex Insular/crescimento & desenvolvimento , Córtex Insular/fisiopatologia , Masculino , Técnicas de Patch-Clamp , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Ratos , Ratos Sprague-Dawley , Maturidade SexualRESUMO
Silica-induced apoptosis of alveolar macrophages (AMs) is an essential part of silicosis formation. Autophagy tends to present a bidirectional effect on apoptosis. Our previous study found that the blockade of autophagy degradation might aggravate the apoptosis of AMs in human silicosis. We presume that targeting the autophagic pathway is regarded as a promising new strategy for silicosis fibrosis. As a main active component of the Atractylodes rhizome, Atractylenolide III (ATL-III) has been widely applied in clinical anti-inflammation. However, the effect and mechanism of ATL-III on autophagy in AMs of silicosis are unknown. In this study, we found that ATL-III might inhibit autophagy by mTOR-dependent manner, thereby improving the blockage of autophagic degradation in AMs. ATL-III alleviated the apoptosis of AMs in human silicosis. Furthermore, Rapamycin reversed the protective effect of ATL-III in AMs. These results indicate that ATL-III may be a potentially protective ingredient targeting autophagy for workers exposed to silica dust. These findings also suggest that inhibition of autophagy may be an effective way to alleviate the apoptosis of AMs in silicosis.
Assuntos
Líquido da Lavagem Broncoalveolar/citologia , Lactonas/farmacologia , Macrófagos Alveolares/efeitos dos fármacos , Sesquiterpenos/farmacologia , Silicose/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Células Cultivadas , Antagonistas Colinérgicos/farmacologia , Humanos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Silicose/metabolismo , Silicose/patologia , Serina-Treonina Quinases TOR/genéticaRESUMO
A progressive increase in drug craving following drug exposure is an important trigger of relapse. CircularRNAs (CircRNAs), key regulators of gene expression, play an important role in neurological diseases. However, the role of circRNAs in drug craving is unclear. In the present study, we trained mice to morphine conditioned place preference (CPP) and collected the nucleus accumbens (NAc) sections on abstinence day 1 (AD1) and day 14 (AD14) for RNA-sequencing. CircTmeff-1, which was highly expressed in the NAc core, was associated with incubation of context-induced morphine craving. The gain- and loss- of function showed that circTmeff-1 was a positive regulator of incubation. Simultaneously, the expression of miR-541-5p and miR-6934-3p were down-regulated in the NAc core during the incubation period. The dual luciferase reporter, RNA pulldown, and fluorescence insitu hybridization assays confirmed that miR-541-5p and miR-6934-3p bind to circTmeff-1 selectively. Furthermore, bioinformatics and western blot analysis suggested that vesicle-associated membrane protein 1 (VAMP1) and neurofascin (NFASC), both overlapping targets of miR-541-5p and miR-6934-3p, were highly expressed during incubation. Lastly, AAV-induced down-regulation of circTmeff-1 decreased VAMP1 and NFASC expression and incubation of morphine craving. These findings suggested that circTmeff-1, a novel circRNA, promotes incubation of context-induced morphine craving by sponging miR-541/miR-6934 in the NAc core. Thus, circTmeff-1 represents a potential therapeutic target for context-induced opioid craving, following prolonged abstinence.
Assuntos
Comportamento Animal , Fissura , Comportamento de Procura de Droga , Dependência de Morfina/metabolismo , Núcleo Accumbens/metabolismo , RNA Circular/metabolismo , Animais , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Sinais (Psicologia) , Modelos Animais de Doenças , Regulação da Expressão Gênica , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Dependência de Morfina/genética , Dependência de Morfina/fisiopatologia , Dependência de Morfina/psicologia , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Núcleo Accumbens/fisiopatologia , RNA Circular/genética , Proteína 1 Associada à Membrana da Vesícula/genética , Proteína 1 Associada à Membrana da Vesícula/metabolismoRESUMO
The two-drug combined chemotherapy of platinum and fluorouracil has been reported to efficiently kill tumor cells as the first-line treatment for advanced gastric cancer. However, the effect of these drugs on T cells remains unclear. Here, we showed that T cells including CD4+ T cells and CD8+ T cells of the patients with advanced gastric cancer after platinum and fluorouracil chemotherapy exhibited enhanced ex vivo proliferation ability as compared to that before chemotherapy. In addition, platinum and fluorouracil also promoted the differentiation of human T cells into Th1 and Th9 subtypes and cytotoxic T lymphocytes (CTLs) in vitro and in vivo. Accordingly, the combination therapy greatly suppressed tumor growth with increased tumor infiltration of Th1, Th9, and CTL cells in a mouse tumor model. Moreover, in activated T cells, long-term treatment with these two drugs further facilitates T cell activation along with promoted nuclear factor-κB (NF-κB) activation. Our findings demonstrate a previously unidentified function of platinum and fluorouracil combination chemotherapy in promoting T cell-mediated antitumor immunity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Fluoruracila/farmacologia , Neoplasias/imunologia , Platina/farmacologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Quimioterapia Combinada/métodos , Fluoruracila/uso terapêutico , Humanos , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/patologia , Camundongos Endogâmicos C57BL , Subunidade p50 de NF-kappa B/metabolismo , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Platina/uso terapêutico , Neoplasias Gástricas/sangue , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
Postretrieval extinction procedures are effective nonpharmacological interventions for disrupting drug-associated memories. Nonetheless, the conditioned stimulus (CS) memory retrieval-extinction procedure is ineffective in inhibiting drug craving and relapse after prolonged withdrawal, which significantly undermines its therapeutic potential. In the present study, we showed that, unlike the CS memory retrieval-extinction procedure, noncontingent heroin injections (unconditioned stimulus [UCS]) 1 hour before the extinction sessions decreased the heroin-priming-induced reinstatement, renewal, and spontaneous recovery of heroin seeking after 28 days of withdrawal (ie, remote heroin-associated memories) in rats. The UCS retrieval manipulation induced reactivation of the basolateral amygdala (BLA) after prolonged withdrawal, and this reactivation was absent with the CS retrieval manipulation. Chemogenetic inactivation of the BLA abolished the inhibitory effect of the UCS memory retrieval-extinction procedure on heroin-priming-induced reinstatement after prolonged withdrawal. Furthermore, the combination of chemogenetic reactivation of BLA and CS retrieval-extinction procedure resembled the inhibitory effect of UCS retrieval-extinction procedure on heroin seeking after prolonged withdrawal. We also observed that the inhibitory effect of the UCS retrieval-extinction procedure is mediated by regulation of AMPA receptor endocytosis in the BLA. Our results demonstrate critical engagement of the BLA in reconsolidation updating of heroin-associated memory after prolonged withdrawal, extending our knowledge of the boundary conditions of the reconsolidation of drug-associated memories.
Assuntos
Complexo Nuclear Basolateral da Amígdala/metabolismo , Comportamento de Procura de Droga/fisiologia , Extinção Psicológica/fisiologia , Dependência de Heroína/metabolismo , Heroína/farmacologia , Consolidação da Memória/fisiologia , Entorpecentes/farmacologia , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Núcleo Central da Amígdala/metabolismo , Núcleo Central da Amígdala/fisiologia , Endocitose , Dependência de Heroína/fisiopatologia , Masculino , Ratos , Receptores de AMPA/metabolismo , Fatores de TempoRESUMO
Exposure to drug-paired cues causes drug memories to be in a destabilized state and interfering with memory reconsolidation can inhibit relapse. Calpain, a calcium-dependent neutral cysteine protease, is involved in synaptic plasticity and the formation of long-term fear memory. However, the role of calpain in the reconsolidation of drug reward memory is still unknown. In the present study, using a conditioned place preference (CPP) model, we found that exposure to drug-paired contextual stimuli induced the activation of calpain and decreased the expression of glutamate receptor interacting protein 1 (GRIP1) in the nucleus accumbens (NAc) core, but not shell, of male rats. Infusions of calpain inhibitors in the NAc core immediately after retrieval disrupted the reconsolidation of cocaine/morphine cue memory and blocked retrieval-induced calpain activation and GRIP1 degradation. The suppressive effect of calpain inhibitors on the expression of drug-induced CPP lasted for at least 14 d. The inhibition of calpain without retrieval 6 h after retrieval or after exposure to an unpaired context had no effects on the expression of reward memory. Calpain inhibition after retrieval also decreased cocaine seeking in a self-administration model and this effect did not recover spontaneously after 28 d. Moreover, the knock-down of GRIP1 expression in the NAc core by lentivirus-mediated short-hairpin RNA blocked disruption of the reconsolidation of drug cue memories that was induced by calpain inhibitor treatment. These results suggest that calpain activity in the NAc core is crucial for the reconsolidation of drug reward memory via the regulation of GRIP1 expression.SIGNIFICANCE STATEMENT Calpain plays an important role in synaptic plasticity and long-term memory consolidation, however, its role in the reconsolidation of drug cue memory remains unknown. Using conditioned place preference and self-administration procedures, we found that exposure to drug-paired cues induced the activation of calpain and decreased glutamate receptor interacting protein 1 (GRIP1) expression in the nucleus accumbens (NAc) core. The inhibition of calpain activity in the NAc core immediately after retrieval disrupted the reconsolidation of cocaine/morphine cue memory that was blocked by prior GRIP1 knock-down. Our findings indicate that calpain-GRIP signaling is essential for the restabilization process that is associated with drug cue memory and the inhibition of calpain activity may be a novel strategy for the prevention of drug relapse.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Calpaína/metabolismo , Sinais (Psicologia) , Comportamento de Procura de Droga/fisiologia , Consolidação da Memória/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Núcleo Accumbens/fisiologia , Recompensa , Animais , Expressão Gênica/fisiologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
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
Extinction therapy has been suggested to suppress the conditioned motivational effect of drug cues to prevent relapse. However, extinction forms a new inhibiting memory rather than erasing the original memory trace and drug memories invariably return. Perineuronal nets (PNNs) are a specialized extracellular matrix around interneurons in the brain that have been suggested to be a permissive factor that allows synaptic plasticity in the adolescent brain. The degradation of PNNs caused by chondroitinase ABC (ChABC) may generate induced juvenile-like plasticity (iPlasticity) and promote experience-dependent plasticity in the adult brain. In the present study, we investigated the effect of removing PNNs in the amygdala of rat on the extinction of drug memories. We found that extinction combined with intra-amygdala injections of ChABC (0.01 U/side) prevented the subsequent priming-induced reinstatement of morphine-induced and cocaine-induced, but not food -induced, conditioned place preference (CPP). Intra-amygdala injections of ChABC alone had no effect on the retention, retrieval, or relearning of morphine-induced CPP and storage of acquired food-induced CPP. Moreover, we found that the procedure facilitated the extinction of heroin- and cocaine-seeking behavior and prevented the spontaneous recovery and drug-induced reinstatement of heroin- and cocaine-seeking behavior. We also found that the effect of PNNs degradation combined with extinction may be mediated by the potentiation of several plasticity-related proteins in the amygdala. Altogether, our findings demonstrate that a combination of extinction training with PNNs degradation in the amygdala erases drug memories and suggest that ChABC may be an attractive candidate for the prevention of relapse.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiologia , Memória , Rede Nervosa/fisiologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Animais , Western Blotting , Condroitina ABC Liase/administração & dosagem , Condroitina ABC Liase/farmacologia , Transtornos Relacionados ao Uso de Cocaína/psicologia , Condicionamento Operante , Extinção Psicológica , Alimentos , Dependência de Heroína/psicologia , Masculino , Microinjeções , Dependência de Morfina/psicologia , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , Prevenção SecundáriaRESUMO
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
Time-dependent increases in cue-induced nicotine and methamphetamine craving during abstinence were recently reported in human drug-dependent individuals. In the present study, we sought to determine whether this 'incubation of craving' phenomenon also occurs in alcoholics. Four groups of 80 inpatient adult male alcoholics were assessed in a single session (between-group design) for cue-induced alcohol craving at 7, 14, 30 and 60 days of abstinence. Another group that included 19 patients was repeatedly tested for cue-induced alcohol craving at the same abstinence days as above. Other psychological and physiological measures were assessed at the four abstinence timepoints. Cue-induced alcohol craving measured with visual analogue scales was the highest at 60 days of abstinence both between and within groups. However, heart rate, blood pressure and skin conductance responses did not differ between abstinent groups. These results provide evidence of the incubation of alcohol craving in humans, extending previous reports with smokers and methamphetamine addicts.
Assuntos
Abstinência de Álcool/psicologia , Alcoolismo/psicologia , Fissura , Adolescente , Adulto , Análise de Variância , Pressão Sanguínea/fisiologia , Sinais (Psicologia) , Resposta Galvânica da Pele/fisiologia , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Abstinência a Substâncias/psicologia , Adulto JovemRESUMO
Leukocytes can cross intact blood-brain barrier under healthy conditions and in many neurological diseases, including psychiatric diseases. In present study, a cyclic RGD (cRGD) peptide with high affinity for integrin receptors of leukocytes was used to modify liposomes. The cRGD-modified liposomes (cRGDL) showed high affinity for monocytes in vitro and in vivo and co-migrated across in vitro BBB model with THP-1. The trefoil factor 3 (TFF3), a macromolecular drug, was rapidly and persistently delivered to brain for at least 12 h when loaded into cRGDL while 2.8-fold increase in drug concentration in basolateral amygdala regions related to depression was observed. A systemic administration of cRGDL-TFF3 mimicked antidepressant-like effect of direct intra-basolateral amygdala administration of TFF3 solution in rats subjected to chronic mild stress. The effective dual-brain targeting delivery resulting from the combination and co-migration of cRGDL with leukocyte cross BBB may be a promising strategy for targeted brain delivery. FROM THE CLINICAL EDITOR: In an effort to treat depression, brain targeted delivery via monocyte-cRGD liposome complexes capable of crossing the intact BBB was performed in this study in a murine model. Similar approaches may be helpful in the treatment of other neuropsychiatric conditions.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Depressão/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Peptídeos Cíclicos/administração & dosagem , Peptídeos/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Depressão/patologia , Sinergismo Farmacológico , Humanos , Leucócitos/efeitos dos fármacos , Lipossomos/administração & dosagem , Masculino , Camundongos , Ratos , Fator Trefoil-3RESUMO
The trefoil factors (TFFs) are a family of three polypeptides, among which TFF1 and TFF3 are widely distributed in the central nervous system. Our previous study indicated that TFF3 was a potential rapid-onset antidepressant as it reversed the depressive-like behaviors induced by acute or chronic mild stress. In order to further identify the antidepressant-like effect of TFF3, we applied an olfactory bulbectomy (OB), a classic animal model of depression, in the present study. To elucidate the mechanism underlying the antidepressant-like activity of TFF3, we tested the role of brain-derived neurotrophic factor (BDNF)-extracellular signal-related kinase (ERK)-cyclic adenosine monophosphate response element binding protein (CREB) signaling in the hippocampus in the process. Chronic systemic administration of TFF3 (0.1 mg/kg, i.p.) for seven days not only produced a significant antidepressant-like efficacy in the OB paradigm, but also restored the expression of BDNF, pERK, and pCREB in the hippocampal CA3. Inhibition of BDNF or extracellular signal-related kinase (ERK) signaling in CA3 blocked the antidepressant-like activity of TFF3 in OB rats. Our findings further confirmed the therapeutic effect of TFF3 against depression and suggested that the normalization of the BDNF-ERK-CREB pathway was involved in the behavioral response of TFF3 for the treatment of depression.
Assuntos
Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Depressão/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neuropeptídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Depressão/etiologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Neuropeptídeos/administração & dosagem , Bulbo Olfatório/cirurgia , Fosforilação , Ratos , Receptor trkB/antagonistas & inibidores , Fator Trefoil-3RESUMO
Repeated exposure to nicotine increases psychomotor activity. Long-lasting neural plasticity changes that contribute to the nicotine-induced development of locomotor sensitization have been identified. The mammalian target of rapamycin complex 1 (mTORC1) signalling pathway is involved in regulating the neuroplasticity of the central nervous system. In this study, we examined the role of mTORC1 in the amygdala in nicotine-induced locomotor sensitization. Rapamycin, an inhibitor of mTORC1, was infused into the basolateral amygdala (BLA) and central amygdala (CeA) or systemically administered to investigate the role of the mTORC1 in the development and expression of nicotine-induced locomotor sensitization. We found that locomotor activity progressively increased during the initiation of nicotine-induced locomotor sensitization and the expression of nicotine sensitization was induced by nicotine challenge injection (0.35 mg/kg s.c.) after five days of withdrawal. The initiation of nicotine-induced locomotor sensitization was accompanied by the increased phosphorylated level of mTORC1 downstream target proteins including p-p70s6k and p-4EBP in the BLA, but not CeA. Intra-BLA infusion or systemic administration of rapamycin blocked locomotor activity. Increased p-p70s6k and p-4EBP were also observed in the expression of nicotine sensitization, which was demonstrated to be inhibited by systemic rapamycin administration. Our findings indicated that mTORC1 activity in the BLA, but not the CeA, mediated the initiation and expression of nicotine-induced locomotor sensitization, and may become a potential target for the treatment of nicotine addiction.
Assuntos
Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Complexos Multiproteicos/metabolismo , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Proteínas de Transporte/metabolismo , Esquema de Medicação , Imunossupressores/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Microinjeções , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Fosfoproteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Sirolimo/farmacologiaRESUMO
BACKGROUND: Currently approved medications for opioid addiction have shown clinical efficacy, but undesired side effects, dependence induced by the medications themselves, and low treatment compliance necessitate the need for novel therapies. METHODS: A novel morphine-keyhole limpet hemocyanin conjugate vaccine was synthesized with 6-glutarylmorphine as the hapten and a lengthened linker of 6 carbon atoms. The titer and specificity of the triggered antibody were assessed by enzyme-linked immunosorbent assay. The effects of the vaccine on the morphine-induced elevation of dopamine levels in the nucleus accumbens were determined by high-performance liquid chromatography. The effects of the vaccine on morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin self-administration were also assessed. RESULTS: After subcutaneous administration in rats, the vaccine triggered a high antibody titer, with comparable specificity for morphine, 6-acetylmorphine, and heroin, but no interaction with dissimilar therapeutic opioid compounds, including buprenorphine, naloxone, and nalorphine, was observed. The vaccine significantly prevented the elevation of dopamine levels in the nucleus accumbens induced by a single morphine challenge. Moreover, the vaccine prevented the expression of morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin seeking, suggesting its potential for preventing relapse. CONCLUSION: These results demonstrate that active immunization with the present vaccine induces a robust morphine/heroin-specific antibody response in rats and attenuates the behavioral effects of morphine and heroin.
Assuntos
Anticorpos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Dopamina/sangue , Morfina/imunologia , Vacinas Conjugadas/administração & dosagem , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Animais , Anticorpos/farmacologia , Cromatografia Líquida de Alta Pressão , Comportamento de Procura de Droga/efeitos dos fármacos , Heroína/administração & dosagem , Heroína/efeitos adversos , Locomoção/efeitos dos fármacos , Masculino , Morfina/administração & dosagem , Morfina/efeitos adversos , Derivados da Morfina/administração & dosagem , Derivados da Morfina/efeitos adversos , Derivados da Morfina/imunologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , Autoadministração , Resultado do Tratamento , Vacinas Conjugadas/farmacologiaRESUMO
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
Shikonin is an active naphthoquinone with antioxidative, anti-inflammatory, and anticancer properties. In this study, we investigated the effects of shikonin on depressive- and anxiety-like behaviors in lipopolysaccharide- (LPS-) induced depression and chronic unpredictable mild stress (CUMS) rat models and explored the potential mechanism. First, a 14-day intraperitoneal administration of shikonin (10 mg/kg) significantly decreased immobility time in forced swimming test (FST) and increased open arm entries in elevated plus maze (EPM) test, without affecting line crossings in open field test (OFT), indicating that shikonin has anti-depressant- and anxiolytic-like effects. Second, chronic shikonin administration (10 mg/kg) reversed depressive- and anxiety-like behaviors in LPS-induced and CUMS depression models, as shown in the sucrose preference test (SPT), FST, EPM, and novel object recognition test (NORT). Finally, shikonin significantly reduced the levels of interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α) in hippocampus, indicating that the anti-depressant- and anxiolytic-like effects of shikonin are related to the reduction of neuroinflammation in hippocampus. These findings suggest that shikonin exerts anti-depressant- and anxiolytic-like effects via an anti-inflammatory mechanism of shikonin in the hippocampus.
Assuntos
Ansiedade , Depressão , Hipocampo , Naftoquinonas , Ratos Sprague-Dawley , Animais , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Depressão/tratamento farmacológico , Ansiedade/tratamento farmacológico , Ratos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Inflamação/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/complicações , Estresse Psicológico/psicologia , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , LipopolissacarídeosRESUMO
Addressing the treatment of depression is crucial; nevertheless, the etiology and pathogenesis remain unelucidated. Therefore, this study investigated the effects of teriflunomide (TF) on corticosterone (CORT)-induced depression-like behaviors in mice. Notably, TF administration resulted in a substantial amelioration of anxiety and depression-like behaviors observed in CORT-treated mice. This was evidenced by behavioral assessments conducted via the sucrose preference test (SPT), open-field test (OFT), novelty-suppressed feeding test (NSFT), forced swimming test (FST), and tail suspension test (TST). The administration of CORT inflicts damage upon oligodendrocytes and neurons within the hippocampus. Our findings indicate that TF offers significant protective effects on oligodendrocytes, mitigating apoptosis both invivo and invitro. Additionally, TF was found to counteract the CORT-induced neuronal loss and synaptic damage, as demonstrated by an increase in Nissl-positive cells across hippocampal regions CA1, CA3, and the dentate gyrus (DG) alongside elevated levels of synapse-related proteins including PSD-95 and synaptophysin. Additionally, TF treatment facilitated a reduction in the levels of apoptosis-related proteins while simultaneously augmenting the levels of Bcl2. Our findings indicate that TF administration effectively mitigates CORT-induced depression-like behaviors and reverses damage to oligodendrocytes and neurons in the hippocampus, suggesting TF as a promising candidate for depression.
RESUMO
Drug addiction is a chronic brain disorder with the hallmark of a high rate of relapse to compulsive drug seeking and drug taking even after long-term abstinence. Addiction has been considered as an aberrant memory that has been termed "addiction memory." Drug-related memory plays a critical role in the maintenance of learned addictive behaviors and emergence of relapse. Disrupting these long-lasting memories by administering amnestic agents or other manipulations during specific phases of drug memory is a promising strategy for relapse prevention. Recent studies on the processes of drug addiction and relapse have demonstrated that the amygdala is involved in associative drug addiction learning processes. In this review, we focus on preclinical studies that used conditioned place preference and self-administration models to investigate the differential roles of the amygdala in each phase of drug-related memory, including acquisition, consolidation, retrieval, reconsolidation, and extinction. These studies indicate that the amygdala plays a critical role in both cue-associative learning and the expression of cue-induced relapse to drug-seeking behavior.
Assuntos
Tonsila do Cerebelo/fisiopatologia , Memória/fisiologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Animais , Humanos , Aprendizagem/fisiologia , Camundongos , Ratos , Recidiva , Autoadministração , Fatores de TempoRESUMO
INTRODUCTION: Several studies have linked inflammation and oxidative stress with the pathogenesis of depression. Artesunate is a commonly used medication to treat malaria and has been shown to produce antioxidant, anti-inflammatory, and immunomodulatory effects. However, its prophylactic effects on depression and depression-related brain pathology are unknown. METHODS: In Experiment 1, using a PC12 cell line, we investigated whether artesunate can prevent hydrogen peroxide (H2 O2 )-induced oxidative injury that mimics oxidative stress commonly observed in the depressed brain. Next, using lipopolysaccharide (LPS)-induced mouse model of depression, we investigated whether artesunate can prevent behavioral deficits observed in the open field test, novelty-suppressed feeding test, sucrose preference test, forced swimming test, and tail suspension procedure. RESULTS: We found that artesunate significantly prevented a H2 O2 -induced reduction in PC12 cell activity, suggesting its antioxidant potential. We also found that mice pretreated with artesunate (5, 15 mg/kg) intraperitoneally (i.p.) prior to the LPS (.8 mg/kg, i.p.) treatment showed fewer and less severe depression- and anxiety-like behaviors than the LPS-treated control mice. CONCLUSION: Our findings indicate that artesunate produces antioxidant effect, as well as antidepressant and anxiolytic effects. Importantly, our findings first demonstrate that artesunate can prevent LPS-induced depression- and anxiety-like symptoms, strongly suggesting its prophylactic potential in the treatment of depression and, perhaps, other psychiatric disorders associated with inflammation and oxidative stress.