RESUMO
Tobacco smoking is positively correlated with non-alcoholic fatty liver disease (NAFLD)1-5, but the underlying mechanism for this association is unclear. Here we report that nicotine accumulates in the intestine during tobacco smoking and activates intestinal AMPKα. We identify the gut bacterium Bacteroides xylanisolvens as an effective nicotine degrader. Colonization of B. xylanisolvens reduces intestinal nicotine concentrations in nicotine-exposed mice, and it improves nicotine-exacerbated NAFLD progression. Mechanistically, AMPKα promotes the phosphorylation of sphingomyelin phosphodiesterase 3 (SMPD3), stabilizing the latter and therefore increasing intestinal ceramide formation, which contributes to NAFLD progression to non-alcoholic steatohepatitis (NASH). Our results establish a role for intestinal nicotine accumulation in NAFLD progression and reveal an endogenous bacterium in the human intestine with the ability to metabolize nicotine. These findings suggest a possible route to reduce tobacco smoking-exacerbated NAFLD progression.
Assuntos
Bactérias , Intestinos , Nicotina , Hepatopatia Gordurosa não Alcoólica , Fumar Tabaco , Animais , Humanos , Camundongos , Bactérias/efeitos dos fármacos , Bactérias/metabolismo , Ceramidas/biossíntese , Nicotina/efeitos adversos , Nicotina/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/microbiologia , Esfingomielina Fosfodiesterase/metabolismo , Fumar Tabaco/efeitos adversos , Fumar Tabaco/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Progressão da DoençaRESUMO
Remote memory usually decreases over time, whereas remote drug-cue associated memory exhibits enhancement, increasing the risk of relapse during abstinence. Memory system consolidation is a prerequisite for remote memory formation, but neurobiological underpinnings of the role of consolidation in the enhancement of remote drug memory are unclear. Here, we found that remote cocaine-cue associated memory was enhanced in rats that underwent self-administration training, together with a progressive increase in the response of prelimbic cortex (PrL) CaMKII neurons to cues. System consolidation was required for the enhancement of remote cocaine memory through PrL CaMKII neurons during the early period post-training. Furthermore, dendritic spine maturation in the PrL relied on the basolateral amygdala (BLA) input during the early period of consolidation, contributing to remote memory enhancement. These findings indicate that memory consolidation drives the enhancement of remote cocaine memory through a time-dependent increase in activity and maturation of PrL CaMKII neurons receiving a sustained BLA input.
Assuntos
Complexo Nuclear Basolateral da Amígdala , Cocaína , Consolidação da Memória , Neurônios , Córtex Pré-Frontal , Animais , Consolidação da Memória/efeitos dos fármacos , Consolidação da Memória/fisiologia , Cocaína/farmacologia , Masculino , Ratos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Memória de Longo Prazo/efeitos dos fármacos , Memória de Longo Prazo/fisiologia , Sinais (Psicologia) , Ratos Sprague-Dawley , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Autoadministração , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/fisiologia , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Memória/efeitos dos fármacos , Memória/fisiologiaRESUMO
Post-traumatic stress disorder (PTSD), a psychological condition triggered by exposure to extreme or chronic stressful events, exhibits a sex bias in incidence and clinical manifestations. Emerging research implicates the gut microbiome in the pathogenesis of PTSD and its roles in stress susceptibility. However, it is unclear whether differential gut microbiota contribute to PTSD susceptibility in male and female rats. Here, we utilized the single prolonged stress animal model and employed unsupervised machine learning to classify stressed animals into stress-susceptible subgroups and stress-resilient subgroups. Subsequently, using 16S V3-V4 rDNA sequencing, we investigated the differential gut microbiota alterations between susceptible and resilient individuals in male and female rats. Our findings revealed distinct changes in gut microbiota composition between the sexes at different taxonomic levels. Furthermore, the abundance of Parabacteroides was lower in rats that underwent SPS modeling compared to the control group. In addition, the abundance of Tenericutes in the stress-susceptible subgroup was higher than that in the control group and stress-resilient subgroup, suggesting that Tenericutes may be able to characterize stress susceptibility. What is particularly interesting here is that Cyanobacteria may be particularly associated with anti-anxiety effects in male rats. This study underscores sex-specific variations in gut microbiota composition in response to stress and sex differences should be taken into account when using macrobiotics for neuropsychiatric treatment, highlighting potential targets for PTSD therapeutic interventions.
Assuntos
Microbioma Gastrointestinal , Resiliência Psicológica , Feminino , Masculino , Animais , Ratos , Caracteres Sexuais , Bacteroidetes , Modelos AnimaisRESUMO
In 1986, Gawin and Kleber reported a progressive increase in cue-induced drug craving in individuals with cocaine use disorders during prolonged abstinence. After years of controversy, as of 2001, this phenomenon was confirmed in rodent studies using self-administration model, and defined as the incubation of drug craving. The intensification of cue-induced drug craving after withdrawal exposes abstinent individuals to a high risk of relapse, which urged us to develop effective interventions to prevent incubated craving. Substantial achievements have been made in deciphering the neural mechanisms, with potential implications for reducing drug craving and preventing the relapse. The present review discusses promising drug targets that have been well investigated in animal studies, including some neurotransmitters, neuropeptides, neurotrophic factors, and epigenetic markers. We also discuss translational exploitation and challenges in the field of the incubation of drug craving, providing insights into future investigations and highlighting the potential of pharmacological interventions, environment-based interventions, and neuromodulation techniques.
Assuntos
Cocaína , Transtornos Relacionados ao Uso de Substâncias , Animais , Fissura , Preparações Farmacêuticas , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Autoadministração , Recidiva , Sinais (Psicologia) , Cocaína/farmacologia , Comportamento de Procura de DrogaRESUMO
Estrogen regulates a wide range of neuronal functions in the brain, such as dendritic spine formation, remodeling of synaptic plasticity, cognition, neurotransmission, and neurodevelopment. Estrogen interacts with intracellular estrogen receptors (ERs) and membrane-bound ERs to produce its effect via genomic and non-genomic pathways. Any alterations in these pathways affect the number, size, and shape of dendritic spines in neurons associated with psychiatric diseases. Increasing evidence suggests that estrogen fluctuation causes changes in dendritic spine density, morphology, and synapse numbers of excitatory and inhibitory neurons differently in males and females. In this review, we discuss the role of estrogen hormone in rodents and humans based on sex differences. First, we explain estrogen role in learning and memory and show that a high estrogen level alleviates the deficits in learning and memory. Secondly, we point out that estrogen produces a striking difference in emotional memories in men and women, which leads them to display sex-specific differences in underlying neuronal signaling. Lastly, we discuss that fluctuations in estrogen levels in men and women are related to neuropsychiatric disorders, including schizophrenia, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BPD), major depressive disorder (MDD), substance use disorder (SUD), and anxiety disorders.
Assuntos
Transtorno do Espectro Autista , Transtorno Depressivo Maior , Humanos , Feminino , Masculino , Transtorno do Espectro Autista/genética , Caracteres Sexuais , Transtorno Depressivo Maior/metabolismo , Estrogênios/metabolismo , Sinapses/metabolismo , EmoçõesRESUMO
The extracellular matrix (ECM) within the brain possesses a distinctive composition and functionality, influencing a spectrum of physiological and pathological states. Among its constituents, perineuronal nets (PNNs) are unique ECM structures that wrap around the cell body of many neurons and extend along their dendrites within the central nervous system (CNS). PNNs are pivotal regulators of plasticity in CNS, both during development and adulthood stages. Characterized by their condensed glycosaminoglycan-rich structures and heterogeneous molecular composition, PNNs not only offer neuroprotection but also participate in signal transduction, orchestrating neuronal activity and plasticity. Interfering with the PNNs in adult animals induces the reactivation of critical period plasticity, permitting modifications in neuronal connections and promoting the recovery of neuroplasticity following spinal cord damage. Interestingly, in the adult brain, PNN expression is dynamic, potentially modulating plasticity-associated states. Given their multifaceted roles, PNNs have emerged as regulators in the domains of learning, memory, addiction behaviors, and other neuropsychiatric disorders. In this review, we aimed to address how PNNs contribute to the memory processes in physiological and pathological conditions.
Assuntos
Encéfalo , Sistema Nervoso Central , Animais , Sistema Nervoso Central/fisiologia , Encéfalo/metabolismo , Neurônios/metabolismo , Memória/fisiologia , Matriz Extracelular/metabolismo , Plasticidade Neuronal/fisiologiaRESUMO
Estrogen (E2) modulates the synaptic structure and plasticity in the hippocampus. Previous studies showed that E2 fluctuations during various phases of the menstrual cycle produce subtle neurosynaptic changes that impact women's behavior, emotion, and cognitive functions. In this study, we explored the transcriptome of the hippocampus via RNA-seq (RNA-sequencing) between proestrus (PE) and diestrus (DE) stages in young female rats to determine the effect of E2 of PE and DE stages on hippocampal gene expression. We identified 238 genes (at 1.5-fold-change selection criteria, FDR adjusted p-value < 0.05) as differentially expressed genes (DEGs) that responded to E2 between PE and DE stages. Functional analysis based on Gene Ontology (GO) revealed that a higher E2 level corresponded to an increase in gene transcription among most of the DEGs, suggesting biological mechanisms operating differentially in the hippocampus of female rats between PE and DE stages in the estrus cycle; while analysis with Kyoto Encyclopedia of Genes and Genomes database (KEGG) found that the DEGs involving neuroactive ligand-receptor interaction, antigen processing, cell adhesion molecules, and presentation were upregulated in PE stage, whereas DEGs in pathways relating to bile secretion, coagulation cascades, osteoclast differentiation, cysteine and methionine metabolism were upregulated in DE stage of the estrus cycle. The high-fold expression of DEGs was confirmed by a follow-up quantitative real-time PCR. Our findings in this current study have provided fundamental information for further dissection of neuro-molecular mechanisms in the hippocampus in response to E2 fluctuation and its relationship with disorders.
Assuntos
Cisteína , Transcriptoma , Humanos , Animais , Feminino , Ratos , Estrogênios , Estro , HipocampoRESUMO
Methamphetamine (METH), a widely abused stimulant drug, induces psychosis in approximately half of abusers; this effect is becoming a major concern for society. Although the Notch1 signalling pathway has been shown to play a part in the pathogenesis of some psychiatric disorders, its role in METH-induced psychosis (MIP) is still unknown. Here, the METH-induced locomotor sensitization model in rodents is considered to represent the underlying neurochemical changes driving psychoses. We found that the Notch1 signalling was downregulated in the medial prefrontal cortex (mPFC) in sensitized mice. Direct genetic and pharmacological manipulations of Notch1 signalling bidirectionally altered METH-induced locomotor sensitization and other MIP-related behaviours through governing neuronal activity in the mPFC. Moreover, Notch1 signalling negatively regulated GABAB1 receptor expression in the mPFC of METH-sensitized mice through Hes1, a transcriptional repressor in Notch1 signalling. Further, we show that Hes1 can directly bind to the GABAB1 receptor promoter. Notably, pharmacological regulation of the GABAB receptor in the mPFC reversed the changes in METH-induced locomotor sensitization caused by the dysfunction of Notch1 signalling. Together, our findings uncover a previously unrecognised Notch1-Hes1-GABAB1 receptor-dependent mechanism involved in regulating mPFC neuronal activity and behavioural phenotypes in MIP. Our work provides mechanistic insight into the aetiology and pathophysiology of MIP.
Assuntos
Estimulantes do Sistema Nervoso Central , Metanfetamina , Transtornos Psicóticos , Receptores de GABA-B , Receptores Notch , Fatores de Transcrição HES-1 , Animais , Camundongos , Estimulantes do Sistema Nervoso Central/farmacologia , Metanfetamina/farmacologia , Atividade Motora , Córtex Pré-Frontal/metabolismo , Transtornos Psicóticos/metabolismo , Receptores de GABA-B/genética , Receptores de GABA-B/metabolismo , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismoRESUMO
Depression is more prevalent among adolescents than adults, but the underlying mechanisms remain largely unknown. Using a subthreshold chronic stress model, here we show that developmentally regulated expressions of the perineuronal nets (PNNs), and one of the components, Neurocan in the prelimbic cortex (PrL) are important for the vulnerability to stress and depressive-like behaviors in both adolescent and adult rats. Reduction of PNNs or Neurocan with pharmacological or viral methods to mimic the expression of PNNs in the PrL during adolescence compromised resilience to stress in adult rats, while virally mediated overexpression of Neurocan reversed vulnerability to stress in adolescent rats. Ketamine, a recent-approved drug for treatment-resistant depression rescued impaired function of Parvalbumin-positive neurons function, increased expression of PNNs in the PrL, and reversed depressive-like behaviors in adolescent rats. Furthermore, we show that Neurocan mediates the anti-depressant effect of ketamine, virally mediated reduction of Neurocan in the PrL abolished the anti-depressant effect of ketamine in adolescent rats. Our findings show an important role of Neurocan in depression in adolescence, and suggest a novel mechanism for the anti-depressant effect of ketamine.
Assuntos
Ketamina , Neurocam , Animais , Ketamina/metabolismo , Ketamina/farmacologia , Neurocam/metabolismo , Neurônios/metabolismo , Parvalbuminas/metabolismo , Córtex Pré-Frontal/metabolismo , RatosRESUMO
Sleep deprivation (SD) is increasingly common in modern society, which can lead to the dysregulation of inflammatory responses and cognitive impairment, but the mechanisms remain unclear. Emerging evidence suggests that gut microbiota plays a critical role in the pathogenesis and development of inflammatory and psychiatric diseases, possibly via gut microbiota-brain interactions and neuroinflammation. The present study investigated the impact of SD on gut microbiota composition and explored whether alterations of the gut microbiota play a causal role in chronic inflammatory states and cognitive impairment that are induced by SD. We found that SD-induced gut dysbiosis, inflammatory responses, and cognitive impairment in humans. Moreover, the absence of the gut microbiota suppressed inflammatory response and cognitive impairment induced by SD in germ-free (GF) mice. Transplantation of the "SD microbiota" into GF mice activated the Toll-like receptor 4/nuclear factor-κB signaling pathway and impaired cognitive function in the recipient mice. Mice that harbored "SD microbiota" also exhibited increases in neuroinflammation and microglial activity in the hippocampus and medial prefrontal cortex. These findings indicate that gut dysbiosis contributes to both peripheral and central inflammatory processes and cognitive deficits that are induced by SD, which may open avenues for potential interventions that can relieve the detrimental consequences of sleep loss.
Assuntos
Disfunção Cognitiva , Microbioma Gastrointestinal , Animais , Disfunção Cognitiva/etiologia , Disbiose , Microbioma Gastrointestinal/fisiologia , Inflamação/complicações , Camundongos , Privação do Sono/complicaçõesRESUMO
Immune dysregulation, specifically of inflammatory processes, has been linked to behavioral symptoms of depression in both human and rodent studies. Here, we evaluated the antidepressant effects of immunization with altered peptide ligands of myelin basic protein (MBP)-MBP87-99[A91, A96], MBP87-99[A91], and MBP87-99[R91, A96]-in different models of depression and examined the mechanism by which these peptides protect against stress-induced depression. We found that a single dose of subcutaneously administered MBP87-99[A91, A96] produced antidepressant-like effects by decreasing immobility in the forced swim test and by reducing the escape latency and escape failures in the learned helplessness paradigm. Moreover, immunization with MBP87-99[A91, A96] prevented and reversed depressive-like and anxiety-like behaviors that were induced by chronic unpredictable stress (CUS). However, MBP87-99[R91, A96] tended to aggravate CUS-induced anxiety-like behavior. Chronic stress increased the production of peripheral and central proinflammatory cytokines and induced the activation of microglia in the prelimbic cortex (PrL), which was blocked by MBP87-99[A91, A96]. Immunization with MBP-derived altered peptide ligands also rescued chronic stress-induced deficits in p11, phosphorylated cyclic adenosine monophosphate response element binding protein, and brain-derived neurotrophic factor expression. Moreover, microinjections of recombinant proinflammatory cytokines and the knockdown of p11 in the PrL blunted the antidepressant-like behavioral response to MBP87-99[A91, A96]. Altogether, these findings indicate that immunization with altered MBP peptide produces prolonged antidepressant-like effects in rats, and the behavioral response is mediated by inflammatory factors (particularly interleukin-6), and p11 signaling in the PrL. Immune-neural interactions may impact central nervous system function and alter an individual's response to stress.
Assuntos
Antidepressivos/química , Antidepressivos/imunologia , Depressão/imunologia , Depressão/terapia , Imunização , Proteína Básica da Mielina/química , Proteína Básica da Mielina/imunologia , Animais , Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Ansiedade/imunologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/tratamento farmacológico , Depressão/etiologia , Modelos Animais de Doenças , Proteína Básica da Mielina/administração & dosagem , Proteína Básica da Mielina/uso terapêutico , Ratos , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/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
Recent research has used context cues (odor or auditory cues) to target memories during sleep and has demonstrated that they can enhance declarative and procedural memories. However, the effects of external cues re-presented during sleep on emotional memory are still not fully understood. In the present study, we conducted a Pavlovian fear conditioning/extinction paradigm and examined the effects of re-exposure to extinction memory associated contextual tones during slow-wave sleep (SWS) and wakefulness on fear expression. The participants underwent fear conditioning on the first day, during which colored squares served as the conditioned stimulus (CS) and a mild shock served as the unconditioned stimulus (US). The next day, they underwent extinction, during which the CSs were presented without the US but accompanied by a contextual tone (pink noise). Immediately after extinction, the participants were required to take a nap or remain awake and randomly assigned to six groups. Four of the groups were separately exposed to the associated tone (i.e. SWS-Tone group and Wake-Tone group) or an irrelevant tone (control tone, CtrT) (i.e. SWS-CtrT group and Wake-CtrT group), while the other two groups were not (i.e. SWS-No Tone group and Wake-No Tone group). Subsequently, the conditioned responses to the CSs were tested to evaluate the fear expression. All of the participants included in the final analysis showed successful levels of fear conditioning and extinction. During the recall test, the fear responses were significantly higher in the SWS-Tone group than that in the SWS-No Tone group or the SWS-CtrT group, while the Wake-Tone group exhibited more attenuated fear responses than either the Wake-No Tone group or Wake-CtrT group. Otherwise, re-exposure to auditory tones during SWS did not affect sleep profiles. These results suggest that distinct conditions during which re-exposure to an extinction memory associated contextual cue contributes to differential effects on fear expression.
Assuntos
Sinais (Psicologia) , Extinção Psicológica/fisiologia , Medo/fisiologia , Memória/fisiologia , Sono/fisiologia , Vigília/fisiologia , Adulto , Condicionamento Clássico/fisiologia , Feminino , Humanos , Masculino , Adulto JovemRESUMO
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.