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Although the negative effects coming along with opiate withdrawal are in part modulated by L-type calcium channels (LTCCs), the distinctive physiological properties and functions of LTCCs subtypes suggest differential roles of subtypes during withdrawal. The present study aimed to examine the contributions of LTCC subtypes, Cav1.2 and Cav1.3, within the dorsal hippocampus (DH) in naloxone-precipitated morphine withdrawal using the conditioned place aversion (CPA) paradigm. Firstly, we injected the non-specific LTCCs antagonist verapamil into the DH of morphine-dependent rats before conditioning an environment with naloxone-precipitated withdrawal. Our results showed that verapamil blocked the acquisition of CPA. Then, to explore the molecular mechanisms of LTCCs subtypes during withdrawal, we measured the protein expression of Cav1.2 and Cav1.3 in morphine-dependent rats under different conditions. In morphine-dependent rats, conditioning with withdrawal increased Cav1.2 expression in the membrane, while only acute naloxone injection increased the membrane expression of Cav1.3. To further determine the causal roles of LTCCs subtypes in the withdrawal process, we used Cav1.2 siRNA or Cav1.3 shRNA to knock down the expression of subtypes and detected the effects on CPA and somatic withdrawal signs in morphine-dependent rats. Cav1.2 siRNA, but not Cav1.3 shRNA, inhibited the acquirement of CPA and relieved somatic withdrawal symptoms. Together, our findings reveal that Cav1.2, but not Cav1.3 plays an important role in mediating morphine withdrawal, suggesting this subtype may serve as a potential therapeutic target for the treatment of negative effects in opiate dependence.
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Dependência de Morfina , Síndrome de Abstinência a Substâncias , Ratos , Animais , Morfina/farmacologia , Canais de Cálcio Tipo L , Naloxona/farmacologia , Dependência de Morfina/metabolismo , Hipocampo/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Verapamil/farmacologia , Antagonistas de Entorpecentes/farmacologia , Aprendizagem da EsquivaRESUMO
Extinction training during the reconsolidation window following memory recall is an effective behavioral pattern for promoting the extinction of pathological memory. However, promoted extinction by recall-extinction procedure has not been universally replicated in different studies. One potential reason for this may relate to whether initially acquired memory is successfully activated. Thus, the methods for inducing the memory into an active or plastic condition may contribute to promoting its extinction. The aim of this study is to find and demonstrate a manipulatable neural circuit that engages in the memory recall process and where its activation improves the extinction process through recall-extinction procedure. Here, naloxone-precipitated conditioned place aversion (CPA) in morphine-dependent mice was mainly used as a pathological memory model. We found that the locus coeruleus (LC)-dentate gyrus (DG) circuit was necessary for CPA memory recall and that artificial activation of LC inputs to the DG just prior to initiating a recall-extinction procedure significantly promoted extinction learning. We also found that activating this circuit caused an increase in the ensemble size of DG engram cells activated during the extinction, which was confirmed by a cFos targeted strategy to label cells combined with immunohistochemical and in vivo calcium imaging techniques. Collectively, our data uncover that the recall experience is important for updating the memory during the reconsolidation window; they also suggest a promising neural circuit or target based on the recall-extinction procedure for weakening pathological aversion memory, such as opioid withdrawal memory and fear memory.
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Giro Denteado , Síndrome de Abstinência a Substâncias , Camundongos , Animais , Giro Denteado/fisiologia , Analgésicos Opioides , Locus Cerúleo , Medo/fisiologia , Naloxona/farmacologia , Extinção PsicológicaRESUMO
Embryonic morphine exposure (EME) leads to abnormal brain development and behavior in the offspring, and the functional alteration of γ-aminobutyric acid (GABA) system is considered to be one of the important mechanisms. To mimic the problem of susceptibility of human gestational drug abuse on addictive drugs in offspring, we administered morphine exposure on days 5-8 and 13-16 of chicken embryo development and examined the functions of GABA neurons and their receptors in postnatal chicks by neuroelectrophysiology, immunohistochemistry and behavioral methods. We found that morphine exposure during embryonic stages 5-8 (MorphineE5-8) significantly reduced the incidence of spontaneous inhibitory postsynaptic potentiation (IPSP) and the induction of evoked IPSP and the mean amplitude of GABAA agonist muscimol-induced response in the intermediate medial interstitial (IMM) region, compared to naïve controls or saline-exposed chicks. The results of immunocytochemistry further suggest that MorphineE5-8 decreased the synaptic density of GAD-expressing sites in the IMM, while increased the expression of the GABAA receptor subtype γ2 isoform. Behavioral results found that Morphine5-8 treatment de-inhibited morphine-induced psychomotor responses in postnatal chicks. Morphine exposure at embryonic stages 13-16 (MorphineE13-16) showed no significant changes in the above indicators compared to the saline group. Evidence suggests that early embryonic morphine exposure leads to defects in GABAergic function in the IMM, which in turn alters the responsiveness of postnatal chicks to addictive drugs. These results will help to understand the GABA mechanisms by which embryonic addictive drug exposure contributes to offspring susceptibility to addiction.
Assuntos
Galinhas , Morfina , Humanos , Animais , Embrião de Galinha , Morfina/farmacologia , Galinhas/metabolismo , Ácido gama-Aminobutírico/metabolismo , Encéfalo/metabolismo , Neurônios , Receptores de GABA-A/metabolismoRESUMO
Borehole extraction is the basic method used for control of gases in coal mines. The quality of borehole sealing determines the effectiveness of gas extraction, and many influential factors result in different types of borehole leaks. To accurately identify the types of leaks from boreholes, characteristic parameters, such as gas concentration, flow rate and negative pressure, were selected, and new indexes were established to identify leaks. A model based on an improved naive Bayes framework was constructed for the first time in this study, and it was applied to analyse and identify boreholes in the 229 working face of the Xiashijie Coal Mine. Eight features related to single hole sealing sections were taken as parameters, and 144 training samples from 18 groups of real-time monitoring time series data and 96 test samples from 12 groups were selected to verify the accuracy and speed of the model. The results showed that the model eliminated strong correlations between the original characteristic parameters, and it successfully identified the leakage conditions and categories of 12 boreholes. The identification rate of the new model was 98.9%, and its response time was 0.0020 s. Compared with the single naive Bayes algorithm model, the identification rate was 31.8% better, and performance was 55% faster. The model developed in this study fills a gap in the use of algorithms to identify types of leaks in boreholes, provides a theoretical basis and accurate guidance for the evaluation of the quality of the sealing of boreholes and borehole repairs, and supports the improved use of boreholes to extract gases from coal mines.
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Carvão Mineral , Gases , Teorema de BayesRESUMO
The putamen (Put) is necessary for habitual actions, while the nucleus caudate (Cd) is critical for goal-directed actions. However, compared with the natural reward (such as sucrose)-seeking habit, how drug-related dysfunction or imbalance between the Put and Cd is involved in cocaine-seeking habit, which is not easy to bias behavior to goal-directed actions, is absent. Therefore, in our present study, in comparison with sucrose-habitual behavior, we evaluated the distinctive changes of the two subtypes of dopamine (DA) receptors (D1R and D2R) in cocaine-seeking habitual behavior animals. Moreover, the adaptive changes of Cav1.2 and Cav1.3, as prime downstream targets of D1R and D2R respectively, were also assessed. Our results showed that a similar percentage of the animals exhibited habitual seeking behavior after cocaine or sucrose variable-interval self-administration (SA) training in tree shrews. In addition, compared with animals with non-habitual behavior, animals with cocaine habitual behavior showed higher D1Rs and Cav1.2 expression in the Put accompanied with lower D2Rs and Cav1.3 expression in the Cd. However, after sucrose SA training, animals with habitual behavior only showed lower membrane expression of D2R in the Put than animals with non-habitual behavior. These results suggested that the upregulation of D1Rs-Cav1.2 signaling may lead to hyper-excitability of the Put, and the inactivation of D2Rs-Cav1.3 signaling may result in depressed activity in the Cd. This imbalance function between the Put and Cd, which causes an inability to shift between habits and goal-directed actions, may underlie the compulsive addiction habit.
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Studies of humans, mammalian animals, and chicks reveal that embryonic opioid exposure (EOE) changes the response to pharmacological rewards in postnatal individuals, which may be an outcome of permanent alterations to neural systems. However, the mechanism behind this alteration remains unclear. GABA transmitter has a trophic effect on early GABAergic neuronal development, and EOE decreases GABA concentration in developing brains. Here, we determined whether the development of inhibitory transmission was affected by EOE and whether altered GABA release was the underlying mechanism. We revealed that morphine administration in the early but not the late embryonic period decreased inhibitory transmission in the striatum of chicks. Meanwhile, day-old chicks with early embryonic morphine exposure showed increased psychomotor activity after acute morphine injection compared with saline-exposed chicks. Furthermore, GABA injection in the chick embryo following morphine administration mitigated damage to GABA transmission and recovered the behavioral response to acute morphine injection in chicks. Collectively, our findings suggest that abnormal GABA release in the early embryonic period induced by opioid exposure is attributable to functional and structural developments of the GABA synapse, and that the dysfunction of striatal GABA transmission may be linked to enhanced psychomotor response during initial drug exposure in postnatal life.
Assuntos
Analgésicos Opioides , Morfina , Analgésicos Opioides/farmacologia , Animais , Embrião de Galinha , Galinhas , Corpo Estriado , Mamíferos , Morfina/farmacologia , Ácido gama-AminobutíricoRESUMO
Impairing reconsolidation may disrupt drug memories to prevent relapse, meanwhile long-term transcription regulations in the brain regions contribute to the occurrence of emotional memories. The basolateral amygdala (BLA) is involved in the drug-cue association, while the nucleus accumbens (NAc) responds to the drug reward. Here, we assessed whether DNA methyltransferases (Dnmts) in these two brain regions function identically in the reconsolidation of morphine reward memory. We show that Dnmts inhibition in the BLA but not in the NAc after memory retrieval impaired reconsolidation of a morphine reward memory. Moreover, the mRNA levels of Dnmt3a and Dnmt3b, rather than Dnmt1, in the BLA were continuously upregulated after retrieval. We further identified the differentially methylated regions (DMRs) in genes in the BLA after retrieval, and focused on the DMRs located in gene promoter regions. Among them were three genes (Gnas, Sox10, and Pik3r1) involved in memory modulation. Furthermore, Gnas promoter hypermethylation was confirmed to be inversely correlated with the downregulation of Gnas mRNA levels. The findings indicate that the specific transcription regulation mechanism in the BLA and NAc on reconsolidation of opiate-associated memories can be dissociable, and DNA hypermethylation of Gnas in the BLA is necessary for the reconsolidation of morphine reward memories.
Assuntos
Complexo Nuclear Basolateral da Amígdala , Morfina , Tonsila do Cerebelo , Animais , DNA , Morfina/farmacologia , Regiões Promotoras Genéticas , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , RecompensaRESUMO
Purpose of the review: The abuse of opioids induces many terrible problems in human health and social stability. For opioid-dependent individuals, withdrawal memory can be reactivated by context, which is then associated with extremely unpleasant physical and emotional feelings during opioid withdrawal. The reactivation of withdrawal memory is considered one of the most important reasons for opioid relapse, and it also allows for memory modulation based on the reconsolidation phenomenon. However, studies exploring withdrawal memory modulation during the reconsolidation window are lacking. By summarizing the previous findings about the reactivation of negative emotional memories, we are going to suggest potential neural regions and systems for modulating opioid withdrawal memory. Recent findings: Here, we first present the role of memory reactivation in its modification, discuss how the hippocampus participates in memory reactivation, and discuss the importance of noradrenergic signaling in the hippocampus for memory reactivation. Then, we review the engagement of other limbic regions receiving noradrenergic signaling in memory reactivation. We suggest that noradrenergic signaling targeting hippocampus neurons might play a potential role in strengthening the disruptive effect of withdrawal memory extinction by facilitating the degree of memory reactivation. Summary: This review will contribute to a better understanding of the mechanisms underlying reactivation-dependent memory malleability and will provide new therapeutic avenues for treating opioid use disorders.
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The distinct preferences between goal-directed and habit-directed behaviors involve numerous neurodegenerative and psychiatric disorders. Chronic stress during adulthood biases behavior toward habit-oriented strategies. However, it remains to be studied how adolescence, as a stage in which brain regions are still undergoing development, suffering stress will affect this preference. Here, we exposed rats to chronic unpredictable stress (CUS) at PND 21 to PND 33 and PND 34 to PND 47 to examine its effect on sugar pellet-based instrumental behavior in adulthood. We showed that rats exposed to CUS in middle adolescence had a biased goal-directed strategy rather than a habit-oriented strategy in adulthood, whereas CUS exposure in early adolescence did not have this effect. Moreover, middle adolescent CUS caused the downregulation of the N-methyl-d-aspartate receptor subtype 2 B (NR2B) in the dorsolateral striatum (DLS) rather than in the dorsomedial striatum (DMS), whereas no change was observed in NR2A or the dopamine D1 receptor (D1R) or the dopamine D2 receptor (D2R) in the DLS. Together, these findings suggest that CUS in middle adolescence inhibits habitual behavior in adulthood and downregulates the expression of NR2B in DLS, providing new evidence to understand the molecular mechanisms of abnormal habitual behaviors induced by adolescent stress.
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Objetivos , N-Metilaspartato , Adolescente , Adulto , Animais , Viés , Corpo Estriado , Humanos , Masculino , Motivação , N-Metilaspartato/metabolismo , N-Metilaspartato/farmacologia , RatosRESUMO
Chronic stress could lead to a bias in behavioral strategies toward habits. However, it remains unclear which neuronal system modulates stress-induced behavioral abnormality during decision making. The corticotropin-releasing factor (CRF) system in the medial prefrontal cortex (mPFC), which has been implicated in governing strategy choice, is involved in the response to stress. The present study aimed to clarify whether altered function in cortical CRF receptors is linked to abnormal behaviors after chronic stress. In results, mice subjected to a 10-day social defeat preferred to use a habitual strategy. The infralimbic cortex (IL), but not the prelimbic cortex (PL) or anterior cingulate cortex (ACC), showed higher cFos expression in stress-subjected mice than in control mice, which may be associated with habitual behavior choice. Furthermore, CRF receptor 1 (CRFR1) agonist and antagonist infusion in IL during behavioral training mimicked and rescued stress-caused behavioral change in the decision-making assessment, respectively. An electrophysiological approach showed that the frequencies of both spontaneous IPSC and spontaneous EPSC, but not their amplitude, increased after stress and were modulated by CRFR1 agents. Further recordings revealed that an increased ratio of excitation to inhibition (E/I ratio) of IL by stress was rescued under conditions with CRFR1 antagonist. Collectively, these data indicate that CRFR1 plays a critical role in stress-permitted or enhanced glutamatergic and GABAergic presynaptic transmission in direct or indirect ways, as well as the modulation for E/I ratio in the IL. Thus, CRFR1 in the mPFC may be a proper target for treating cases of chronic stress-altered behavior.
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Córtex Pré-Frontal , Receptores de Hormônio Liberador da Corticotropina , Animais , Hormônio Liberador da Corticotropina/metabolismo , Camundongos , Córtex Pré-Frontal/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Estresse Psicológico/metabolismoRESUMO
Drug-related memory can be transiently destabilized by memory retrieval, after which memories are reconsolidated. Neurons in the basolateral amygdala (BLA) that are activated by emotional information may be one of the key mechanisms underlying this destabilization. However, the specific neural circuits underlying this destabilization process remain unknown. Because BLA receives noradrenergic inputs from the nucleus tractus solitarius (NTS) and locus coeruleus (LC), we studied the role of afferent projections into the BLA in the destabilization of morphine self-administration memory in rats. We first showed that morphine (unconditioned stimulus, US) + morphine-associated conditioned stimuli (CS) exposure, rather than CS exposure alone, destabilized morphine self-administration memory. Then, we measured projection-specific activation after the US + CS or CS retrieval test using c-fos (activity marker)-labeling in projection areas. Compared with CS exposure, we found that US + CS exposure induced more neuronal activation in the BLA and NTS but not in the LC. Next, we determined the effects of chemogenetic inactivation or activation of NTS or LC projections to BLA (NTS â BLA or LC â BLA) on this destabilization. We found that NTS â BLA, but not LC â BLA inactivation during memory retrieval, prevented memory destabilization induced by US + CS exposure. Furthermore, NTS â BLA, but not LC â BLA activation during CS retrieval induced destabilization. Thus, our results identify a specific neural circuit underlying the transformation of a stable opiate-associated memory into an unstable memory and subsequently guide reconsolidation.
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Analgésicos Opioides/farmacologia , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Locus Cerúleo/fisiologia , Memória/efeitos dos fármacos , Morfina/farmacologia , Núcleo Solitário/fisiologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Masculino , Norepinefrina , Ratos , AutoadministraçãoRESUMO
Patrinia villosa (Thunb.) Juss (P. villosa), a perennial herb, is widely used as a medicinal plant in Chinese folk. This study aims to isolate and identify the chemical constituents from P. villosa and evaluate their antioxidant activity. Normal silica column chromatography, ODS silica column chromatography, Sephadex LH-20 column chromatography and semi-preparative HPLC methods were used to obtain a new compound named 3-n-pentadecyl-4'-methoxyluteolin (1) and two known compounds including luteolin-7-O-ß-D-glucuronide methyl ester (2) and apigenin-7-O-ß-D-glucuronide methyl ester (3). The antioxidant activity of these compounds was determined by DPPH and ABTS methods and the IC50 values were calculated. The IC50 values of ABTS scavenging activity of 1, 2 and 3 were 12.99 ± 0.09 µM, 7.13 ± 0.07 µM and 5.15 ± 0.08 µM, respectively, and the IC50 values of DPPH scavenging activity of 1, 2 and 3 were 51.86 ± 0.41 µM, 23.95 ± 0.71 µM and 25.06 ± 0.65 µM, respectively. All the compounds exhibited good antioxidant activities in vitro.
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Patrinia , Antioxidantes/farmacologia , Ésteres , Flavonoides/farmacologia , Patrinia/química , Dióxido de SilícioRESUMO
The progressively increased motivation for cocaine during abstinence is closely associated with the dysfunction of dopamine (DA) system. As DA receptors also dynamically regulate L-type calcium channels (LTCCs), in this study we examined how DA receptors (D1R or D2R) and LTCCs (Cav 1.2 or Cav 1.3) exert their influences on cocaine-seeking in a tree shrew (Tupaia belangeri chinensis) model. First, we demonstrated the 'incubation' effect by showing tree shrews exhibited a significantly higher seeking behaviour on withdrawal day (WD) 45 than on WD1. Then, we confirmed that longer abstinence period induced higher D1R expression in the nucleus accumbens (NAc). Next, we showed that LTCCs in the NAc participated in drug seeking. Moreover, Cav 1.2 expression in the NAc was increased on WD45, and disruption of the Cav 1.2 inhibited drug seeking. Finally, we found that D1R antagonist blocked the increase of Cav 1.2 on drug-seeking test. Collectively, these findings suggest that D1R-mediated upregulation of Cav 1.2 is involved in the incubation of cocaine craving.
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Canais de Cálcio Tipo L/metabolismo , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Corpo Estriado/fisiopatologia , Comportamento de Procura de Droga/fisiologia , Receptores de Dopamina D1/metabolismo , Animais , Masculino , Motivação , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Dopaminérgicos/metabolismo , Autoadministração , Fatores de Tempo , Tupaiidae , Regulação para CimaRESUMO
The infants experience withdrawal from opiates, and time-dependent adaptations in neuronal activity of nucleus accumbens (NAc) may be crucial for this process. A key adaptation is an increased release of acetylcholine. The present study investigates muscarinic acetylcholine receptors (mAChRs) functions in the NAc at short-term (SWT) and long-term (LWT) withdrawal time following chronic morphine exposure in neonatal rats. The inhibitory role of presynaptic mAChRs activation in spontaneous excitatory postsynaptic currents (sEPSCs) in medium spiny neurons was decreased at LWT but not at SWT. Whereas, the excitatory role of post/extrasynaptic mAChRs activation in membrane currents was reduced at LWT but enhanced at SWT. Furthermore, the inhibitory effect of acute morphine on post/extrasynaptic mAChRs-mediated inward currents was enhanced at SWT but not at LWT. These results suggest that withdrawal from morphine leads to downregulation of presynaptic and post/extrasynaptic mAChRs functions in the NAc, which may coregulate the development of withdrawal in neonates.NEW & NOTEWORTHY We investigated for the first time how the duration of withdrawal affects mAChRs functions in the nucleus accumbens in neonatal rats. Compared with short-term withdrawal time, rats showed downregulation of presynaptic and post/extrasynaptic mAChRs functions during long-term withdrawal time. Our finding introduces a new possible correlation between the mAChRs dysfunction in the nucleus accumbens and the development of withdrawal in neonates.
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Potenciais Pós-Sinápticos Excitadores/fisiologia , Morfina/farmacologia , Entorpecentes/farmacologia , Síndrome de Abstinência Neonatal/metabolismo , Núcleo Accumbens/metabolismo , Receptores Muscarínicos/metabolismo , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Masculino , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Fatores de TempoRESUMO
The development of opioid addiction involves DNA methylation. Accordingly, the DNA demethylation, induced by ten-eleven translocation (Tet) enzymes, may represent a novel approach to prevent opioid addiction. The present study examined the role of TET1 and TET3 in the development of morphine-seeking behavior in rats. We showed that 1 day of morphine self-administration (SA) training upregulated TET3 but not TET1 expression in the hippocampal CA1. With 7 days of morphine SA training, the expression of TET3 in the CA1 returned to the baseline level, while the TET1 expression was downregulated. No change of TET1 and TET3 in the nucleus accumbens shell was observed in morphine SA trained rats, or in the yoked morphine rats, or in rats trained for saccharin SA. Furthermore, we found that knocking down TET3 expression in the CA1 accelerated the acquisition of morphine SA, while overexpression of the catalytic domain of TET1 in the CA1 attenuated the acquisition. Together, these findings suggest that TET1 and TET3 in the CA1 are important epigenetic modulators involved in the morphine-seeking behavior and provide a new strategy in the treatment of opioid addiction.
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Dioxigenases/metabolismo , Hipocampo/metabolismo , Morfina/metabolismo , Animais , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo , Masculino , Núcleo Accumbens/metabolismo , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Ratos , AutoadministraçãoRESUMO
OBJECTIVE: Previous studies have linked emotional eating with negative affect and decreased inhibitory control. However, studies on inhibitory control have generally focused on motor inhibition. How to stop higher-level cognitive processes, such as food-related memory retrieval or voluntary thoughts, received few direct investigation in field of food intake or food-related decision making. The current study, adopting Anderson and Green's Think/No-Think paradigm, aimed to investigate the relationship between emotional eating, negative affect and food-related memory suppression. METHOD: Sixty-one young females participated in the current study, during which they finished food specific Think/No-Think task. Their positive and negative affect and eating style were measured using Positive Affect and Negative Affect Schedule and Dutch Eating Behavior Question. The reward value of the food item used in the Think/No-Think task was measured using liking and wanting ratings. RESULTS: As hypothesized, negative affect and emotional eating were associated with decreased memory suppression of palatable food cues. Further analysis showed that higher emotional eating was associated with greater wanting only among the food items which were previously suppressed however remembered later. DISCUSSION: The current study presents the first evidence that negative affect and emotional eating were associated with impaired memory suppression of palatable food cues, and it provided insight into the interaction between reward valuation for the food cues and hippocampal memory mechanisms during retrieval suppression.
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Afeto , Comportamento Alimentar/psicologia , Inibição Psicológica , Transtornos da Memória/psicologia , Rememoração Mental , Adolescente , Sinais (Psicologia) , Ingestão de Alimentos/psicologia , Emoções , Feminino , Alimentos , Humanos , Memória , Recompensa , Análise e Desempenho de Tarefas , Adulto JovemRESUMO
BACKGROUND: Identifying neural substrates that are differentially affected by drugs of abuse and natural rewards is key to finding a target for an efficacious treatment for substance abuse. Melanin-concentrating hormone is a polypeptide with an inhibitory effect on the mesolimbic dopamine system. Here we test the hypothesis that melanin-concentrating hormone in the lateral hypothalamus and nucleus accumbens shell is differentially involved in the regulation of morphine and food-rewarded behaviors. METHODS: Male Sprague-Dawley rats were trained with morphine (5.0 mg/kg, subcutaneously) or food pellets (standard chow, 10-14 g) to induce a conditioned place preference, immediately followed by extinction training. Melanin-concentrating hormone (1.0 µg/side) or saline was infused into the nucleus accumbens shell or lateral hypothalamus before the reinstatement primed by morphine or food, and locomotor activity was simultaneously monitored. As the comparison, melanin-concentrating hormone was also microinjected into the nucleus accumbens shell or lateral hypothalamus before the expression of food or morphine-induced conditioned place preference. RESULTS: Microinfusion of melanin-concentrating hormone into the nucleus accumbens shell (but not into the lateral hypothalamus) prevented the reinstatement of morphine conditioned place preference but had no effect on the reinstatement of food conditioned place preference. In contrast, microinfusion of melanin-concentrating hormone into the lateral hypothalamus (but not in the nucleus accumbens shell) inhibited the reinstatement of food conditioned place preference but had no effect on the reinstatement of morphine conditioned place preference. CONCLUSIONS: These results suggest a clear double dissociation of melanin-concentrating hormone in morphine/food rewarding behaviors and melanin-concentrating hormone in the nucleus accumbens shell. Melanin-concentrating hormone could be a potential target for therapeutic intervention for morphine abuse without affecting natural rewards.
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Comportamento de Procura de Droga/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Hormônios Hipotalâmicos/farmacologia , Melaninas/farmacologia , Morfina/farmacologia , Núcleo Accumbens/metabolismo , Hormônios Hipofisários/farmacologia , Animais , Condicionamento Operante/efeitos dos fármacos , Hormônios Hipotalâmicos/administração & dosagem , Masculino , Melaninas/administração & dosagem , Microinjeções , Hormônios Hipofisários/administração & dosagem , Ratos , Ratos Sprague-Dawley , RecompensaRESUMO
Drug-reinforced excessive operant responding is one fundamental feature of long-lasting addiction-like behaviors and relapse in animals. However, the transcriptional regulatory mechanisms responsible for the persistent drug-specific (not natural rewards) operant behavior are not entirely clear. In this study, we demonstrate a key role for one of the de novo DNA methyltransferase, DNMT3a, in the acquisition of morphine self-administration (SA) in rats. The expression of DNMT3a in the hippocampal CA1 region but not in the nucleus accumbens shell was significantly up-regulated after 1- and 7-day morphine SA (0.3 mg/kg/infusion) but not after the yoked morphine injection. On the other hand, saccharin SA did not affect the expression of DNMT3a or DNMT3b. DNMT inhibitor 5-aza-2-deoxycytidine (5-aza) microinjected into the hippocampal CA1 significantly attenuated the acquisition of morphine SA. Knockdown of DNMT3a also impaired the ability to acquire the morphine SA. Overall, these findings suggest that DNMT3a in the hippocampus plays an important role in the acquisition of morphine SA and may be a valid target to prevent the development of morphine addiction.
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Região CA1 Hipocampal/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Dependência de Morfina/metabolismo , Morfina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , DNA Metiltransferase 3A , Modelos Animais de Doenças , Masculino , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Entorpecentes/farmacologia , Ratos , Ratos Sprague-Dawley , Recompensa , AutoadministraçãoRESUMO
Nowadays, cell membrane-targeted therapy, which owns high antitumor efficacy by avoiding cell barriers, has received great attention. Here, a cell membrane-targeted self-delivery theranostic chimeric peptide CMP-PpIX is designed for simultaneously targeted photodynamic therapy (PDT) of tumor and real-time therapeutic feedback. Self-assembled CMP-PpIX nanoparticles can effectively accumulate in tumor by enhanced permeability and retention effect without additional vector. And this chimeric peptide CMP-PpIX has low background fluorescence, which is due to its relatively high intramolecular Förster resonance energy transfer (FRET) quenching efficiency between 5(6)-carboxyfluorescein (FAM) and 4-(dimethylaminoazo)-benzene-4-carboxylic acid (Dabcyl). More importantly, CMP-PpIX can be anchored on the tumor cell membrane for more than 8 h. Under irradiation, reactive oxygen species produced by CMP-PpIX directly damage cell membrane and rapidly induce apoptosis, which significantly improve the efficacy of PDT in vitro and in vivo. Then, peptide sequence Asp-Glu-Val-Asp (DEVD) is subsequently cleaved by activated caspase-3 and activated caspase-7, which separates the FAM and Dabcyl and terminates the FRET process. Therefore, fluorescence of FAM is recovered to monitor the expression of activated caspase-3 in vitro and in vivo to feedback real-time PDT therapeutic efficacy. In general, a novel cell membrane-targeted self-delivery theranostic chimeric peptide offers new promise for effective imaging-guided PDT.
Assuntos
Membrana Celular/metabolismo , Nanopartículas/química , Peptídeos/química , Fármacos Fotossensibilizantes/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Feminino , Transferência Ressonante de Energia de Fluorescência , Corantes Fluorescentes/química , Humanos , Luz , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Nanopartículas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Peptídeos/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Protoporfirinas/química , Protoporfirinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The ability to identify strange conspecifics in societies is supported by social memory, which is vital for gregarious animals and humans. The function of hippocampal principal neurons in social memory has been extensively investigated; however, the nonprincipal neuronal mechanism underlying social memory remains unclear. Here, we first observed parallel changes in the ability for social recognition and the number of parvalbumin interneurons (PVIs) in the ventral CA1 (vCA1) after social isolation. Then, using tetanus toxin-mediated neuronal lesion and optogenetic stimulation approaches, we revealed that vCA1-PVIs specifically engaged in the retrieval stage of social memory. Finally, through the in vivo Ca2+ imaging technique, we demonstrated that vCA1-PVIs exhibited higher activities when subjected mice approached a novel mouse than to a familiar one. These results highlight the crucial role of vCA1-PVIs for distinguishing novel conspecifics from other individuals and contribute to our understanding of the neuropathology of mental diseases with social memory deficits.