Berberine ameliorates nonalcoholic fatty liver disease-induced bone loss by inhibiting ferroptosis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) may contribute to osteoporosis. Berberine is a traditional Chinese medicine and was recently shown to be beneficial in NAFLD. However, little is known about its impact on bone loss induced by NAFLD. AIM: We aimed to explore the role of berberine in bone loss and determine its underlying mechanisms in NAFLD. METHODS: C57BL/6 mice were fed a high-fat high-fructose high-glucose diet (HFFGD) for 16 weeks to establish a NAFLD mouse model. The mice were administered berberine (300 mg/kg/d) by gavage, and fatty liver levels and bone loss indicators were tested. RESULTS: Berberine significantly improved HFFGD-induced weight gain, hepatic lipid accumulation and increases in serum liver enzymes, thereby alleviating NAFLD. Berberine increased trabecular number (Tb. N), trabecular thickness (Tb. Th), bone volume to tissue volume ratio (BV/TV), and decreased trabecular separation (Tb. Sp) and restored bone loss in NAFLD. Mechanistically, berberine significantly inhibited ferroptosis and 4-hydroxynonenal (4-HNE), prostaglandin-endoperoxide synthase 2 (PTGS2), and transferrin (TF) levels and increased ferritin heavy chain (FTH) levels in the femurs of HFFGD-fed mice. Moreover, berberine also activated the solute carrier family 7 member 11 (SLC7A11)/glutathione (GSH)/glutathione peroxidase 4 (GPX4) signaling pathway. CONCLUSION: Berberine significantly ameliorates bone loss induced by NAFLD by activating the SLC7A11/GSH/GPX4 signaling pathway and inhibiting ferroptosis. Therefore, berberine may serve as a therapeutic agent for NAFLD-induced bone loss.

3D hotspot engineering and analytes strategy enabled ultrasensitive SERS platform for biosensing of depression biomarker.

Nowadays, the diagnose of depression mainly relies on clinical examination while impossible to accurately evaluate the occurrence of depression. Chemical approaches are captivating to analyze stress biomarkers for feedbacking body's endocrine response to stress stimuli. However, it remains challenging in exploring accurate, reliable and sensitive approaches. Herein, we rationally design a newly SERS platform with integrated hotspots engineering and analyte strategy to achieve highly sensitive analysis for estrogen, a typical depression biomarker in adolescent female. On the one hand, the 3D micro/nano plasmonic substrate containing Au-Ag Alloy Nanourchins (AAA-NUs) and arrays-based monolayer films of Au nanoparticles (Au NSs) was constructed to achieve high density and availability of hotspots. On the other hand, the analyte strategy was designed via rapid azotizing reaction to further enhance the scattering cross-section of estrogen in the form of azido compounds. With the synergism of them, the proposed SERS platform displayed high sensitivity for estrogen with a limit of detection down to 10-11 mg/mL. More importantly, the blood estrogen levels of depressed patients were evaluated via the proposed SERS platform and presented high consistence with clinical diagnostic results. This integrated SERS platform paves the way for universal and ultrasensitive biosensing and possess great potential for applying in multi-target detection and disease prediction.

TRPV1 is a risk factor for sleep disturbance in patients with gastro-oesophageal reflux disease: a case control study.

BACKGROUND/AIMS: Gastro-oesophageal reflux disease (GORD) is a chronic high-morbidity disease with a bidirectional relationship with sleep disturbance (SD) that may occur via the transient receptor potential vanilloid type 1 receptor (TRPV1) in the oesophageal mucosa. Yet the related mechanism was still unclear, the aim of this study is to investigate whether TRPV1 is associated with the presence of SD in GORD patients. METHODS: A case-control study was performed. After the screening, A total of 88 subjects were assigned to GORD without sleep disturbance (GORD + NOSD, n = 28), GORD comorbid sleep disturbance (GORD + SD, n = 30) and matched healthy controls (n = 30). Mucosal tissue was obtained from the participants by digestive endoscopy, the levels of TRPV1 expressed in the oesophageal mucosa were detected via RT-qPCR and western blot in different groups, and the correlation between GORD and SD were also analysed. RESULTS: In this study, we found that the Gastroesophageal Reflux Disease Diagnostic Questionnaire (GerdQ) scores was positively correlated with Pittsburgh Sleep Quality Index (PSQI) scores but negatively correlated with total sleep time (TST). We also found that the level of TRPV1 expressed in the oesophageal mucosa of GORD + SD was significantly higher than GORD + NOSD patients, and they were all higher than healthy controls. CONCLUSION: The current study suggested a closer link exists between GORD and sleep disturbance, and TRPV1 in oesophageal mucosa may be a crucial factor affecting sleep in GORD patients.

Benzodiazepine-Receptor Agonist Utilization in Outpatients with Anxiety Disorder: A Retrospective Study Based on Electronic Healthcare Data from a Large General Tertiary Hospital.

Benzodiazepine-receptor agonists (BZRAs), including benzodiazepines (BZDs) and drugs related to BZDs (Z-drugs), are commonly used for anxiety, but often have side effects. We retrospectively investigated the utilization and prescription characteristics of BZRAs for patients with anxiety disorders in a large tertiary care general hospital between 2018 and 2021, based on electronic healthcare records. We also examined the pattern of simultaneous consumption of multiple BZRA drugs, and the diseases coexisting with anxiety that are associated with this. The numbers of patients and BZRA prescriptions increased over the 4 years. Moreover, 7195 prescriptions from 694 patients contained two or more BZRAs, of which 78.08% contained both BZDs and Z-drugs, 19.78% contained multiple BZDs, and 2.14% contained multiple Z-drugs. For anxiety patients with concomitant Alzheimer's disease or Parkinson's disease, and dyslipidemia, they were more likely to consume multiple BZRAs simultaneously, whereas patients with concomitant insomnia, depression, hypertension, diabetes, or tumors were less likely to consume multiple BZRAs (all p < 0.05). Furthermore, older patients who consume multiple BZRAs simultaneously may have higher probabilities of long-term drug use. Better interventions supporting standardized BZD utilization may be needed to minimize the side effects of inappropriate BZRA administration.

Ruxolitinib Alleviates Inflammation, Apoptosis, and Intestinal Barrier Leakage in Ulcerative Colitis via STAT3.

BACKGROUND: Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disorder of the colonic mucosa with increasing prevalence and limited management. Ruxolitinib is a new anti- JAK/STAT3 biologic agent that has shown potential in protecting against colitis. METHODS: We first constructed an in vivo UC model and an in vitro colonic epithelial cell inflammation model. Ruxolitinib was administered via gavage in mice. After treatment, colon tissues, cells, and cell lysates were collected and prepared for histological evaluation, immunohistochemistry, immunofluorescence staining, quantitative reverse-transcriptase polymerase chain reaction, Western blotting, terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining, and cytokine analysis. STAT3 expression was silenced and overexpressed via small interfering RNA and overexpression plasmid transfection, respectively, and quantitative reverse-transcriptase polymerase chain reaction was used to examine the downstream effects. RESULTS: Ruxolitinib administration significantly alleviated colitis both in vivo and in vitro, as manifested by reduced body weight loss, shortened colon lengths, relieved disease activity (measured by the disease activity index), and prolonged survival. A mechanistic study showed that ruxolitinib attenuated nuclear factor kappa B-induced inflammation, reduced apoptosis, and ameliorated epithelial barrier leakage, and thereby reduced colitis activity in vivo. STAT3 knockdown partially reversed the protective effect of ruxolitinib against colitis, while STAT3 overexpression exaggerated the reductions in proinflammatory cytokine levels upon ruxolitinib treatment. CONCLUSIONS: We demonstrate that ruxolitinib alleviates colitis by inhibiting nuclear factor kappa B-related inflammation and apoptosis in addition to restoring epithelial barrier function via STAT3, providing a new strategy for UC treatment.

We studied the effect and mechanism of ruxolitinib on ulcerative colitis. We discovered that ruxolitinib administration significantly alleviated murine colitis by relieving disease activity and prolonged survival through intestinal epithelial cell nuclear factor kappa B­induced inflammation, reduced apoptosis, and ameliorated epithelial barrier leakage via STAT3.

Efficacy of an internet-based cognitive behavioral therapy for subthreshold depression among Chinese adults: a randomized controlled trial.

BACKGROUND: Subthreshold depression (sD) negatively impacts well-being and psychosocial function and is more prevalent compared with major depressive disorder (MDD). However, as adults with sD are less likely to seek face-to-face intervention, internet-based cognitive-behavioral therapy (ICBT) may overcome barriers of accessibility to psychotherapy. Although several trials explored the efficacy of ICBT for sD, the results remain inconsistent. This study evaluated whether ICBT is effective in reducing depressive symptoms among Chinese adults with sD. METHODS: A randomized controlled trial was performed. The participants were randomly assigned to 5 weeks of ICBT, group-based face-to-face cognitive-behavioral therapy (CBT), or a waiting list (WL). Assessments were conducted at baseline, post-intervention and at a 6-month follow-up. The primary outcome measured depressive symptoms using the Center for Epidemiological Studies Depression Scale (CES-D). Outcomes were analyzed using a mixed-effects model to assess the effects of ICBT. RESULTS: ICBT participants reported greater reductions on all the outcomes compared to the WL group at post-intervention. The ICBT group showed larger improvement on the Patient Health Questionnaire-9 (PHQ-9) at post-intervention (d = 0.12) and at follow-up (d = 0.10), and with CES-D at post-intervention (d = 0.06), compared to the CBT group. CONCLUSIONS: ICBT is effective in reducing depressive symptoms among Chinese adults with sD, and improvements in outcomes were sustained at a 6-month follow-up. Considering the low rates of face-to-face psychotherapy, our findings highlight the considerable potential and implications for the Chinese government to promote the use of ICBT for sD in China.

Left intermittent theta burst stimulation combined with right low-frequency rTMS as an additional treatment for major depression: A retrospective study.

Background: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depression (MD). We retrospectively analyzed the efficacy of intermittent theta burst stimulation (iTBS) on the left dorsolateral prefrontal cortex (DLPFC) combined with low-frequency rTMS (LF-rTMS) on the right DLPFC as an additional therapy to standard medication treatment. Materials and Methods: The study included 54 patients with MD who completed 10 courses (5 days per week) of rTMS as an add-on therapy. Thirty patients were treated in the combination group (120% resting motor threshold; left DLPFC, iTBS, 600 stimuli + right DLPFC, 1-Hz rTMS, 600 stimuli), while 24 patients were in the high-frequency rTMS (HF-rTMS) group (120% resting motor threshold; left DLPFC, 10-Hz rTMS, 3000 stimuli). The outcome was assessed based on the changes in scores of 24-item Hamilton Depression Scale (HAMD-24) and 14-item Hamilton Anxiety Scale (HAMA-14). Results: Both depression and anxiety were significantly improved after 2 weeks of treatment by rTMS combined with medication. The combination of iTBS and LF-rTMS was significantly superior to HF-rTMS in improving the scores of HAMD-24 (P = 0.041) and HAMA-14 (P = 0.0095), and the response rate (P = 0.027). Conclusion: The pilot study showed that the combination of iTBS and LF-rTMS may hold promise as a potentially effective alternative therapy for MD due to its efficacy and time-saving benefit. The preliminary results shed light on the study of the efficacy and acceptability of the combination of iTBS and LF-rTMS for MD.

Deficits in N-Methyl-D-Aspartate Receptor Function and Synaptic Plasticity in Hippocampal CA1 in APP/PS1 Mouse Model of Alzheimer's Disease.

The N-methyl-D-aspartate receptor is a critical molecule for synaptic plasticity and cognitive function. Impaired synaptic plasticity is thought to contribute to the cognitive impairment associated with Alzheimer's disease (AD). However, the neuropathophysiological alterations of N-methyl-D-aspartate receptor (NMDAR) function and synaptic plasticity in hippocampal CA1 in transgenic rodent models of AD are still unclear. In the present study, APP/PS1 mice were utilized as a transgenic model of AD, which exhibited progressive cognitive impairment including defective working memory, recognition memory, and spatial memory starting at 6 months of age and more severe by 8 months of age. We found an impaired long-term potentiation (LTP) and reduced NMDAR-mediated spontaneous excitatory postsynaptic currents (sEPSCs) in the hippocampal CA1 of APP/PS1 mice with 8 months of age. Golgi staining revealed that dendrites of pyramidal neurons had shorter length, fewer intersections, and lower spine density in APP/PS1 mice compared to control mice. Further, the reduced expression levels of NMDAR subunits, PSD95 and SNAP25 were observed in the hippocampus of APP/PS1 mice. These results suggest that NMDAR dysfunction, impaired synaptic plasticity, and disrupted neuronal morphology constitute an important part of the neuropathophysiological alterations associated with cognitive impairment in APP/PS1 mice.

Internet-based cognitive behavioral therapy for psychological distress in older adults without cognitive impairment living in nursing homes during the COVID-19 pandemic: A feasibility study.

BACKGROUND: The COVID-19 pandemic has had a detrimental effect on the mental health of older adults living in nursing homes. Very few studies have examined the effects of Internet-based Cognitive Behavioral Therapy (ICBT) on older adults living in nursing homes during the pandemic. We conducted a feasibility study using a single-group design, to explore the effectiveness of ICBT on psychological distress in 137 older adults (without cognitive impairment) from 8 nursing homes in 4 southeast cities in China, between January and March 2020. METHODS: Symptoms of depression, anxiety, general psychological distress, and functional disability were measured at baseline, post-treatment (5 weeks) and at a 1-month follow-up. Mixed-effects model was used to assess the effects of ICBT. RESULTS: Statistically significant changes with large effect sizes were observed from pre- to post-treatment on the PHQ-9 (p < .001, Cohen's d = 1.74), GAD-7 (p < .001, d = 1.71), GDS (p < .001, d = 1.30), K-10 (p < .001, d = 1.93), and SDS (p < .001, d = 2.03). Furthermore, improvements in treatment outcomes were sustained at 1-month follow-up, and high levels of adherence and satisfaction were indicated. CONCLUSION: ICBT was effective in reducing psychological distress in older adults without cognitive impairments living in nursing homes during the COVID-19 pandemic. Thus, it could be applied in improving the mental health of this vulnerable group during the pandemic.

REM Sleep Fragmentation in Patients With Short-Term Insomnia Is Associated With Higher BDI Scores.

Objective: To observe the changes in sleep characteristics and BDI scores in patients with short-term insomnia disorder (SID) using a longitudinal observational study. Methods: Fifty-four patients who met the criteria for SID of the International Classification of Sleep Disorders, third edition, were recruited. Depression levels were assessed using the Beck depression inventory (BDI) at enrollment and after 3 months of follow-up, respectively. Sleep characteristics were assessed by polysomnography. Results: After 3 months of follow-up, the group was divided into SID with increased BDI score (BDI >15) and SID with normal BDI score (BDI ≤ 15) according to the total BDI score of the second assessment. The differences in rapid eye movement (REM) sleep latency, REM sleep arousal index, and NREM sleep arousal index between the two groups were statistically significant. The total BDI score was positively correlated with REM and NREM sleep arousal index and negatively correlated with REM sleep latency, which were analyzed by Pearson correlation coefficient. Multiple linear regression was used to construct a regression model to predict the risk of depression in which the prediction accuracy reached 83.7%. Conclusion: REM sleep fragmentation is closely associated with future depressive status in patients with SID and is expected to become an index of estimating depression risk.

Akt and its phosphorylation in nucleus accumbens mediate heroin-seeking behavior induced by cues in rats.

Akt is initially identified as one of the downstream targets of phosphatidylinositol-3 kinase (PI3K) and is involved in morphine reward and tolerance. However, whether phospholyration of Akt (p-Akt) mediates heroin relapse remains unclear. Here, we aimed to explore the role of p-Akt in the nucleus accumbens (NAc) in cue-induced heroin-seeking behaviors after withdrawal. First, rats were trained to self-administer heroin for 14 days, after which we assessed heroin-seeking behaviors induced by a context cue (CC) or by discrete conditioned cues (CS) after 1 day or 14 days of withdrawal. We found that the active responses induced by CC or CS after 14 days of withdrawal were higher than those after 1 day of withdrawal. Meanwhile, the expression of p-Akt in the NAc was also greatest when rats were exposed to the CS after 14 days of withdrawal. Additionally, a microinjection of LY294002, an inhibitor of PI3K, into the NAc inhibited the CS-induced heroin-seeking behaviors after 14 days of withdrawal, paralleling the decreased levels of p-Akt in the NAc. Finally, Akt1 or ß-arrestin 2 was downregulated via a lentiviral injection to assess the effect on heroin seeking after 14 days of withdrawal. CS-induced heroin-seeking behavior was inhibited by downregulation of Akt1, but not ß-arrestin 2, in the NAc. These data demonstrate that Akt phosphorylation in the NAc may play an important role in the incubation of heroin-seeking behavior, suggesting that the PI3K/Akt pathways may be involved in the process of heroin relapse and addiction.

Increased plasma asprosin levels in patients with drug-naive anorexia nervosa.

PURPOSE: Asprosin is a centrally acting appetite-promoting hormone and promotes glucose production in the liver. This study is the first to investigate the difference in asprosin in the plasma between anorexia nervosa (AN) and healthy controls, and to explore the relationship between asprosin changes and plasma glucose levels and AN symptoms. METHODS: Plasma asprosin and glucose concentrations were detected in AN patients (n = 46) and healthy control subjects (n = 47). Eating Disorder Inventory-2 (EDI-2) was used to assess subjects' eating disorder symptoms and related personality traits. The patient's concomitant levels of depression and anxiety were also measured using the beck depression inventory and beck anxiety inventory, respectively. RESULTS: Results indicate that AN patients had a higher asprosin concentration in their plasma compared to healthy controls (p = 0.033). Among AN patients, plasma asprosin levels correlated positively with EDI-2 interoceptive awareness subscale score (p = 0.030) and negatively with duration of illness (p = 0.036). Multiple linear regression analyses showed that increases in asprosin levels (p = 0.029), glucose levels (p = 0.024) and body mass index (p = 0.003) were associated with an increase of the score of EDI-2 bulimia subscale. CONCLUSIONS: Our findings suggest that the increase in plasma asprosin concentration in patients with AN may be a compensation for the body's energy shortage, and asprosin may be involved in the development of bulimia and lack of interoceptive awareness in AN patients. LEVEL OF EVIDENCE: Level III, case-control analytic study.

Mental health status among family members of health care workers in Ningbo, China, during the coronavirus disease 2019 (COVID-19) outbreak: a cross-sectional study.

BACKGROUND: To date, the psychological impact of COVID-19 epidemic among family members of health care workers (HCWs) in China has been neglected. This cross-sectional study investigates the mental health status and related factors in families of HCWs employed in designated hospitals in Ningbo, China. METHODS: Family members of HCWs in five designated hospitals in Ningbo, China, were recruited in February, 2020 for this study. Demographic variables, COVID-19-related events in the lives of the participants, knowledge of COVID-19, and the working status of family members (that is, HCWs) were collected using online self-administered questionnaires. Mental health status was assessed using the Chinese versions of the Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9). Multivariable logistic regression analyses were performed to identify the main factors associated with the mental health conditions. RESULTS: In total, 845 participants completed the questionnaires correctly (95.80% response rate). The prevalence of anxiety and depression symptoms were respectively 33.73% (95% CI: 30.53-36.92%) and 29.35% (95% CI: 26.27-32.43%) when a cut-off score of 5 was used for GAD-7 and PHQ-9. Risk factors for anxiety symptoms included more time (hours) spent thinking about the COVID-19, and whether or not family members (that is, HCWs) had direct contact with confirmed or suspected COVID-19 patients while high participants' self-reported safety scores for HCW's protective equipment was a protective factor. More time (hours) spent thinking about COVID-19, longer average working time per week worked by family members (that is, HCWs), and being parents and other next of kin of HCWs were risk factors for depressive symptoms. Compared to participants who were HCWs, participants who were private sector workers were more likely to develop depressive symptoms, while government or institutional employees were less likely to suffer from depressive symptoms. CONCLUSIONS: Psychological responses to COVID-19 have been dramatic among family members of HCWs during the rising phase of the outbreak. Our findings provide strong evidence to examine and attend to the mental health of this population during the COVID-19 epidemic.

Role of endoplasmic reticulum stress in depression (Review).

Depression is a devastating mood disorder that causes profound disability worldwide. Despite the increasing number of antidepressant medications available, the treatment options for depression are limited. Therefore, understanding the etiology and pathophysiology of depression, and exploiting potential novel agents to treat and prevent this disorder are imperative. Endoplasmic reticulum (ER) stress activates the unfolded protein response and mediates the pathogenesis of psychiatric diseases, including depression. Emerging evidence in human and animal models suggests an intriguing link between ER stress and depression. The ER serves as an important subcellular organelle for the synthesis, folding, modification, and transport of proteins, a process that is highly developed in neuronal cells. Perturbations of ER homeostasis lead to ER stress, and ER stress helps to restore the normal ER function by restoring the protein­folding capacity of the ER. This biological defense mechanism is imperative to prevent the disease. However, excessive or persistent ER stress eventually causes cell death. If the damage occurs in the hippocampus, the amygdala and striatum and other areas of the neurons will be involved in the development of depression. In this review article, we explore how ER stress might have an important role in the pathophysiology of depression and how different drugs affect depression through ER stress.

Diffuse large B-cell lymphoma with concurrent hepatitis B virus infection in the MabThera era: Unique clinical features and worse outcomes.

AIM OF STUDY: Hepatitis B virus (HBV) infection is a risk factor in diffuse large B-cell lymphoma (DLBCL); however, little is known other than the prevalence evidence. In addition, the impact of HBV infection to DLBCL remains controversial. The purpose of this study was to investigate the HBV infection status of 136 patients with DLBCL, analyze the clinical property of HBV-infected patients, and determine the effects of HBV infection to the outcomes of DLBCL patients. MATERIALS AND METHODS: A retrospective analysis was performed in our center from January 2007 to December 2014. A total of 136 DLBCL patients accepting three or more cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen were analyzed. RESULTS: Of the 136 patients, 55 were HBV-infected and their clinical features were different in several aspects such as young onset age (P = 0.027), frequent occurrence of B symptom (P = 0.009), and advanced disease stage (Stage III/IV, P = 0.037). Besides more HBV-infected patients exhibited lower levels of peripheral lymphocyte-to-monocyte ratio (≤2.0). In the survival assessment, HBV-infected patients were worse in both progression-free survival (PFS) (P = 0.001) and overall survival (OS) (P = 0.030) in MabThera treated group, but get a draw in CHOP regimen group (P = 0.658 in PFS and P = 0.798 in OS). Sort of surprisingly, HBV-infected patients treated with MabThera did not have a superior to the traditional regimen in both PFS (P = 0.969) and OS (P = 0.875). CONCLUSION: DLBCL patients with HBV infection are subset with unique clinical characters and have worse outcomes. The benefit of MabThera to HBV-infected DLBCL patients was uncertain thus have to be weighed against the costs before application.

Vesicular glutamate transporter 1 (VGLUT1)-mediated glutamate release and membrane GluA1 activation is involved in the rapid antidepressant-like effects of scopolamine in mice.

Emerging data have identified certain drugs such as scopolamine as rapidly acting antidepressants for major depressive disorder (MDD) that increase glutamate release and induce neurotrophic factors through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation in rodent models. However, little research has addressed the direct mechanisms of scopolamine on AMPAR activation or vesicular glutamate transporter 1 (VGLUT1)-mediated glutamate release in the prefrontal cortex (PFC) of mice. Herein, using a chronic unpredictable stress (CUS) paradigm, acute treatment with scopolamine rapidly reversed stress-induced depression-like behaviors in mice. Our results showed that CUS-induced depression-like behaviors, accompanied by a decrease in membrane AMPAR subunit 1 (GluA1), phosphorylated GluA1 Ser845 (pGluA1 Ser845), brain-derived neurotrophic factor (BDNF) and VGF (non-acronymic) and an increase in bicaudal C homolog 1 gene (BICC1) in the PFC of mice, and these biochemical and behavioral abnormalities were ameliorated by acute scopolamine treatments. However, pharmacological block of AMPAR by NBQX infusion into the PFC significantly abolished these effects of scopolamine. In addition, knock down of VGLUT1 by lentiviral-mediated RNA interference in the PFC of mice was sufficient to induce depression-like phenotype, to decrease extracellular glutamate accumulation and to cause similar molecular changes with CUS in mice. Remarkably, VGLUT1 knockdown alleviated the rapid antidepressant-like actions of scopolamine and the effects of scopolamine on membrane GluA1-mediated BDNF, VGF and BICC1 changes. Altogether, our findings suggest that VGLUT1-mediated glutamate release and membrane GluA1 activation may play a critical role in the rapid-acting antidepressant-like effects of scopolamine in mice.

Blockade of mGluR5 in the nucleus accumbens shell but not core attenuates heroin seeking behavior in rats.

AIM: Glutamatergic neurotransmission in the nucleus accumbens (NAc) is crucial for the relapse to heroin seeking. The aim of this study was to determine whether mGluR5 in the NAc core or shell involved in heroin seeking behavior in rats. METHODS: Male SD rats were self-administered heroin under a fixed-ratio 1 (FR1) reinforcement schedule for 14 d, and subsequently withdrawn for 2 weeks. The selective mGluR5 antagonist 2-methyl-6-phenylethynyl-pyridine (MPEP, 5, 15 and 50 nmol per side) was then microinjected into the NAc core or shell 10 min before a heroin-seeking test induced by context, cues or heroin priming. RESULTS: Microinjection of MPEP into the NAc shell dose-dependently decreased the heroin seeking induced by context, cues or heroin priming. In contrast, microinjection of MPEP into the NAc core did not alter the heroin seeking induced by cues or heroin priming. In addition, microinjection with MPEP (15 nmol per side) in the NAc shell reversed both the percentage of open arms entries (OE%) and the percentage of time spent in open arms (OT%) after heroin withdrawal. Microinjection of MPEP (50 nmol per side) in the striatum as a control location did not affect the heroin seeking behavior. Microinjection of MPEP in the 3 locations did not change the locomotion activities. CONCLUSION: Blockade of mGluR5 in NAc shell in rats specifically suppresses the relapse to heroin-seeking and anxiety-like behavior, suggesting that mGluR5 antagonists may be a potential candidate for the therapy of heroin addiction.

Chronic treatment with curcumin enhances methamphetamine locomotor sensitization and cue-induced reinstatement of methamphetamine self-administration.

OBJECTIVES: Curcumin, a major active component of Curcuma longa, possesses antidepressant effects that are mediated by the 5-HT system. However, little is known about the effect of curcumin on the behavioral consequences of methamphetamine (METH). METHODS: The subjects were male, adult Sprague-Dawley rats. In Experiment 1, the effects of 20 and 40 mg/kg curcumin (i.p.) on response rates and breakpoints of 0.06 mg/kg/infusion METH were evaluated. In Experiment 2, rats were self-administering METH for 10 days followed by a 14-day abstinence period. During the abstinence period, the animals were treated with DMSO, 20 or 40 mg/kg curcumin. All rats were then tested for extinction responding and cue-induced reinstatement. In Experiment 3, rats were treated with DMSO, 20, or 40 mg/kg curcumin 15 min before a METH-induced locomotor activity test for 14 consecutive days. In Experiment 4, rats were pretreated with DMSO or curcumin (20 mg/kg or 40 mg/kg) for 13 days and were subsequently tested for METH-induced locomotor activity on the 14th day. In Experiment 5, three groups were tested for locomotor activity after an injection of DMSO, 20, or 40 mg/kg curcumin. The test was repeated for 14 days. RESULTS: Curcumin produced little effect on response rates and breakpoints maintained by METH. Chronic treatment of only 40 mg/kg curcumin during the abstinence phase enhanced cue-induced reinstatement of METH self-administration. Chronic administration of curcumin increased METH-induced sensitization of locomotor activity at the lower (20 mg/kg) but not higher (40 mg/kg) dose. However pretreatment of curcumin alone showed no significant effect on acute locomotor responses to METH and locomotor responses per se. CONCLUSIONS: Curcumin enhanced, rather than inhibited the behavioral effects of METH.

The effects of rearing condition on methamphetamine self-administration and cue-induced drug seeking.

BACKGROUND: Little is known about the effect of different rearing conditions on the effects of methamphetamine and whether the introduction of enriched rearing conditions at different stages of development could produce different behavioral outcomes. METHODS: In Experiment 1, rats were reared in either enriched (EE) or isolated environments (IE) from PND 21 to 60. In Experiment 2, two groups of animals were handled in the same fashion as those in Experiment 1. Additional two groups were housed in IE during the first 20 or 30 days and then housed under EE for the remaining 20 or 10 days respectively. Locomotor activity and Morris Water Maze were tested. The effects of rearing conditions on methamphetamine (METH) self-administration were investigated. RESULTS: IE animals exhibited higher levels of locomotion than EE animals, but EE animals showed enhanced Morris water maze performance. Animals reared in IE for 30 and 40 days more readily acquired METH self-administration, compared to those reared in IE for 20 and in EE for 40 days respectively. However, the effect of rearing conditions was only seen at the lowest dose tested under FR schedule and breakpoints obtained from PR schedule were not significantly affected. Those reared in IE for 20 and EE for 40 days animals produced significantly fewer responses during the extinction and cue-induced reinstatement of METH self-administration, compared with animals reared in IE for 30 and 40 days, respectively. CONCLUSION: Rearing condition plays a significant role in locomotor activity, spatial memory and behavioral effects of METH.