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  • Rapid effects of S-ketamine on the morphology of hippocampal astrocytes and BDNF serum levels in a sex-dependent manner
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2020-01-20
    Maryam Ardalan; Betina Elfving; Ali H. Rafati; Monireh Mansouri; Carlos A. Zarate; Aleksander A. Mathe; Gregers Wegener

    The prevalence of major depressive disorder (MDD) is higher in women than men. Importantly, a differential behavioral response by sex to the antidepressant response to ketamine in rodents has been reported. Mechanistically, male depressed-like animals showed an increased spine density after ketamine treatment via restoration of synaptic protein levels while those proteins were not altered in female rats. In addition, preclinical studies indicate that the impairment of astrocytic plasticity is one of the contributing mechanisms in the pathophysiology of MDD. Accordingly, in this study, we determined the effect of sex on the rapid morphological alteration of hippocampal astrocytes and the serum level of BDNF one hour after S-ketamine injection. A single intraperitoneal dose of S-ketamine (15 mg/kg) or saline was injected to the male and female Flinders Sensitive Line (FSL) rats, a genetic animal model of depression and their brains were perfused one hour after treatment. The size of the GFAP positive astrocytes in the hippocampal subregions was measured. The volume of different hippocampal subregions was assessed using the Cavalieri estimator. Moreover, serum levels of BDNF were measured with enzyme-linked immunosorbent assay (ELISA) kits. The volume of hippocampal subregions significantly increased one hour after S-ketamine in both male and female FSL animals. However, a substantial alteration in the morphology of the hippocampal astrocytes was observed only in the female rats. Additionally, significantly increased serum BDNF levels in the female depressed rats were observed one hour after S-ketamine treatment. Our results indicate that the rapid effects of S-ketamine on the morphology of the hippocampal astrocytes and the serum level of BDNF are sex-dependent.

    更新日期:2020-01-21
  • Placebo—To be or not to be? Are there really alternatives to placebo-controlled trials?
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2020-01-17
    Fas Jacob Krol; Michal Hagin; Eduard Vieta; Rephael Harazi; Amit Lotan; Rael D. Strous; Bernard Lerer; Dina Popovic

    Recent success of established treatment has driven concerns about the ethics of using placebo-controlled trials in psychiatry. Active-controlled (superiority or non-inferiority) trials do not include a placebo-arm and thus avoid the associated ethical concerns but show disadvantages in other respects. The aim of this paper is to review the available literature and critically discuss the evidence regarding the use of placebo-controlled- versus active-controlled trials. A MEDLINE/PubMed and Google Scholar search was performed. Studies included focused on the deliberation on placebo-controlled- versus active-controlled trials. Twenty-six studies were included. The most cited benefits of placebo-controlled trials were greater scientific reliability of the results and no average impact on patients' health. Disadvantages were mainly related to withholding effective treatment and limited generalizability. The most frequent argument in favor of active-controlled trials is the lower chance of receiving ineffective medication during the trial. Downsides include larger sample sizes, higher costs and lower scientific reliability of results. Most authors agree that all trial designs are relevant to psychiatric research depending on study goals. Whatsoever, data does not support forgoing placebo-controlled trials. Expert consensus is warranted to permit drawing conclusions on the debate on the relevance of placebo-controlled trials.

    更新日期:2020-01-17
  • Duration of illness and cortical thickness in trichotillomania: Preliminary evidence for illness change over time
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2020-01-15
    Jon E. Grant; Nancy J. Keuthen; Dan J. Stein; Christine Lochner; Samuel R. Chamberlain

    Trichotillomania is a psychiatric condition characterized by repetitive pulling out of one's hair, leading to marked functional impairment. The aim of this study was to examine the association between duration of trichotillomania (defined as time between initial age of onset and current age) and structural brain abnormalities by pooling all available global data. Authors of published neuroimaging studies of trichotillomania were contacted and invited to contribute de-identified MRI scans for a pooled analysis. Freesurfer pipelines were used to examine whether cortical thickness and sub-cortical volumes were associated with duration of illness in adults with trichotillomania. The sample comprised 50 adults with trichotillomania (100% not taking psychotropic medication; mean [SD] age 34.3 [12.3] years; 92% female). Longer duration of illness was associated with lower cortical thickness in bilateral superior frontal cortex and left rostral middle frontal cortex. Volumes of the a priori sub-cortical structures of interest were not significantly correlated with duration of illness (all p > 0.05 uncorrected). This study is the first to suggest that trichotillomania is associated with biological changes over time. If this finding is supported by prospective studies, it could have important implications for treatment (i.e. treatment might need to be tailored for stage of illness). Viewed alongside prior work, the data suggest that brain changes in trichotillomania may be differentially associated with vulnerability (excess thickness in right inferior frontal cortex) and with chronicity (reduced thickness in medial and superior frontal cortex). Longitudinal research is now indicated.

    更新日期:2020-01-15
  • Role of the serotonergic system in ethanol-induced aggression and anxiety: A pharmacological approach using the zebrafish model
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2020-01-14
    Talise E. Müller; Paola R. Ziani; Barbara D. Fontana; Tâmie Duarte; Flavia V. Stefanello; Julia Canzian; Adair R.S. Santos; Denis B. Rosemberg

    Acute ethanol (EtOH) consumption exerts a biphasic effect on behavior and increases serotonin levels in the brain. However, the molecular mechanisms underlying alcohol-mediated behavioral responses still remain to be fully elucidated. Here, we investigate pharmacologically the involvement of the serotonergic pathway on acute EtOH-induced behavioral changes in zebrafish. We exposed zebrafish to 0.25, 0.5, 1.0% (v/v) EtOH for 1 h and analyzed the effects on aggression, anxiety-like behaviors, and locomotion. EtOH concentrations that changed behavioral responses were selected to the subsequent experiments. As a pharmacological approach, we used pCPA (inhibitor of tryptophan hydroxylase), WAY100135 (5-HT1A antagonist), buspirone (5-HT1A agonist), CGS12066A and CGS12066B (5-HT1B antagonist and agonist, respectively), ketanserin (5-HT2A antagonist) and (±)-DOI hydrochloride (5-HT2A agonist). All serotonergic receptors tested modulated aggression, with a key role of 5-HT2A in aggressive behavior following 0.25% EtOH exposure. Because CGS12066B mimicked 0.5% EtOH anxiolysis, which was antagonized by CGS12066A, we hypothesized that anxiolytic-like responses are possibly mediated by 5-HT1B receptors. Conversely, the depressant effects of EtOH are probably not related with direct changes on serotonergic pathway. Overall, our novel findings demonstrate a role of the serotonergic system in modulating the behavioral effects of EtOH in zebrafish. These data also reinforce the growing utility of zebrafish models in alcohol research and help elucidate the neurobiological mechanisms underlying alcohol abuse and associated complex behavioral phenotypes.

    更新日期:2020-01-15
  • Antidepressant-like effects of pharmacological inhibition of FAAH activity in socially isolated female rats
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2020-01-13
    Luca Carnevali; Rosario Statello; Federica Vacondio; Francesca Ferlenghi; Gilberto Spadoni; Silvia Rivara; Marco Mor; Andrea Sgoifo

    Pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which terminates signaling of the endocannabinoid N-arachidonoylethanolamine (or anandamide, AEA), exerts favourable effects in rodent models of stress-related depression. Yet although depression seems to be more common among women than men and in spite of some evidence of sex differences in treatment efficacy, preclinical development of FAAH inhibitors for the pharmacotherapy of stress-related depression has been predominantly conducted in male animals. Here, adult female rats were exposed to six weeks of social isolation and, starting from the second week, treated with the FAAH inhibitor URB694 (0.3 mg/kg/day, i.p.) or vehicle. Compared to pair-housed females, socially isolated female rats treated with vehicle developed behavioral (mild anhedonia, passive stress coping) and physiological (reduced body weight gain, elevated plasma corticosterone levels) alterations. Moreover, prolonged social isolation provoked a reduction in brain-derived neurotrophic factor (BDNF) and AEA levels within the hippocampus. Together, these changes are indicative of an increased risk of developing a depressive-like state. Conversely, pharmacological inhibition of FAAH activity with URB694 restored both AEA and BDNF levels within the hippocampus of socially isolated rats and prevented the development of behavioral and physiological alterations. These results suggest a potential interplay between AEA-mediated signaling and hippocampal BDNF in the pathogenesis of depression-relevant behaviors and physiological alterations and antidepressant action of FAAH inhibition in socially isolated female rats.

    更新日期:2020-01-13
  • Sex differences in the vulnerability to cocaine's addictive effects after early-life stress in mice
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2020-01-07
    Adriana Castro-Zavala; Ana Martín-Sánchez; Olga Valverde

    Even though men are more likely to use drugs, women tend to progress faster from drug use to drug abuse, especially in the case of psychostimulants such as cocaine. Preclinical studies evaluating the differences in cocaine self-administration (SA) between sexes are contradictory. While some have shown no between-sex differences, others have reported female rodents to acquire higher percentages of cocaine SA criteria. Furthermore, early-life adversity is a risk factor for substance-use disorder and clinical evidence showed that women who have experienced childhood adversity are more likely to use drugs in comparison with males. However, the molecular differences between sexes as a consequence of early-life adversity or cocaine consumption have scarcely been explored. The aim of our study was to evaluate the differences in the expression of the GluA1, GluA2 subunits of AMPA receptors, pCREB and CREB in male and female mice exposed to maternal separation with early weaning (MSEW). Moreover, we evaluated the effects of cocaine SA in both sexes during adulthood, and the possible changes in GluA1, GluA2, pCREB and CREB expressions. Our results showed a higher acquisition percentage in females and an MSEW-induced increase in cocaine-seeking solely in males. Additionally, we observed sex differences in GluA1, GluA2, CREB and pCREB levels in the NAc and the VTA. The present results displayed changes in molecules that play a crucial role in the regulation of the rewarding effects of cocaine, helping to elucidate the mechanisms involved in the progression from cocaine use to cocaine abuse in both females and males.

    更新日期:2020-01-07
  • Long-term metabolic and cardiovascular effects of antipsychotic drugs. A meta-analysis of randomized controlled trials
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2020-01-06
    Francesco Rotella; Emanuele Cassioli; Enrico Calderani; Lisa Lazzeretti; Benedetta Ragghianti; Valdo Ricca; Edoardo Mannucci

    Most of the randomized controlled trials (RCTs) on antipsychotics (APs) have efficacy as their primary endpoint, leading to a lack of evidence on long-term metabolic effects of APs. The aim of the present meta-analysis is to compare different APs for the long-term modification of risk of major adverse cardiovascular events (MACE) and related mortality, in patients with schizophrenia and bipolar disorder. All RCTs found on Medline/Embase of at least 52 weeks up to 19 December 2017, enrolling patients with bipolar disorder or schizophrenia and comparing an AP with another AP or placebo were included. The primary outcome of this analysis was the association of APs with the incidence of cardiovascular death, myocardial infarction (MI), and stroke. 3013 studies were screened, 92 met the selection criteria. MI, stroke and cardiovascular death were reported in 11, 6 and 24 studies, respectively. No significant difference was observed with respect to MI and Stroke; a significantly higher cardiovascular mortality was observed for sertindole when compared to risperidone (Mantel-Haenszel Odds Ratio: 2.56, 95% CI: 1.33 − 5). Long-term cardiovascular effects of APs deserve to be studied more extensively. The request by regulatory authorities of cardiovascular safety data from specifically designed trials would be useful.

    更新日期:2020-01-06
  • Neuron-specific deletion of VEGF or its receptor Flk-1 impairs recognition memory
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2020-01-03
    Satoshi Deyama; Xiao-Yuan Li; Ronald S. Duman

    Vascular endothelial growth factor (VEGF, also known as VEGF-A) is a pleiotropic factor which is expressed by neurons, astrocytes and perivascular macrophages, as well as endothelial cells, in the brain. Recently, VEGF signaling has been implicated in learning and memory, and several clinical and preclinical studies demonstrate that VEGF inhibitors induce cognitive impairment. However, the role of endogenous neuronal VEGF signaling in recognition memory remains unclear. Recently, we have developed mice with forebrain excitatory neuron-specific deletion of VEGF or its receptor, fetal liver kinase 1 (Flk-1) by crossing Camk2a-Cre mice with Vegfaflox/flox and Flk-1flox/flox mice, respectively. Using these conditional knockout mice, the present study addressed the influence of forebrain excitatory neuron-specific deletion of VEGF or Flk-1 on recognition memory in the novel object recognition test. The results show that both short-term (2 h) and long-term (24 h) recognition memory are impaired by neuron-specific deletion of either Flk-1 or VEGF. These findings indicate the physiological importance of endogenous neuronal VEGF-Flk-1 signaling in recognition memory. In addition, the current results also suggest that the impairment of neuronal VEGF-Flk-1 signaling can be a cause of anti-VEGF chemotherapy-induced cognitive impairment.

    更新日期:2020-01-04
  • Obstetric complications in bipolar disorder: Psychiatric factors and the risk of caesarean section
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2020-01-03
    Eva Solé; Alba Roca; Anna Torres; Ana Sandra Hernández; Noemí Fernández; Carmen Naranjo Díaz; Eduard Vieta; Lluïsa Garcia-Esteve

    Bipolar Disorder (BD) is a chronic psychiatric condition with somatic morbidity that requires continuous mood stabilizing treatment to prevent relapses. Pregnant women with BD have shown an increased rate of caesarean section (C-Section) in comparison with women without BD. Because specific differentiated profiles between mothers with BD that require C-Section and those that do not require C-Section have not been largely discussed, we aim to explore the risk factors associated with the type of delivery in pregnant women with BD. A prospective cohort study was conducted at the Perinatal Mental Health Unit. 100 pregnant women with BD were followed throughout their pregnancy by obstetric and psychiatric services at the same hospital. The cohort was developed in order to compare psychiatric and obstetric outcomes between women with BD that required C-Section (N = 40) versus women that did not require C-Section (N = 60). Final regression models showed an increased risk for obstetric complications during labour (OR 4,52, 95% CI 1,66–12,29), higher rates of hypothyroidism (OR 3,73, 95% CI 1,04–13,73) and treatment with lithium + antidepressant (OR 4,24, 95% CI 1,34–13,40) amongst the C-Section group when compared to the non-C-Section group. In our sample, women with BD treated with lithium plus antidepressant, with hypothyroidism and without obstetric complications have a 70,5% probability of C-Section. In conclusion, psychopharmacology and thyroid function might help understanding which women with BD will have more probability of C-Section. The implementation of more targeted interventions in selected patients might be useful to avoid complications during delivery.

    更新日期:2020-01-04
  • Intermittent theta burst transcranial magnetic stimulation for methamphetamine addiction: A randomized clinical trial
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2020-01-02
    Hang Su; Tianzhen Chen; Haifeng Jiang; Na Zhong; Jiang Du; Ke Xiao; Ding Xu; Weidong Song; Min Zhao

    Methamphetamine is the most commonly used illicit drug in China. We previously demonstrated that 10 Hz rTMS over the DLPFC reduces craving in methamphetamine users. Here, we applied intermittent theta burst stimulation (iTBS), a new form of rTMS, in a large sample at four clinical centers. 126 participants (age 31.64 ± 6.33; 106 men) with severe methamphetamine use disorder according to DSM-5 were randomized to receive either iTBS or sham over the DLPFC for four weeks (20 daily sessions, 900 pulses per day). Cue-induced craving and cognitive function were assessed before and after rTMS intervention. Relapse was followed up by urine test after discharge from the rehabilitation center. iTBS significantly reduced craving and improved cognition and sleep quality. This study suggests that rTMS may be a useful and safe treatment option for methamphetamine use disorder, warranting future large scale trials.

    更新日期:2020-01-02
  • What is good mental health? A scoping review
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-12-31
    Paolo Fusar-Poli; Gonzalo Salazar de Pablo; Andrea De Micheli; Dorien H. Nieman; Christoph U. Correll; Lars Vedel Kessing; Andrea Pfennig; Andreas Bechdolf; Stefan Borgwardt; Celso Arango; Therese van Amelsvoort

    Promotion of good mental health in young people with and without mental disorders has received little empirical research attention and interventions for improving mental health in young people are not well established. This situation could be explained among other reasons due to the difficulties to define and operationalise what good mental health is. The current manuscript, produced by the European College of Neuropsychopharmacology Thematic Working Group on the Prevention of Mental Disorders and Mental Health Promotion (ECNP TWG PMD-MHP), presents a critical review of the available operationalizations for good mental health. A pragmatic conceptual operationalisation of good mental health is a much-needed step towards more standardised research in this field. Good mental health can be defined as a state of well-being that allows individuals to cope with the normal stresses of life and function productively. Universal and selective interventions are suitable to promote mental health. Core domains that define good mental health encompass: (i) mental health literacy, (ii) attitude towards mental disorders, (iii) self-perceptions and values, (iv) cognitive skills, (v) academic/ occupational performance, (vi) emotions, (vii) behaviours, (viii) self-management strategies, (ix) social skills, (x) family and significant relationships (xi) physical health, (xii) sexual health, (xiii) meaning of life, (xiv) and quality of life. These domains should be widely traceable in the literature and can be used to conduct further empirical research in the field of good mental health. Such data can lead to more robust evidence to identify and establish the pathways to follow in order to improve mental health.

    更新日期:2020-01-01
  • Impulsive decision-making and gambling severity: The influence of γ-amino-butyric acid (GABA) and glutamate-glutamine (Glx)
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-12-31
    Kathrin Weidacker; Stephen J. Johnston; Paul G. Mullins; Fred Boy; Simon Dymond

    Discounting larger, delayed rewards for smaller, immediate rewards is a stable psychological trait known to be impaired in gambling disorder (GD). Neuroimaging with non-GD populations indicates involvement of anterior cingulate (ACC) and dorsolateral prefrontal cortex (dlPFC) in delay discounting. However, little is known about the role of intrinsic properties of brain functioning, such as neurotransmitter action, in impaired discounting in GD. Here, we used magnetic resonance spectroscopy to assess glutamate-glutamine (Glx) and γ-amino-butyric acid (GABA+) concentrations in the dorsal ACC (dACC), dlPFC and occipital cortex of human males with and without GD. Gambling symptom severity correlated negatively with Glx levels in the dACC and occipital voxels. Discounting of small and medium delayed rewards was negatively associated with GABA+ in the dACC, while the discounting of large delayed rewards was negatively associated with GABA+/Glx ratios in the dlPFC. Additionally, in GD, discounting of large delayed rewards was negatively correlated with occipital GABA+ levels. Overall, these findings show that high gambling symptom severity is associated with low levels of Glx and that dACC (GABA+), right dlPFC (GABA+/Glx), and occipital areas (GABA+) track the magnitude of delayed rewards during discounting.

    更新日期:2020-01-01
  • Physical exercise modifies behavioral and molecular parameters related to opioid addiction regardless of training time
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-12-31
    H.Z. Rosa; R.C.S. Barcelos; H.J. Segat; Kr. Roversi; V.T. Dias; L.H. Milanesi; M.E. Burger

    Addiction is a devastating worldwide disorder that requires effective and innovative therapies. Physical exercise could be useful in addiction treatment because it shares a common neural circuit with addictive drugs. Based on this, molecular adaptations consequent to time of exercise in opioid exposed animals were evaluated. Rats were designed as sedentary (SED) or exercised (EXE). This last group was separated to perform three different periods of swimming: short-term (S-EXE), medium-term (M-EXE) and long-term (L-EXE) for 14, 28 and 42 days, respectively. On the last exercising week, one-half of the animals from SED and all animals from S-, M- and l-EXE were concomitantly exposed to morphine-conditioned place preference (CPP) paradigm and y-maze task for behavioral assessments followed by molecular assays in both Nucleus accumbens (NAc) and hippocampus. Between SED groups, morphine conditioning showed drug-CPP and increased dopamine transporter (DAT), dopamine receptor type-1 (D1R), type-2 (D2R) and glucocorticoid receptor (GR) in both brain areas in relation to saline group. Besides the small morphine-CPP in relation to SED group, all periods decreased DAT, D1R, and GR immunoreactivity in NAc, DAT and D1R in hippocampus, while D2R in both brain areas and GR in hippocampus were primarily decreased by L-EXE. Our findings show that even a short-term exercise modifies behaviors related to drug withdrawal, changing DA targets and GR, which are closely linked to addiction. Therefore, our outcomes involving physical exercise are interesting to perform a possible clinical trial, thus expanding the knowledge about drug addiction.

    更新日期:2019-12-31
  • Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-12-26
    Nicholas Chak Lam Yung; Corine Sau Man Wong; Joe Kwun Nam Chan; Philip Chi Fai Or; Eric Yu Hai Chen; Wing Chung Chang

    Evidence shows that schizophrenia is associated with increased incidence of stroke. However, relationship between schizophrenia and short-term mortality risk is understudied, and mixed findings were observed. In this retrospective population-based cohort study, we identified individuals admitted for incident ischemic stroke between 2006 and 2016 using a territory-wide electronic medical record database of public healthcare system in Hong Kong to examine 30-day and 1-year mortality rates in 817 schizophrenia patients compared with 8170 patients without psychotic disorder (10:1 matched to schizophrenia patients on demographics, treatment sites and calendar-period for index admission). Multivariate regression analyses adjusting for medical comorbidities revealed that schizophrenia patients experienced elevated 1-year (16.9% vs 12.1%; p < 0.001) and 30-day mortality (7.2% vs 5.3%; p = 0.053) relative to control group. Additional age- and gender-stratified analyses revealed even more pronounced effect of schizophrenia on raised mortality risk, as indicated by higher odds, in younger-age (<65 years) group and men. Our results indicate that schizophrenia is associated with heightened short-term mortality following incident ischemic stroke. Further research is warranted to identify factors contributing to excess post-stroke deaths among schizophrenia patients to facilitate development of effective interventions for mortality risk reduction.

    更新日期:2019-12-27
  • Oxytocin changes behavior and spatio-temporal brain dynamics underlying inter-group conflict in humans
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-12-26
    Bastian Schiller; Gregor Domes; Markus Heinrichs

    Inter-group conflicts drive human discrimination, mass migration, and violence, but their psychobiological mechanisms remain largely unknown. Here, we investigated whether the neuropeptide oxytocin modulates behavior and spatio-temporal brain dynamics in naturalistic inter-group conflict. Eighty-six male members of natural rival social groups received either oxytocin or placebo intranasally. In a decision-making paradigm involving real monetary stakes, participants could sacrifice their own resources to modulate the monetary gains and losses of in- and out-group members. Oxytocin eliminated the reduction in out-group gains – particularly in individuals with low emotional empathy, whereas those given placebo exhibited this negative social behavior. Our spatio-temporal analysis of event-related potentials elicited by outcome valuation revealed that oxytocin replaced a neurophysiological process associated with the negative valuation of out-group gains via a process associated with positive valuation between 200-500ms after outcome presentation. Oxytocin thus seems to modulate inter-group behavior in humans via a specific alteration of valuation-related brain dynamics.

    更新日期:2019-12-27
  • An investigation into the modulation of T cell phenotypes by amitriptyline and nortriptyline
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-12-24
    Jonathan Royds; Melissa J. Conroy; Margaret R. Dunne; Connail McCrory; Joanne Lysaght

    Amitriptyline is prescribed for treating the symptoms of neuroinflammatory disorders including neuropathic pain and fibromyalgia. As amitriptyline has evidence of modulating the neuroimmune interface; the effects of amitriptyline treatment on T-cell phenotype and function were examined in vitro. Peripheral blood mononuclear cells(PBMCs) were isolated and treated with amitriptyline, nortriptyline and a combination of both drugs. Toxicity for T-cells was assessed by Annexin V/Propidium Iodide staining. Activation status and cytokine expression by T-cells post treatment was assessed by flow cytometry. The levels of secreted cytokines, chemokines and neurotrophins were measured by ELISA in the supernatants. There was no significant increase in T-cell death following 24 or 48 h compared to controls. There were significantly lower frequencies of CD8+ T-cells after treatment with amitriptyline, nortriptyline and a combination of both compared to a Vehicle Control(VC)(p<0.001). The frequencies of naive CD8+CD45RA+ cells were significantly lower after amitriptyline, nortriptyline and a combination of both (p<0001). The frequencies of CD27+CD4+(p<0.05) and CD27+CD8+(p<0.01) T-cells were also significantly lower following combination drug treatment. Significantly lower frequencies of IFN-γ-producing CD8+ T-cells were observed with all treatment combinations(p<0.05) and frequencies of IL-17-producing CD4+ and CD8+ T-cells were significantly lower following amitriptyline treatment (p<0.05). Frequencies of Natural Killer T-cells were significantly higher following treatment with nortriptyline (p<0.05). Significantly higher levels of IL-16 (p<0.001) and lower levels of TNF-β (p<0.05) were observed in supernatants. This data indicates that both amitriptyline and nortriptyline modulate the phenotype and function of T-cells and this may have clinical relevance in the pathologies of its off-label applications.

    更新日期:2019-12-25
  • Clinical application of genomic high-throughput data: Infrastructural, ethical, legal and psychosocial aspects
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-12-20
    Nadine Umbach; Tim Beißbarth; Annalen Bleckmann; Gunnar Duttge; Laura Flatau; Alexander König; Jessica Kuhn; Julia Perera-Bel; Julia Roschauer; Thomas G. Schulze; Mark Schweda; Alexander Urban; Anja Zimmermann; Ulrich Sax

    Genomic high-throughput technologies (GHTT) such as next-generation sequencing represent a fast and cost-effective tool toward a more comprehensive understanding of the molecular background of complex diseases. However, technological advances contrast with insufficient application in clinical practice. Thus, patients, physicians, and other professionals are faced with tough challenges that forestall the efficient and effective implementation. With the increasing application of genetic testing, it is of paramount importance that physicians and other professionals in healthcare recognize the restrictions and potential of GHTT, in order to understand and interpret the complex data in the context of health and disease. At the same time, the growing volume and complexity of data is forever increasing the need for sustainable infrastructure and state-of-the-art tools for efficient data management, including their analysis and integration. The large pool of sensitive information remains difficult to interpret and fundamental questions spanning from billing to legal, social, and ethical issues have still not been resolved. Here we summarize and discuss these obstacles in an interdisciplinary context and suggest ways to overcome them. Continuous discussion with clinicians, data managers, biostatisticians, systems medicine experts, ethicists, legal scholars, and patients illuminates the strengths, weakness, and current practices in the pipeline from biomaterial to sequencing and data management. This discussion also highlights the new, cross-disciplinary working collaborations to realize the wide-ranging challenges in clinical genomics including the exceptional demands placed on the staff preparing and presenting the data, as well as the question as to how to report the data and results to patients.

    更新日期:2019-12-20
  • Systematic review and practical guideline for the prevention and management of the renal side effects of lithium therapy
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-12-11
    Tessa S. Schoot, Thomas H.J. Molmans, Koen P. Grootens, Angèle P.M. Kerckhoffs

    Lithium is the first line therapy of bipolar mood disorder. Lithium-induced nephrogenic diabetes insipidus (Li-NDI) and lithium nephropathy (Li-NP, i.e., renal insufficiency) are prevalent side effects of lithium therapy, with significant morbidity. The objective of this systematic review is to provide an overview of preventive and management strategies for Li-NDI and Li-NP. For this, the PRISMA guideline for systematic reviews was used. Papers on the prevention and/or treatment of Li-NDI or Li-NP, and (influenceable) risk factors for development of Li-NDI or Li-NP were included. We found that the amount of evidence on prevention and treatment of Li-NDI and Li-NP is scarce. To prevent Li-NDI and Li-NP we advise to use a once-daily dosing schedule, target the lowest serum lithium level that is effective and prevent lithium intoxication. We emphasize the importance of monitoring for Li-NDI and Li-NP, as early diagnosis and treatment can prevent further progression and permanent damage. Collaboration between psychiatrist, nephrologist and patients themselves is essential. In patients with Li-NDI and/or Li-NP cessation of lithium therapy and/or switch to another mood stabilizer should be considered. In patients with Li-NDI, off label therapy with amiloride can be useful.

    更新日期:2019-12-11
  • Modelling decision-making under uncertainty: A direct comparison study between human and mouse gambling data
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-12-11
    Lidia Cabeza, Julie Giustiniani, Thibault Chabin, Bahrie Ramadan, Coralie Joucla, Magali Nicolier, Lionel Pazart, Emmanuel Haffen, Dominique Fellmann, Damien Gabriel, Yvan Peterschmitt

    Decision-making is a conserved evolutionary process enabling us to choose one option among several alternatives, and relies on reward and cognitive control systems. The Iowa Gambling Task allows the assessment of human decision-making under uncertainty by presenting four card decks with various cost-benefit probabilities. Participants seek to maximise their monetary gain by developing long-term optimal-choice strategies. Animal versions have been adapted with nutritional rewards, but interspecies data comparisons are scarce. Our study directly compares the non-pathological decision-making performance between humans and wild-type C57BL/6 mice. Human participants completed an electronic Iowa Gambling Task version, while mice a maze-based adaptation with four arms baited in a probabilistic way. Our data shows closely matching performance between both species with similar patterns of choice behaviours. However, mice showed a faster learning rate than humans. Moreover, both populations were clustered into good, intermediate and poor decision-making categories with similar proportions. Remarkably, mice characterised as good decision-makers behaved the same as humans of the same category, but slight differences among species are evident for the other two subpopulations. Overall, our direct comparative study confirms the good face validity of the rodent gambling task. Extended behavioural characterisation and pathological animal models should help strengthen its construct validity and disentangle the determinants in animals and humans decision-making.

    更新日期:2019-12-11
  • Effect of add-on ramelteon therapy on sleep and circadian rhythm disruption in patients with schizophrenia: A randomized controlled trial
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-12-09
    Archana Mishra, Rituparna Maiti, Biswa Ranjan Mishra, Monalisa Jena, Santanu Nath, Pallabi Sahu

    The sleep and circadian rhythm disruptions in schizophrenia are attributed to a decrease in nocturnal melatonin level which may worsen if treated with conventional sedative drugs. This study was planned to evaluate the effects of add-on ramelteon on sleep and circadian rhythm disturbances in schizophrenia. A randomized, rater-blinded clinical trial was conducted on 120 patients with schizophrenia. Patients were categorized into predominantly positive (PG) or negative (NG) symptoms depending on Positive and Negative Syndrome Scale (PANSS) scoring, and then they were randomized into control (haloperidol/risperidone) or test (add-on ramelteon) groups. After recruitment, baseline serum melatonin, serum AANAT, urinary melatonin and Pittsburgh Sleep Quality Index (PSQI) were evaluated. Patients were reassessed after 4 weeks of therapy with antipsychotics with or without ramelteon. A significantly greater increase in night-time melatonin level (PG: 10·19; 95%CI: 1·42 to 18·97; p = 0·024; NG: 18·74; 95%CI: 8·48 to 29·0; p = 0·001), decrease in PSQI scores (PG: −1·57; 95%CI: −2·59 to −0·55; p = 0·003; NG: −2·49; 95%CI: −4·59 to −0·39; p = 0·021), increase in urinary melatonin (PG: 0·20; 95% CI: 0·056 to 0·35; p = 0·008; NG :0·15; 95% CI: 0·01 to 0·29; p = 0·034), increase in serum AANAT (PG: 4·61; 95%CI: 1·34 to 7·87; p = 0·007; NG:3·46; 95%CI: 1·30 to 5·63; p = 0·002) and improvement in PANSS score were found in patients receiving add-on ramelteon. The increase in serum melatonin and decrease in PSQI score were greater with predominantly negative symptom group in comparison to positive symptom group. Ramelteon may be considered as an add-on therapy with antipsychotic drugs for sleep and circadian rhythm disturbances in schizophrenia.

    更新日期:2019-12-09
  • Computational modeling of the monoaminergic neurotransmitter and male neuroendocrine systems in an analysis of therapeutic neuroadaptation to chronic antidepressant
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-12-09
    Mariam Bonyadi Camacho, Warut D. Vijitbenjaronk, Thomas J. Anastasio

    Second-line depression treatment involves augmentation with one (rarely two) additional drugs, of chronic administration of a selective serotonin reuptake inhibitor (SSRI), which is the first-line depression treatment. Unfortunately, many depressed patients still fail to respond even after months to years of searching to find an effective combination. To aid in the identification of potentially effective antidepressant combinations, we created a computational model of the monoaminergic neurotransmitter (serotonin, norepinephrine, and dopamine), stress-hormone (cortisol), and male sex hormone (testosterone) systems. The model was trained via machine learning to represent a broad range of empirical observations. Neuroadaptation to chronic drug administration was simulated through incremental adjustments in model parameters that corresponded to key regulatory components of the neurotransmitter and neurohormone systems. Analysis revealed that neuroadaptation in the model depended on all of the regulatory components in complicated ways, and did not reveal any one or a few specific components that could be targeted in the design of antidepressant treatments. We used large sets of neuroadapted states of the model to screen 74 different drug and hormone combinations and identified several combinations that could potentially be therapeutic for a higher proportion of male patients than SSRIs by themselves.

    更新日期:2019-12-09
  • Gene expression signature of antidepressant treatment response/non-response in Flinders Sensitive Line rats subjected to maternal separation
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-12-06
    Luca Marchetti, Mario Lauria, Laura Caberlotto, Laura Musazzi, Maurizio Popoli, Aleksander A. Mathé, Enrico Domenici, Lucia Carboni

    Neurobiological underpinnings of treatment-resistant depression, a debilitating condition associated with significant functional impairment, have not been elucidated. Consequently, the aim of this study was to use animal models of response and resistance to antidepressant treatment, in an attempt to identify differences in associated transcriptional responses. Flinders Sensitive Line rats were subjected to maternal separation (MS) and chronically treated with Escitalopram or Nortriptyline. Antidepressants reduced immobility time in the forced swim test in non-MS rats, while lack of antidepressant behavioural response was observed in MS animals. We developed a novel bioinformatic algorithm that enabled identification of transcriptional signatures in hippocampus and pre-frontal cortex that discriminate vehicle- and antidepressant-treated subjects in both MS and non-MS rats. Functional annotation analysis showed that in antidepressant-responder rats the most enriched pathways included IQGAPs activation, toll-like receptor trafficking, energy metabolism, and regulation of endopeptidase activity. The analysis of interacting proteins implicated synaptic vesicles and neurotransmitter release, ubiquitin regulation, cytoskeleton organisation and carbohydrate metabolism. In contrast, in treatment-resistant MS rats, main expression changes were revealed in ribosomal proteins, inflammatory responses, transcriptional/epigenetic regulation, and small GTPases. Susceptibility signature shared Rtn1, Zdhhc5, Igsf6, and Sim1 genes with the latest depression GWAS meta-analysis, while antidepressant resistance signature shared Ctnnd1, Rbms3, Atp1a3, and Pla2r1 genes. In conclusion, this study demonstrated that distinct transcriptional signatures are associated with behavioural response or non-response to antidepressant treatment. The identification of genes involved in antidepressant response will increase the comprehension of the neurobiological underpinnings of treatment-resistant depression, thus contributing to identification of novel therapeutic targets.

    更新日期:2019-12-06
  • Verbal suggestions of nicotine content modulate ventral tegmental neural activity during the presentation of a nicotine-free odor in cigarette smokers
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-12-04
    Vanda Faria, Pengfei Han, Akshita Joshi, Paul Enck, Thomas Hummel

    Expectancies of nicotine content have been shown to impact smokers’ subjective responses and smoking behaviors. However, little is known about the neural substrates modulated by verbally induced expectancies in smokers. In this study we used functional magnetic resonance imaging (fMRI) to investigate how verbally induced expectations, regarding the presence or absence of nicotine, modulated smokers’ neural response to a nicotine-free odor. While laying in the scanner, all participants (N = 24) were given a nicotine-free odor, but whereas one group was correctly informed about the absence of nicotine (control group n = 12), the other group was led to believe that the presented odor contained nicotine (expectancy group n = 12). Smokers in the expectancy group had significantly increased blood-oxygen-level-dependent (BOLD) responses during the presentation of the nicotine-free odor in the left ventral tegmental area (VTA), and in the right insula, as compared to smokers in the control group (Regions of interest analysis with pFWE-corrected p ≤ 0.05). At a more liberal uncorrected statistical level (p-unc ≤ 0.001), increased bilateral reactivity in the dorsolateral prefrontal cortex (dlPFC) was also observed in the expectancy group as compared with the control group. Our findings suggest that nicotine-expectancies induced through verbal instructions can modulate nicotine relevant brain regions, without nicotine administration, and provide further neural support for the key role that cognitive expectancies play in the cause and treatment of nicotine dependence.

    更新日期:2019-12-04
  • Neurological soft signs in schizophrenia spectrum disorders are not confounded by current antipsychotic dosage
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-11-25
    Stefan Fritze, Fabio Sambataro, Katharina M. Kubera, Alina L. Bertolino, Cristina E. Topor, Robert C. Wolf, Dusan Hirjak

    Neurological soft signs (NSS) have garnered increasing attention in psychiatric research on motor abnormalities in schizophrenia spectrum disorders (SSD). However, it remains unclear whether the assessment of NSS severity could have been confounded by current antipsychotic dosage. In this study, we recruited 105 patients with SSD that underwent a comprehensive motor assessment evaluating NSS and extrapyramidal motor symptoms (EPMS) by means of standardized instruments. Current antipsychotic dosage equivalence estimates were determined by the classical mean dose method (doses equivalent to 1 mg/d olanzapine). We used multiple regression analyses to describe the relationship between NSS, EPMS and antipsychotic medication. In line with our expectations, current antipsychotic dosage had no significant effects on NSS total score (p = 0.27), abnormal involuntary movements (p = 0.17), akathisia (p = 0.32) and parkinsonism (p = 0.26). Further, NSS total score had a significant effect on akathisia (p = 0.003) and parkinsonism (p = 0.0001, Bonferroni corr.), but only marginal effect on abnormal involuntary movements (p = 0.08). Our results support the notion that NSS are not significantly modulated by current antipsychotic dosage in SSD. The associations between NSS, akathisia and parkinsonism, as revealed by this study, support the genuine rather than medication-dependent origin of particular motor abnormalities in SSD.

    更新日期:2019-11-26
  • Ethosuximide improves chronic pain-induced anxiety- and depression-like behaviors
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-11-22
    Nicolas Kerckhove, Ludivine Boudieu, Guillaume Ourties, Justine Bourdier, Laurence Daulhac, Alain Eschalier, Christophe Mallet

    Chronic pain is a heavy burden disease. Current treatments are generally weakly effective or associated with adverse effects. New therapeutic approaches are therefore needed. Recent studies have suggested T-type calcium channels as an attractive target for the treatment of chronic pain. In this perspective, it was decided to perform a preclinical evaluation of the efficacy of ethosuximide, a T-type channel blocker used clinically as an antiepileptic, as a novel pharmacological treatment for chronic pain. Assessment of the effect of ethosuximide was thus made in both nociception and pain-related comorbidities as anxiety and depression are frequently encountered in chronic pain patients. Our results show that such symptoms occurred in three animal models of chronic pain designed to reflect traumatic neuropathic, chemotherapy-induced neuropathic and inflammatory pain conditions. Administration of ethosuximide reduced both chronic pain and comorbidities with a marked intensity ranging from partial reduction to a complete suppression of symptoms. These results make ethosuximide, and more broadly the inhibition of T-type calcium channels, a new strategy for the management of uncontrolled chronic pain, likely to improve not only pain but also the accompanying anxiety and depression.

    更新日期:2019-11-26
  • Clinical utility of the Negative Symptom Assessment-16 in individuals with schizophrenia
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-11-22
    Gurpreet Rekhi, Larry Alphs, Mei San Ang, Jimmy Lee

    This study examined the clinical utility of the Negative Symptom Assessment-16 (NSA-16) in schizophrenia. 274 individuals with schizophrenia were assessed on the NSA-16, Positive and Negative Syndrome Scale (PANSS), Clinical Assessment for Negative Symptoms (CAINS), Calgary Depression Scale for Schizophrenia (CDSS), Social and Occupational Functioning Assessment Scale (SOFAS) and the Simpson-Angus Extrapyramidal Side Effects Scale (SAS). Factor analyses were conducted and Cronbach's alpha was computed. Correlations were assessed using Spearman's correlation coefficient. The 5-factor model of the NSA-16 did not give good fit statistics from our sample. Exploratory factor analysis on a randomly selected split-half of the sample followed by confirmatory factor analysis on the remaining sample supported a 4-factor structure with 12 items. The factors were: Restricted speech, Poor quality of speech, Affective blunting and Amotivation. The NSA-16 with the 12 items was termed as the NSA-12. The NSA-12 showed good internal reliability. The NSA-12 total score and global negative symptom rating had strong correlations with CAINS total and PANSS negative factor scores, suggesting good convergent validity. Weak correlations of the NSA-12 total score and global negative symptom rating with PANSS positive, CDSS and SAS scores suggested good divergent validity. The NSA-12 total score and global negative symptom rating were strongly and inversely associated with SOFAS and positively associated with NSA-12 global level of functioning. In conclusion, the NSA-12 is useful to evaluate negative symptoms in clinical and research settings in individuals with schizophrenia. Our study results also support a 4-factor structure of the NSA-12 in outpatients with schizophrenia.

    更新日期:2019-11-22
  • Be positive about negatives–recommendations for the publication of negative (or null) results
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-11-18
    Anton Bespalov, Thomas Steckler, Phil Skolnick

    Both positive and negative (null or neutral) results are essential for the progress of science and its self-correcting nature. However, there is general reluctance to publish negative results, and this may be due a range of factors (e.g., the widely held perception that negative results are more difficult to publish, the preference to publish positive findings that are more likely to generate citations and funding for additional research). It is particularly challenging to disclose negative results that are not consistent with previously published positive data, especially if the initial publication appeared in a high impact journal. Ideally, there should be both incentives and support to reduce the costs associated with investing efforts into preparing publications with negative results. We describe here a set of criteria that can help scientists, reviewers and editors to publish technically sound, scientifically high-impact negative (or null) results originating from rigorously designed and executed studies. Proposed criteria emphasize the importance of collaborative efforts and communication among scientists (also including the authors of original publications with positive results).

    更新日期:2019-11-19
  • Nucleus accumbens connectivity at rest is associated with alcohol consumption in young male adults
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-11-18
    Ilya M. Veer, Paul Jetzschmann, Maria Garbusow, Stephan Nebe, Robin Frank, Sören Kuitunen-Paul, Miriam Sebold, Stephan Ripke, Andreas Heinz, Eva Friedel, Michael N. Smolka, Henrik Walter

    Alcohol consumption during adolescence might impede normal brain development, while more excessive drinking during this period poses a risk for developing alcohol use disorder. Here it was tested whether nucleus accumbens (NAcc) resting-state functional connectivity could be associated with lifetime drinking behavior in young adults, and whether it could predict their alcohol consumption during a one-year follow-up period. The current investigation was part of the bicentric Learning and Alcohol Dependence (LeAD) population-based prospective cohort study. One hundred and eighty-four 18-year-old male social drinking volunteers without a lifetime diagnosis of psychotic, bipolar, or alcohol use disorder were recruited from the general population. Seed-based resting-state functional connectivity was calculated for the bilateral NAcc in each participant. Across the group, the association between NAcc functional connectivity and lifetime alcohol consumption was assessed (p < .05, whole-brain FWE-corrected). Individual connectivity values were then extracted from regions that demonstrated a significant association to predict drinking behavior during a one-year follow-up period (n = 143), correcting for lifetime alcohol consumption. Weaker connectivity between the left NAcc and bilateral dorsolateral prefrontal cortex, inferior frontal gyrus, left caudate nucleus, left putamen, and left insula was associated with greater lifetime alcohol consumption, as well as with greater alcohol consumption during the one-year follow-up period. Our findings underscore the relevance of fronto-striatal connectivity to the field of alcohol research. Impaired prefrontal cognitive control might mediate excessive drinking behavior and may prove a promising biomarker for risk of future alcohol (ab)use.

    更新日期:2019-11-19
  • Application of transcranial magnetic stimulation for major depression: Coil design and neuroanatomical variability considerations
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-07-05
    Samuel Zibman, Gaby S. Pell, Noam Barnea-Ygael, Yiftach Roth, Abraham Zangen

    High-frequency repeated transcranial magnetic stimulation (rTMS) as a treatment for major depressive disorder (MDD) has received FDA clearance for both the figure-of-8 coil (figure-8 coil) and the H1 coil. The FDA-cleared MDD protocols for both coils include high frequency (10–18 Hz) stimulation targeting the dorsolateral prefrontal cortex (dlPFC) at an intensity that is 120% of the right-hand resting motor threshold. Despite these similar parameters, the two coils generate distinct electrical fields (e-fields) which result in differences in the cortical stimulation they produce. Due to the differences in coil designs, the H1 coil induces a stimulation e-field that is broader and deeper than the one induced by the figure-8 coil. In this paper we review theoretical and clinical implications of these differences between the two coils and compare evidence of their safety and efficacy in treating MDD. We present the design principles of the coils, the challenges of identifying, finding, and stimulating the optimal brain target of each individual (both from functional and connectivity perspectives), and the possible implication of stimulating outside that target. There is only one study that performed a direct comparison between clinical effectiveness of the two coils, using the standard FDA-approved protocols in MDD patients. This study indicated clinical superiority of the H1 coil but did not measure long-term effects. Post-marketing data suggest that both coils have a similar safety profile in clinical practice, whereas effect size comparisons of the two respective FDA pivotal trials suggests that the H1 coil may have an advantage in efficacy. We conclude that further head-to-head experiments are needed, especially ones that will compare long-term effects and usage of similar temporal stimulation parameters and similar number of pulses.

    更新日期:2019-11-18
  • Role of conduct problems in the relation between Attention-Deficit Hyperactivity disorder, substance use, and gaming
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2018-10-03
    G.H. Schoenmacker, A.P. Groenman, E. Sokolova, J. Oosterlaan, N. Rommelse, H. Roeyers, R.D. Oades, S.V. Faraone, B. Franke, T. Heskes, A. Arias Vasquez, T. Claassen, J.K. Buitelaar

    Known comorbidities for Attention-Deficit Hyperactivity Disorder (ADHD) include conduct problems, substance use disorder and gaming. Comorbidity with conduct problems may increase the risk for substance use disorder and gaming in individuals with ADHD. The aim of the study was to build a causal model of the relationships between ADHD and comorbid conduct problems, and alcohol, nicotine, and other substance use, and gaming habits, while accounting for age and sex. We used a state-of-the-art causal discovery algorithm to analyze a case-only sample of 362 ADHD-diagnosed individuals in the ages 12–24 years. We found that conduct problem severity mediates between ADHD severity and nicotine use, but not with more severe alcohol or substance use. More severe ADHD-inattentive symptoms lead to more severe gaming habits. Furthermore, our model suggests that ADHD severity has no influence on severity of alcohol or other drug use. Our findings suggest that ADHD severity is a risk factor for nicotine use, and that this effect is fully mediated by conduct problem severity. Finally, ADHD-inattentive severity was a risk factor for gaming, suggesting that gaming dependence has a different causal pathway than substance dependence and should be treated differently. By identifying these intervention points, our model can aid both researchers and clinicians.

    更新日期:2019-11-18
  • Saliva oxytocin, cortisol, and testosterone levels in adolescent boys with autism spectrum disorder, oppositional defiant disorder/conduct disorder and typically developing individuals
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2018-09-07
    M.J. Bakker-Huvenaars, C.U. Greven, P. Herpers, E. Wiegers, A. Jansen, R. van der Steen, A.E. van Herwaarden, A.N. Baanders, K.S. Nijhof, F. Scheepers, N. Rommelse, J.C. Glennon, J.K. Buitelaar

    The aim of the current study was to compare levels of oxytocin, cortisol, and testosterone in adolescents with either autism spectrum disorder (ASD), or oppositional defiant disorder (ODD)/conduct disorder (CD), and in typically developing individuals (TDI), and relate hormone levels to severity and subtype of aggression and callous-unemotional (CU) traits. Saliva concentrations of oxytocin, cortisol, and testosterone were assessed in 114 male participants (N = 49 ASD, N = 37 ODD/CD, N = 28 TDI,) aged 12–19 years (M = 15.4 years, SD = 1.9). The ASD and the ODD/CD groups had significantly lower levels of oxytocin than the TDI group, and the ODD/CD group had significantly higher levels of testosterone than the ASD group. There were no group effects on cortisol levels. Group differences remained for oxytocin after correcting for the influence of CU traits, but were not significant after controlling for aggression. Results for testosterone became non-significant after correction for either CU traits or aggression. Across groups, higher levels of CU traits were related to higher levels of cortisol and testosterone, however, proactive and reactive aggression were unrelated to all three hormonal levels. The current findings show that, regardless of cognitive ability or comorbid disorders, the diagnostic groups (ASD, ODD/CD) differ from each other by their hormonal levels, with the ASD group characterized by relative low level of oxytocin, and the ODD/CD group by a relative low level of oxytocin and high level of testosterone. These group effects were partly driven by differences in CU traits between the groups.

    更新日期:2019-11-18
  • Intoxicated aggression: Do alcohol and stimulants cause dose-related aggression? A review
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2018-06-23
    KPC Kuypers, RJ Verkes, W van den Brink, JGC van Amsterdam, JG Ramaekers

    Rationale Violence and drug use are significant public health challenges that are strongly linked. It is known that alcohol plays a major role in the causation of unnatural deaths and that stimulants like cocaine and amphetamine are often implicated in aggressive acts or violence. However, a clear causal relationship between these substances and aggression, and more specifically a blood concentration threshold at which intoxicated aggression emerges is lacking. In case of a crime and subsequent law enforcement, knowledge about dose-response relationships could be of pivotal importance when evaluating the role of alcohol and drugs in aggressive offences. Aims The present review aimed to determine whether there is a causal relation between intoxication with these psychoactive substances and aggression, and to define blood concentration thresholds above which these substances elicit aggression. Methods Empirical articles published between 2013 and 2017 and review papers containing the predefined search strings were identified through searches in the PubMed and Embase databases and additional reference list searches. The complete search query yielded 1578 publications. Initially all articles were manually screened by title and abstract. Articles with irrelevant titles, given the selected search terms and review aims were discarded. Remaining articles were carefully studied and those that did not comply with the main objectives of this review were discarded. At the end of this process, 167 titles were found eligible for review. Findings and Conclusion While placebo-controlled experimental studies clearly showed a causal link between alcohol and aggression, it is evident that such a link has not yet been established for cocaine and amphetamines. In case of alcohol, it is clear that there are various individual and contextual factors that may contribute to the occurrence of an aggressive act during intoxication. A clear threshold blood alcohol concentration has not been defined yet for alcohol, but a statistically significant increase of aggression has been demonstrated at a dose of 0.75 g/kg and higher. Future studies into intoxicated aggression should include multiple doses of alcohol and stimulants and take into account individual and contextual factors.

    更新日期:2019-11-18
  • Cortical control of aggression: GABA signalling in the anterior cingulate cortex
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2017-12-20
    Amanda Jager, Houshang Amiri, Natalia Bielczyk, Sabrina van Heukelum, Arend Heerschap, Armaz Aschrafi, Geert Poelmans, Jan K. Buitelaar, Tamas Kozicz, Jeffrey C. Glennon

    Reduced top-down control by cortical areas is assumed to underlie pathological forms of aggression. While the precise underlying molecular mechanisms are still elusive, it seems that balancing the excitatory and inhibitory tones of cortical brain areas has a role in aggression control. The molecular mechanisms underpinning aggression control were examined in the BALB/cJ mouse model. First, these mice were extensively phenotyped for aggression and anxiety in comparison to BALB/cByJ controls. Microarray data was then used to construct a molecular landscape, based on the mRNAs that were differentially expressed in the brains of BALB/cJ mice. Subsequently, we provided corroborating evidence for the key findings from the landscape through 1H-magnetic resonance imaging and quantitative polymerase chain reactions, specifically in the anterior cingulate cortex (ACC). The molecular landscape predicted that altered GABA signalling may underlie the observed increased aggression and anxiety in BALB/cJ mice. This was supported by a 40% reduction of 1H-MRS GABA levels and a 20-fold increase of the GABA-degrading enzyme Abat in the ventral ACC. As a possible compensation, Kcc2, a potassium-chloride channel involved in GABA-A receptor signalling, was found increased. Moreover, we observed aggressive behaviour that could be linked to altered expression of neuroligin-2, a membrane-bound cell adhesion protein that mediates synaptogenesis of mainly inhibitory synapses. In conclusion, Abat and Kcc2 seem to be involved in modulating aggressive and anxious behaviours observed in BALB/cJ mice through affecting GABA signalling in the ACC.

    更新日期:2019-11-18
  • Monoamine and neuroendocrine gene-sets associate with frustration-based aggression in a gender-specific manner
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2017-11-27
    Marjolein M.J. van Donkelaar, Martine Hoogman, Elena Shumskaya, Jan K. Buitelaar, Janita Bralten, Barbara Franke

    Investigating phenotypic heterogeneity in aggression and understanding the molecular biological basis of aggression subtypes may lead to new prevention and treatment options. In the current study, we evaluated the taxonomy of aggression and examined specific genetic mechanisms underlying aggression subtypes in healthy males and females. Confirmatory Factor Analysis (CFA) was used to replicate a recently reported three-factor model of the Reactive Proactive Questionnaire (RPQ) in healthy adults (n = 661; median age 24.0 years; 41% male). Gene-set association analysis, aggregating common genetic variants within (a combination of) three molecular pathways previously implicated in aggression, i.e. serotonergic, dopaminergic, and neuroendocrine signaling, was conducted with MAGMA software in males and females separately (total n = 395) for aggression subtypes. We replicate the three-factor CFA model of the RPQ, and found males to score significantly higher on one of these factors compared to females: proactive aggression. The genetic association analysis showed a female-specific association of genetic variation in the combined gene-set with a different factor of the RPQ; reactive aggression due to internal frustration. Both the neuroendocrine and serotonergic gene-sets contributed significantly to this association. Our genetic findings are subtype- and sex-specific, stressing the value of efforts to reduce heterogeneity in research of aggression etiology. Importantly, subtype- and sex-differences in the underlying pathophysiology of aggression suggest that optimal treatment options will have to be tailored to the individual patient. Male and female needs of intervention might differ, stressing the need for sex-specific further research of aggression. Our work highlights opportunities for sample size maximization offered by population-based studies of aggression.

    更新日期:2019-11-18
  • RBFOX1, encoding a splicing regulator, is a candidate gene for aggressive behavior
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2017-11-23
    Noèlia Fernàndez-Castillo, Gabriela Gan, Marjolein M.J. van Donkelaar, Mariliis Vaht, Heike Weber, Wolfgang Retz, Andreas Meyer-Lindenberg, Barbara Franke, Jaanus Harro, Andreas Reif, Stephen V. Faraone, Bru Cormand

    The RBFOX1 gene (or A2BP1) encodes a splicing factor important for neuronal development that has been related to autism spectrum disorder and other neurodevelopmental phenotypes. Evidence from complementary sources suggests that this gene contributes to aggressive behavior. Suggestive associations with RBFOX1 have been identified in genome-wide association studies (GWAS) of anger, conduct disorder, and aggressive behavior. Nominal association signals in RBFOX1 were also found in an epigenome-wide association study (EWAS) of aggressive behavior. Also, variants in this gene affect temporal lobe volume, a brain area that is altered in several aggression-related phenotypes. In animals, this gene has been shown to modulate aggressive behavior in Drosophila. RBFOX1 has also been associated with canine aggression and is upregulated in mice that show increased aggression after frustration of an expected reward. Associated common genetic variants as well as rare duplications and deletions affecting RBFOX1 have been identified in several psychiatric and neurodevelopmental disorders that are often comorbid with aggressive behaviors. In this paper, we comprehensively review the cumulative evidence linking RBFOX1 to aggression behavior and provide new results implicating RBFOX1 in this phenotype. Most of these studies (genetic and epigenetic analyses in humans, neuroimaging genetics, gene expression and animal models) are hypothesis-free, which strengthens the validity of the findings, although all the evidence is nominal and should therefore be taken with caution. Further studies are required to clarify in detail the role of this gene in this complex phenotype.

    更新日期:2019-11-18
  • Nitric oxide interacts with monoamine oxidase to modulate aggression and anxiety-like behaviour
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2017-09-23
    Héctor Carreño Gutiérrez, Aet O’Leary, Florian Freudenberg, Giorgio Fedele, Rob Wilkinson, Eleanor Markham, Freek van Eeden, Andreas Reif, William H.J. Norton

    Nitric oxide (NO) is a gaseous neurotransmitter that has important behavioural functions in the vertebrate brain. In this study we compare the impact of decreased nitric NO signalling upon behaviour and neurobiology using both zebrafish and mouse. nitric oxide synthase mutant (nos1−/−) zebrafish show significantly reduced aggression and an increase in anxiety-like behaviour without altered production of the stress hormone cortisol. Nos1−/− mice also exhibit decreased aggression and are hyperactive in an open field test. Upon reduction of NO signalling, monoamine neurotransmitter metabolism is reduced as a consequence of decreased Monoamine oxidase activity. Treatment of nos1−/− zebrafish with the 5-HT receptor 1A agonist 8-OH-DPAT rescues aggression and some aspects of anxiety-like behaviour. Taken together, the interplay between NO and 5-HT appears to be critical to control behaviour. Our cross-species approach challenges the previous notion that reduced neuronal NOS leads to increased aggression. Rather, Nos1 knock-out can also lead to decreased aggression in some situations, a finding that may have implications for future translational research.

    更新日期:2019-11-18
  • Associations of multiple trauma types and MAOA with severe aggressive behavior and MAOA effects on training outcome
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2017-07-01
    Danique Smeijers, Erik Bulten, Barbara Franke, Jan Buitelaar, Robbert-Jan Verkes

    Previous research showed that the disposition to react with disproportionate aggression in adults is influenced by an interaction between a variant in the X-chromosomal monoamine oxidase A gene (MAOA) and early traumatic events. Such studies have often focused on a single type of trauma, whereas we know that experiencing multiple trauma types is associated with more detrimental consequences. The differential susceptibility hypothesis suggests that individuals who are most susceptible to adversity, are also most likely to benefit from supportive experiences in childhood. Differences in susceptibility are thought to be partly genetically driven. In the present study we explored whether a genotype of MAOA linked to lower expression of the gene (MAOA-L) modified the effect of multiple types of trauma on aggression and/or altered responsiveness to treatment among adults with severe aggression. Forensic psychiatric outpatients (FPOs) (N=150) receiving treatment for aggression regulation problems were recruited. Traumatic events and aggression were measured using self-report. FPOs with multiple trauma types and those with the MAOA-L allele reported more severe levels of aggression. No interaction effects between MAOA genotype and trauma emerged. There were no differences in response to the intervention between FPOs with and without the MAOA-L variant, whereas FPOs with a single type of trauma showed the slowest reduction of aggression. FPOs with multiple types of trauma reported the highest levels of aggression over the course of treatment. Future research is needed to elucidate this association in further detail. The current study emphasized the importance of early recognition of early traumatic events.

    更新日期:2019-11-18
  • The effects of nalmefene on emotion processing in alcohol use disorder – A randomized, controlled fMRI study
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-11-15
    Sabine Vollstädt-Klein, J. Malte Bumb, Amelie Otto, Christina Dinter, Damian Karl, Anne Koopmann, Derik Hermann, Karl Mann, Falk Kiefer

    Nalmefene is a µ- and δ-opioid receptor antagonist and a partial κ-opioid receptor agonist. The drug is suggested to reduce the craving for, and the consumption of alcohol effectively, also alleviating anxiety and anhedonia. The present fMRI study is the first to investigate the processing of emotions as a possible mechanism of action of nalmefene in humans. Fifteen non-treatment-seeking participants suffering from alcohol use disorder (AUD) (24–66 years; 5 females) finished this randomized, placebo controlled, double blind study. Following a cross over design, participants received either a single dose nalmefene or a placebo, with an interval of one week between sessions. Using fMRI, we investigated neural reactivity during the presentation of emotional faces picture sets. Additionally, we performed a visual dot-probe task to detect nalmefene's effects on attentional bias. We detected an increase in the response to emotional faces in the supramarginal gyrus, the angular gyrus as well as the putamen in the nalmefene vs. placebo condition. However, contradictory to our initial hypotheses, amygdala activation was not altered significantly in the placebo condition – a limitation, which might be associated with a lack of activation in the placebo condition maybe due to the small sample size. Attentional bias analyses revealed an interaction effect by trend, which was driven by a significant effect in a sub-analysis showing increased attentional shift towards happy compared to fearful facial expressions under nalmefene. Nalmefene increased brain activation in areas responsible for empathy, social cognition and behavior, which might help alleviating the reinforcing properties of alcohol.

    更新日期:2019-11-15
  • 更新日期:2019-11-15
  • Nutritional psychiatry: Towards improving mental health by what you eat
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-11-14
    Roger A.H. Adan, Eline M. van der Beek, Jan K. Buitelaar, John F. Cryan, Johannes Hebebrand, Suzanne Higgs, Harriet Schellekens, Suzanne L. Dickson

    Does it matter what we eat for our mental health? Accumulating data suggests that this may indeed be the case and that diet and nutrition are not only critical for human physiology and body composition, but also have significant effects on mood and mental wellbeing. While the determining factors of mental health are complex, increasing evidence indicates a strong association between a poor diet and the exacerbation of mood disorders, including anxiety and depression, as well as other neuropsychiatric conditions. There are common beliefs about the health effects of certain foods that are not supported by solid evidence and the scientific evidence demonstrating the unequivocal link between nutrition and mental health is only beginning to emerge. Current epidemiological data on nutrition and mental health do not provide information about causality or underlying mechanisms. Future studies should focus on elucidating mechanism. Randomized controlled trials should be of high quality, adequately powered and geared towards the advancement of knowledge from population-based observations towards personalized nutrition. Here, we provide an overview of the emerging field of nutritional psychiatry, exploring the scientific evidence exemplifying the importance of a well-balanced diet for mental health. We conclude that an experimental medicine approach and a mechanistic understanding is required to provide solid evidence on which future policies on diet and nutrition for mental health can be based.

    更新日期:2019-11-14
  • Serotonin 5-HT2A receptor expression and functionality in postmortem frontal cortex of subjects with schizophrenia: Selective biased agonism via Gαi1-proteins
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-11-14
    Aintzane García-Bea, Patricia Miranda-Azpiazu, Carolina Muguruza, Sara Marmolejo-Martinez-Artesero, Rebeca Diez-Alarcia, Ane M Gabilondo, Luis F Callado, Benito Morentin, Javier González-Maeso, J Javier Meana

    Serotonin 5-HT2A receptors (5-HT2ARs) have been implicated in schizophrenia. However, postmortem studies on 5-HT2ARs expression and functionality in schizophrenia are scarce. The 5-HT2AR mRNA and immunoreactive protein expression were evaluated in postmortem tissue from dorsolateral prefrontal cortex (DLPFC) of antipsychotic-free (n = 18) and antipsychotic-treated (n = 9) subjects with schizophrenia, and matched controls (n = 27). Functional coupling of 5-HT2AR to G-proteins was tested by measuring the activation induced by the agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride ((±)DOI) in antibody-capture [35S]GTPγS scintillation proximity assays (SPA). In antipsychotic-free schizophrenia subjects, 5-HT2AR mRNA expression and protein immunoreactivity in total homogenates was similar to controls. In contrast, in antipsychotic-treated schizophrenia subjects, lower mRNA expression (60±9% vs controls) and a trend to reduced protein immunoreactivity (86±5% vs antipsychotic-free subjects) just in membrane-enriched fractions was observed. [35S]GTPγS SPA revealed a significant ~6% higher stimulation of Gαi1-protein by (±)DOI in schizophrenia, whereas activation of the canonical Gαq/11-protein pathway by (±)DOI remained unchanged. Expression of Gαi1- and Gαq/11-proteins did not differ between groups. Accordingly, in rats chronically treated with clozapine, but not with haloperidol, a 30–40% reduction was observed in 5-HT2AR mRNA expression, 5-HT2AR protein immunoreactivity and [3H]ketanserin binding in brain cortical membranes. Overall, the data suggest a supersensitive 5-HT2AR signaling through inhibitory Gαi1-proteins in schizophrenia. Together with previous results, a dysfunctional pro-hallucinogenic agonist-sensitive 5-HT2AR conformation in postmortem DLPFC of subjects with schizophrenia is proposed. Atypical antipsychotic treatment would contribute to counterbalance this 5-HT2AR supersensitivity by reducing receptor expression.

    更新日期:2019-11-14
  • The effect of second-generation antipsychotics on basal ganglia and thalamus in first-episode psychosis patients
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-11-08
    Auria Albacete, Carolina Makowski, M. Mallar Chakravarty, Ridha Joober, Ashok K. Malla, Fernando Contreras, José Manuel Menchón, Martin Lepage

    Patients who have recently experienced a first of episode psychosis (FEP) exhibit considerable heterogeneity in subcortical brain volumes. These results become even more divergent when exploring the effect of antipsychotic medication among other clinical and cognitive features. We aimed to contrast volumetric measures in basal ganglia and thalamus in patients with a FEP treated with different second-generation antipsychotics. T1-weighted magnetic resonance images were obtained and subcortical structures were extracted with MAGeT-Brain. Relationships with cognitive functioning were also explored with a Global Cognitive Index obtained, on average, within one month from the scan. Subgroups included: risperidone (n = 26), aripiprazole (n = 22), olanzapine (n = 19) and controls (n = 80). The olanzapine subgroup displayed significant enlargement of the right globus pallidus volume compared with all other groups. Moreover, despite not exhibiting poorer cognitive capacity than the rest of patients, results from a stepwise multiple-regression linear regression analysis identified a significant negative association between right globus pallidus volume and scores on the Global Cognitive Index among these patients. To our knowledge, this is the first study to associate treatment with olanzapine with an increase in globus pallidus volume in a sample of FEP patients with a relatively short time of antipsychotic monotherapy. Such enlargement was also found to be associated with poorer global cognitive functioning. Exploration of the biological underpinnings of this early medication-induced enlargement should be the focus of future investigations since it may lend insight towards achieving a better clinical outcome for these patients.

    更新日期:2019-11-08
  • Incidence of adverse events in antipsychotic-naïve children and adolescents treated with antipsychotic drugs: Results of a multicenter naturalistic study (ETAPE)
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-11-04
    Marie-Line Menard, Susanne Thümmler, Marianna Giannitelli, Coralie Cruzel, Olivier Bonnot, David Cohen, Florence Askenazy

    The main objective of ETAPE study was to determine the incidence of adverse events (AEs) potentially related to antipsychotic (AP) during a 12-months observational study of naturalistic treatment. ETAPE is a naturalistic prospective multicenter study conducted between April 2013 and May 2016. 200 patients were included. The mean age was 12 ± 3 years, with 73.6% being males. Patients presented a significant clinical improvement over time. At baseline, 92% of patients received a second generation AP, 74% AP monotherapy and 79.5% off-label AP prescriptions. Clinical diagnoses were heterogeneous including psychosis, anxiety, mood and neurodevelopmental disorders. The overall AE incidence rate was 11.52 AEs per person-years. Among AEs potentially attributable to AP, 15.4% were neuromotor, 14.8% gastroenterological, 12.2% metabolic and 11.8% general symptoms. Weight and body mass index increased significantly. More than half of AE appeared during the first 3 months, but onset of AE was noted all over follow-up. The presence of AEs was stable over time. ETAPE study highlights a high incidence rate of AE in children treated with AP. A careful and continuous clinical and biological monitoring is required to adapt treatment decisions based on benefice-risk-analysis. Moreover, additional research is warranted, also in regard of high proportion of off-label prescriptions.

    更新日期:2019-11-04
  • Reward anticipation in individuals with subclinical psychotic experiences: A functional MRI approach
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-11-01
    Stijn Michielse, Iris Lange, Jindra Bakker, Liesbet Goossens, Simone Verhagen, Silvia Papalini, Marieke Wichers, Ritsaert Lieverse, Koen Schruers, Therese van Amelsvoort, Jim van Os, Graham K Murray, Machteld Marcelis

    Previous research in patients with psychotic disorder has shown widespread abnormalities in brain activation during reward anticipation. Research at the level of subclinical psychotic experiences in individuals unexposed to antipsychotic medication is limited with inconclusive results. Therefore, brain activation during reward anticipation was examined in a larger sample of individuals with subclinical psychotic experiences (PE). Participants in the PE-group were included based on CAPE scores. A sample of emerging adults aged 16–26 years (n = =47) with PE and healthy controls (HC) (n = =40) underwent fMRI scanning. The Monetary Incentive Delay task was conducted with cues related to win, loss or neutral conditions. fMRI nonparametric tests were used to examine the reward versus neutral cue contrast. A significant main effect of the large win (€3.00) > neutral contrast was found in both groups showing activation in many brain areas, including classic reward regions. Whole brain analysis on the group comparison regarding the large win > neutral contrast showed significantly decreased activation in the right insula, putamen and supramarginal gyrus in the PE-group compared to controls. There was no group difference in the hypothesized reward-related region. Decreased activation in the right insula, putamen and supramarginal gyrus during reward anticipation in individuals with PE may be consistent with altered processing of sensory information, related to decreased emotional valuing and motivational tendencies and/or altered motor-cognitive processes. The absence of group differences in striatal activation suggests that activation here is intact in the earliest stages of psychosis and may exhibit progressive deterioration in as the disease develops.

    更新日期:2019-11-01
  • Screening for drugs to reduce zebrafish aggression identifies caffeine and sildenafil
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-11-01
    Héctor Carreño Gutiérrez, Irene Vacca, Gido Schoenmacker, Madeleine Cleal, Anna Tochwin, Bethan O'Connor, Andrew M.J. Young, Alejandro Arias Vasquez, Matthew J. Winter, Matthew O. Parker, William H.J. Norton

    Although aggression is a common symptom of psychiatric disorders the drugs available to treat it are non-specific and can have unwanted side effects. In this study we have used a behavioural platform in a phenotypic screen to identify drugs that can reduce zebrafish aggression without affecting locomotion. In a three tier screen of ninety-four drugs we discovered that caffeine and sildenafil can selectively reduce aggression. Caffeine also decreased attention and increased impulsivity in the 5-choice serial reaction time task whereas sildenafil showed the opposite effect. Imaging studies revealed that both caffeine and sildenafil are active in the zebrafish brain, with prominent activation of the thalamus and cerebellum evident. They also interact with 5-HT neurotransmitter signalling. In summary, we have demonstrated that juvenile zebrafish are a suitable model to screen for novel drugs to reduce aggression, with the potential to uncover the neural circuits and signalling pathways that mediate such behavioural effects.

    更新日期:2019-11-01
  • The selective κ-opioid receptor antagonist JDTic attenuates the alcohol deprivation effect in rats
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-10-31
    Johanna Uhari-Väänänen, Tony Eteläinen, Pia Bäckström, Ville Oinio, F. Ivy Carroll, Atso Raasmaja, Kalervo Kiianmaa, Petteri Piepponen

    The mechanisms behind relapse to ethanol intake in recovering alcoholics are still unclear. The negative reinforcing effects contributing to ethanol addiction, including relapse, are considered to be partly driven by the κ-opioidergic system. As the κ-opioidergic system interacts with the mesolimbic reward pathway, the aim of the study was to clarify the role of nucleus accumbens shell κ-opioidergic mechanisms in relapse to ethanol intake by using the alcohol deprivation effect (ADE) paradigm. The ADE is defined as a transient increase in voluntary ethanol intake after a forced period of abstinence. Male Long-Evans rats were trained to voluntarily consume 10% (v/v) ethanol solution. Ethanol access and deprivation cycles were initiated after stable ethanol intake baselines had been reached and bilateral guide cannulas had been implanted above the nucleus accumbens shell. One cycle consisted of 10 days of 90 min access to ethanol followed by 6 days of ethanol deprivation. The ADE was measured in the beginning of a new cycle. Rats received JDTic, a selective κ-antagonist, either subcutaneously (10 mg/kg) or intra-accumbally (15 µg/site) or, as a reference substance, systemic naltrexone (0.3 mg/kg) before ethanol re-access, and the effects on the ADE were evaluated. Systemic and intra-accumbal JDTic significantly attenuated the ADE on the first day of ethanol re-access, as did systemic naltrexone. Additionally, naltrexone decreased ethanol intake levels. These results suggest that nucleus accumbens shell κ-opioidergic mechanisms may have a role in mediating relapse to ethanol intake. Additionally, κ-antagonism could be a valuable adjunct in ethanol relapse prevention.

    更新日期:2019-11-01
  • Glutamatergic function in a genetic high-risk group for psychosis: A proton magnetic resonance spectroscopy study in individuals with 22q11.2 deletion
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-10-21
    Maria Rogdaki, Pamela Hathway, Maria Gudbrandsen, Robert A. McCutcheon, Sameer Jauhar, Eileen Daly, Oliver Howes

    Glutamatergic dysregulation is one of the leading theories regarding the pathoaetiolopy of schizophrenia. Meta-analysis of magnetic resonance spectroscopy studies in schizophrenia shows increased levels of glutamate and glutamine (Glx) in the medial frontal cortex and basal ganglia in clinical high-risk groups for psychosis and increased glutamine levels in the thalamus, but it is unclear if this is also the case in people at genetic high risk for psychosis. The aim of this study was to investigate glutamatergic function in the anterior cingulate cortex, striatum and thalamus in carriers of a genetic variant (22q11.2 deletion) associated with a high risk for psychosis. 53 volunteers (23 22q11.2 deletion carriers and 30 controls) underwent proton magnetic resonance spectroscopy imaging and neuropsychological assessments for prodromal psychotic symptoms, schizotypy, anxiety, depression and FSIQ. We did not find any difference between groups in Glx in the anterior cingulate cortex, striatum or thalamus (Glx: t(50)=-1.26, p = 0.21; U = 251, z = −0.7, p = 0.49; U = 316, z= -0.26, p = 0.79, respectively). No correlation was detected between Glx levels in any region and symptomatology or FSIQ. Our findings indicate that glutamatergic function is not altered in people at genetic high risk of psychosis due to the 22q11.2 deletion, which could suggest that this is not the mechanism underlying psychosis risk in 22q11.2 deletion carriers.

    更新日期:2019-10-21
  • Skeletal muscle DNA methylation modifications and psychopharmacologic treatment in bipolar disorder
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-10-19
    Kyle J. Burghardt, Bradley H. Howlett, Elani Sanders, Sabrina E. Dass, Zaher Msallaty, Abduallah Mallisho, Berhane Seyoum, Zhengping Yi

    Both severe mental illness and atypical antipsychotics have been independently associated with insulin resistance and weight gain. Altered regulation of skeletal muscle DNA methylation may play a role. We aimed to evaluate DNA methylation modifications in human skeletal muscle samples to further understand its potential role in the metabolic burden observed in psychiatric patients and psychopharmacologic treatment. Subjects were included in our study if they had a bipolar diagnosis and were currently treated with a mood stabilizer or atypical antipsychotic. A healthy control group free of psychiatric or physical disease was also included for comparisons. Anthropometric, BMI and hemoglobin A1C (HbA1C%) were measured. Fasting skeletal muscle biopsies were obtained and methylation levels of 5-methycytosine (5-mC), 5-hydroxymethylcytosine (5-hmC) and 5-formylcytosine (5-fC) were measured. Skeletal muscle global methylation of 5-mC and 5-fC were significantly higher in bipolar subjects compared to healthy controls. 5-mC was significantly higher in the AAP group compared to the mood stabilizer group. Significant correlations were observed between 5-fC methylation and HbA1C%. Our findings suggest that psychiatric disease and treatment may influence some methylation measures in the skeletal muscle of patients with bipolar disorder, which may be further influenced by medication treatment.

    更新日期:2019-10-19
  • α7 nicotinic receptor full agonist reverse basolateral amygdala hyperactivity and attenuation of dopaminergic neuron activity in rats exposed to chronic mild stress
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-10-12
    Gilda A. Neves, Anthony A. Grace

    Neuroimaging and preclinical studies showing that nicotinic receptors (nAChR) may play a role in mood control has increased interest in targeting the cholinergic system for treatment of major depressive disorder. Indeed, modulation of nAChRs in the basolateral amygdala (BLA) are sufficient to produce an anti-immobility effect in the mouse tail suspension test. However, how α7 nAChR modulation impacts BLA neuronal activity in vivo as well as the downstream mechanisms involved in its mood-related effects are not understood. In this work, we used the unpredictable chronic mild stress (CMS) model to investigate the mechanisms underlying the antidepressant-like effect of an α7 nAChR full agonist on BLA-induced changes in dopaminergic neurotransmission. Male adult Sprague-Dawley rats were exposed to four weeks of CMS. Behavioral and electrophysiological experiments were performed within one week following stress. CMS exposure increased rats’ immobility time in the forced swimming test, decreased the number of spontaneously active dopamine neurons in the ventral tegmental area and increased the firing rate of putative projection neurons in the BLA. Stress-induced behavioral and electrophysiological changes were reversed by a single systemic administration of PNU282987. In summary, our findings corroborate previous descriptions of a potential rapid antidepressant effect for the α7 nAChR full agonist. This effect appears to involve a mechanism distinct from those of classic antidepressants: normalization of BLA hyperactivity and, consequently, of DA hypofunction. These observations corroborate the role of α7 nAChR as a potential target for novel antidepressant drug development.

    更新日期:2019-10-12
  • Impact of dopamine and cognitive impairment on neural reactivity to facial emotion in Parkinson's disease
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-10-10
    Rotem Dan, Filip Růžička, Ondrej Bezdicek, Jan Roth, Evžen Růžička, Josef Vymazal, Gadi Goelman, Robert Jech

    Emotional and cognitive impairments in Parkinson's disease (PD) are prevalent, hamper interpersonal relations and reduce quality of life. It is however unclear to what extent these domains interplay in PD-related deficits and how they are influenced by dopaminergic availability. This study examined the effect of cognitive impairment and dopaminergic medication on neural and behavioral mechanisms of facial emotion recognition in PD patients. PD patients on and off dopaminergic medication and matched healthy controls underwent an emotional face matching task during functional MRI. In addition, a comprehensive neuropsychological evaluation of cognitive function was conducted. Increased BOLD response to emotional faces was found in the visual cortex of PD patients relative to controls irrespective of cognitive function and medication status. Administration of dopaminergic medication in PD patients resulted in restored behavioral accuracy for emotional faces relative to controls and decreased retrosplenial cortex BOLD response to emotion relative to off-medication state. Furthermore, cognitive impairment in PD patients was associated with reduced behavioral accuracy for non-emotional stimuli and predicted BOLD response to emotion in the anterior and posterior cingulate cortices, depending on medication status. Findings of aberrant visual and retrosplenial BOLD response to emotion are suggested to stem from altered attentional and/or emotion-driven modulation from subcortical and higher cortical regions. Our results indicate neural disruptions and behavioral deficits in emotion processing in PD patients that are dependent on dopaminergic availability and independent of cognitive function. Our findings highlight the importance of dopaminergic treatment not only for the motor symptoms but also the emotional disturbances in PD.

    更新日期:2019-10-10
  • Is the computerized assessment of psychomotor speed more sensitive to cognitive effects of antiepileptic pharmacotherapy than tests with a focus on higher-order cognitive processing? Implications for the choice of sensitive test parameters
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-10-09
    Christoph Helmstaedter, Philipp Durch, Christian Hoppe, Juri-Alexander Witt

    The study evaluated whether it is psychomotor speed or higher-order cognitive processing which is primarily affected by antiepileptic drug (AED) treatment in epilepsy and whether computerized testing versus paper-pencil testing of executive functions is more sensitive. In this retrospective observational study, 55 patients with epilepsy underwent NeuroCog FXⓇ, a computerized battery assessing “psychomotor speed/alertness” and “cognitive processing” via 8 tasks, and EpiTrackⓇ, a paper-pencil screening of “executive functions and working memory” based on 6 subtests. Test performance was related to the number of drugs and the Defined Daily Dose and the presence/absence of AEDs with known adverse psychotropic effects. EpiTrackⓇ performance correlated with "cognitive processing" of the NeuroCog FXⓇ but not with "psychomotor speed/alertness". Significant correlations with drug load were mainly yielded for EpiTrackⓇ (number of AEDs: r = –0.551, total DDD: r = –0.452) and "cognitive processing" (number of AEDs: r = -0.433, total DDD: r = –0.415). "Psychomotor speed/alertness" was less related to drug load (number of AEDs: r = -0.285, total DDD: r = –0.232). Statistical control for “psychomotor speed/alertness” hardly changed the correlations of EpiTrackⓇ or “cognitive processing” with drug load indices. AEDs with known adverse profiles negatively affected EpiTrackⓇ and the "cognitive processing" but not the “psychomotor speed/alertness” domain of the computerized test. The results demonstrate that it is less basal psychomotor speed than higher-order cognitive processing which is negatively affected by antiepileptic pharmacotherapy. The results question the value of (computer-)tests with a major emphasis on psychomotor speed and alertness for cognitive drug monitoring.

    更新日期:2019-10-10
  • Multivariate genome-wide analysis of stress-related quantitative phenotypes
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-10-09
    Dick Schijven, Elbert Geuze, Christiaan H. Vinkers, Sara L. Pulit, Remmelt R. Schür, Marie Malgaz, Erwin Bekema, Jelena Medic, Kendrick E. van der Kust, Jan H. Veldink, Marco P. Boks, Eric Vermetten, Jurjen J. Luykx

    Exposure to traumatic stress increases the odds of developing a broad range of psychiatric conditions. Genetic studies targeting multiple stress-related quantitative phenotypes may shed light on mechanisms underlying vulnerability to psychopathology in the aftermath of stressful events. We applied a multivariate genome-wide association study (GWAS) to a unique military cohort (N = 583) in which we measured biochemical and behavioral phenotypes. The availability of pre- and post-deployment measurements allowed to capture changes in these phenotypes in response to stress. For genome-wide significant loci, we performed functional annotation, phenome-wide analysis and quasi-replication in PTSD case-control GWASs. We discovered one genetic variant reaching genome-wide significant association, surviving permutation and sensitivity analyses (rs10100651, p = 9.9 × 10−9). Functional annotation prioritized the genes INTS8 and TP53INP1. A phenome-wide scan revealed a significant association of these same genes with sleeping problems, hypertension and subjective well-being. Finally, a targeted lookup revealed nominally significant association of rs10100651 in a PTSD case-control GWAS in the UK Biobank (p = 0.02). We provide comprehensive evidence from multiple resources hinting at a role of the highlighted genetic variant in the human stress response, marking the power of multivariate genome-wide analysis of quantitative measures in stress research. Future genetic and functional studies can target this locus to further assess its effects on stress mediation and its possible role in psychopathology or resilience.

    更新日期:2019-10-10
  • European college of neuropsychopharmacology network on the prevention of mental disorders and mental health promotion (ECNP PMD-MHP)
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-10-09
    Paolo Fusar-Poli, Michael Bauer, Stefan Borgwardt, Andreas Bechdolf, Christoph U. Correll, Kim Q. Do, Katharina Domschke, Silvana Galderisi, Lars Vedel Kessing, Nikolaos Koutsouleris, Marie-Odile Krebs, Belinda Lennox, Philip McGuire, Andreas Meyer-Lindenberg, Mark J. Millan, Dorien Nieman, Andrea Pfennig, Michael Sand, Celso Arango

    Prevention is the most promising way to reduce the high personal, familial, societal, clinical and economic costs of mental disorders in Europe and worldwide. A complementary approach is to go beyond the prevention of mental ill health, to promote good mental health. This manuscript highlights the first European consortium fostering cutting-edge multidisciplinary research in these two areas. The ECNP-funded Network on the Prevention of Mental Disorders and Mental Health Promotion (ECNP PMD-MHP) brings together European sites of excellence with different expertise for translational research collaboration, including partnerships with the industry. The ECNP PMD-MHP Network adopts a transdiagnostic, lifespan, clinical staging model which cuts across different mental disorders and different methodologies. The main aims of the ECNP PMD-MHP Network are to facilitate multidisciplinary collaboration, enhance knowledge and data sharing, standardise core assessment and outcome measures, promote clinical research, apply for grant funding, and generate research reports. By supporting collaborative research, the ECNP PMD-MHP Network will be vital for fostering European psychiatry in the field of prevention of mental disorders and promotion of good mental health.

    更新日期:2019-10-10
  • Expert advice on the management of valproate in women with bipolar disorder at childbearing age
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-10-04
    Gerard Anmella, Isabella Pacchiarotti, Wiesław Jerzy Cubała, Dominika Dudek, Giuseppe Maina, Pierre Thomas, Eduard Vieta

    Introduction The perinatal period is associated with up to 2/3 relapses in untreated bipolar disorder (BD), with important consequences on the clinical BD outcome and on fetal and child development. Valproate (VPA), one of the most effective treatments in BD, is associated with the highest risk of serious neurodevelopmental disorders in exposed children. This has brought to tightened restrictions to its use by regulatory agencies and clinical guidelines. Methods A panel of experts on the pharmacological treatment of BD conducted a non-systematic review of the scientific literature and clinical guidelines until March 2019, and provided specific evidence-based and experience-based clinical recommendations for VPA switching/discontinuation in BD women of childbearing potential. Results After the review of the evidence in a face-to-face meeting, the panel concluded that several clinical criteria need to be considered to make a clinical decision about VPA discontinuation and switch. The plateau cross-taper switch may be preferred. Abrupt switching may bear augmented risk of relapse Conclusions BD childbearing women treated with VPA must be managed on a personalized basis according to the clinical situation. It is mandatory to stop VPA during pregnancy. The duration of the discontinuation/switch process depends on different clinical variables. Lithium, lamotrigine, quetiapine, olanzapine or aripiprazole are good options for switch in stable BD patients in planned/unplanned pregnancy. In unstable BD patients planning pregnancy, stability is paramount. Prevention of post-partum episodes requires reinstatement of effective treatment before or after birth (in the case of VPA). VPA is still an option in the post-partum period and beyond.

    更新日期:2019-10-04
  • Differential COMT DNA METHYLATION in PATIENTS with Borderline Personality Disorder: Genotype matters
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-10-03
    Mara Thomas, Nora Banet, Annalena Wallisch, Katarzyna Glowacz, Julia Becker-Sadzio, Friederike Gundel, Vanessa Nieratschker

    Differential DNA methylation in peripheral tissues has been associated with Borderline Personality Disorder (BPD). Alterations have been found in several genes, among them the Catechol-O-methyltransferase (COMT) gene. COMT is a known neuropsychiatric candidate gene, which contains a genotype variant (Val108/158Met) that affects protein function and has been found associated with several psychiatric disorders. In addition, this variant also affects COMT DNA methylation. However, in previous epigenetic studies, the DNA methylation results have not always been controlled for genotype, even though overrepresentation of the Met allele has been frequently reported in cohorts of BPD patients. Therefore, in the present study, we investigated whether alteration of COMT DNA methylation in BPD patients is indeed associated with mental health status or merely influenced by a differential distribution of the COMT genotype between BPD patients and healthy control individuals. We found significant group differences, as well as a strong effect of genotype on COMT DNA methylation. While the direction of effect was different compared to a previous study, our study supports the finding of altered COMT DNA methylation in patients with BPD and reinforces the need to include genotype information in future DNA methylation studies of COMT.

    更新日期:2019-10-03
  • In vivo knockdown of astroglial glutamate transporters GLT-1 and GLAST increases excitatory neurotransmission in mouse infralimbic cortex: Relevance for depressive-like phenotypes
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-10-01
    Mª Neus Fullana, Ana Covelo, Analía Bortolozzi, Alfonso Araque, Francesc Artigas

    Alterations of energy metabolism and of astrocyte number/function in ventral anterior cingulate cortex (vACC) have been reported in major depressive disorder (MDD) patients and may contribute to MDD pathophysiology. We recently developed a mouse model of MDD mimicking these alterations. We knocked down the astroglial glutamate transporters GLAST and GLT-1 in infralimbic cortex (IL, rodent equivalent of vACC) using small interfering RNA (siRNA). GLAST and GLT-1 siRNA microinfusion in IL evoked a depressive-like phenotype, associated with a reduced serotonergic function and reduced forebrain BDNF expression. Neither effect occurred after siRNA application in the adjacent prelimbic cortex (PrL), thus emphasizing the critical role of vACC/IL in MDD pathogenesis. Here we examined the cellular/network basis of the changes induced in IL using intracellular recordings of layer V pyramidal neurons from mice microinjected with siRNA 24 h before. We analyzed (i) the electrophysiological characteristics of neurons; (ii) the synaptic transmission properties, by monitoring miniature, spontaneous and evoked EPSCs, and (iii) the gliotransmission, by monitoring slow inward currents (SICs), mediated by astrocytic glutamate release and activation of extra-synaptic NMDA receptors. GLT-1 and GLAST knockdown led to a more depolarized membrane potential and increased action potential firing rate of layer V pyramidal neurons, and enhanced excitatory synaptic transmission, as shown by the enhanced amplitude/frequency of spontaneous EPSCs. Gliotransmission was also increased, as indicated by the enhanced SIC amplitude/frequency. Hence, the depressive-like phenotype is associated with IL hyperactivity, likely leading to an excessive top-down inhibitory control of serotonergic activity through IL-midbrain descending pathways.

    更新日期:2019-10-01
  • Relationship between obsessive compulsive disorder and cortisol: Systematic review and meta-analysis
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-09-17
    João Sousa-Lima, Pedro Silva Moreira, Catarina Raposo-Lima, Nuno Sousa, Pedro Morgado

    Altered stress response and consequent elevated levels of circulating glucocorticoids have been found in neuropsychiatric disorders such as depression or anxiety disorders and proposed to also play a role in the pathophysiology of obsessive–compulsive disorder (OCD). Despite the observation that stressful events may precede the disease onset or even exacerbate its symptoms, studies in this field do not always report consistent results regarding the cortisol profile of OCD patients. As such, a systematic review and meta-analysis was developed to clarify this issue. This systematic review and meta-analysis was elaborated according to the PRISMA method. The analytical procedures were implemented using Metafor package in R software. Nineteen studies were included in the systematic review and 18 were included in the meta-analysis. The meta-analytic results demonstrated that OCD patients had significantly higher cortisol levels compared to controls (d = 0.76, SE = 0.146, p < 0.001). For studies using the average of multiple assessments, the standardized coefficient was significantly higher when compared to studies focusing on single measurements. Both the systematic review and meta-analysis suggest that cortisol levels are significantly higher in OCD patients than healthy individuals.

    更新日期:2019-09-18
  • Enhancement of the antipsychotic effect of risperidone by sodium nitroprusside in rats
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-09-16
    Joep Titulaer, Anna Malmerfelt, Monica M. Marcus, Torgny H. Svensson

    Recently, a single injection of the nitric oxide donor sodium nitroprusside (SNP) was found to induce a rapid and sustained antipsychotic effect in treatment-resistant schizophrenia (TRS). Moreover, a single i.p. injection of SNP in rats was found to generate both rapid and persisting changes in brain synaptic plasticity, including enhanced excitatory postsynaptic current responses and spine morphology in layer V pyramidal cells in the medial prefrontal cortex (mPFC) brain slices. Here we used the conditioned avoidance response (CAR) test in rats to investigate the antipsychotic-like efficacy of SNP in combination with low-dose risperidone. In addition, we performed microdialysis experiments in freely moving rats to measure neurotransmitter efflux in the mPFC and the nucleus accumbens (NAc). Risperidone caused only 20% suppression of CAR, which is far below the degree of CAR suppression required to predict a significant clinical antipsychotic effect. Addition of a low dose of SNP to risperidone dramatically enhanced the antipsychotic-like effect to a clinically relevant level. SNP significantly enhanced the risperidone-induced dopamine output in the mPFC but not in the NAc. The increased prefrontal dopamine release induced by the drug combination may also improve cognition as indicated by previous preclinical and clinical studies and, furthermore, via enhanced synaptic spine function and morphology in mPFC generate a both rapid and prolonged antipsychotic and pro-cognitive effect. Our results delineate SNP as a promising new treatment option for schizophrenia, including TRS, when added to currently available antipsychotic medication in order to improve efficacy at maintained or even reduced dosage.

    更新日期:2019-09-16
  • DNA-methylation of the dopamin receptor 2 gene is altered during alcohol withdrawal
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-09-14
    Thomas Hillemacher, Mathias Rhein, Alexandra Burkert, Annemarie Heberlein, Julia Wilhelm, Alexander Glahn, Marc Andre Nicolas Muschler, Kai G. Kahl, Johannes Kornhuber, Stefan Bleich, Helge Frieling

    The dopaminergic neurotransmission is known to be of crucial importance in addictive behavior. Epigenetic regulation like methylation of DNA influences the function of dopaminergic transmission. The present study investigated alterations of DNA methylation in the dopamine D2 receptor (DRD2)-gene in patients suffering from alcohol dependence. The study sample consists of 99 alcohol dependent males admitted for alcohol withdrawal treatment and a control group of 33 healthy participants. Blood samples underwent bisulfite sequencing to determine levels of DNA-methylation of the promoter region of the DRD2 gene. Mixed linear modeling was used to test differences between patients and controls, course of methylation during detoxification. While DRD2-gene methylation did not differ significantly between patients and controls, we found a significant increase of DRD2-gene methylation during alcohol withdrawal/early abstinence. Craving, measured with the Obsessive Compulsive Drinking Scale (OCDS), was significantly associated with DRD2-gene methylation. Furthermore, smoking significantly influenced DRD2-gene methylation in both, patients and controls. As in other types of addictive disorders, DRD2-gene methylation is altered during alcohol withdrawal/early abstinence. The findings regarding an association with alcohol craving and tobacco consumption point towards a crucial role of DRD2-gene methylation in the neurobiology of addictive behavior.

    更新日期:2019-09-16
  • Double immunofluorescent evidence that oxidative stress-associated activation of JNK/AP-1 signaling participates in neuropeptide-mediated appetite control
    Eur. Neuropsychopharm. (IF 4.468) Pub Date : 2019-09-10
    Shu-Chen Chu, Pei-Ni Chen, Ching-Han Yu, Yih-Shou Hsieh, Dong-Yih Kuo

    Amphetamine (AMPH), an appetite suppressant, alters expression levels of neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus. This study explored the potential role of cJun-N-terminal kinases (JNK) in appetite control, mediated by reactive oxygen species (ROS) and activator protein-1 (AP-1) in AMPH-treated rats. Rats were given AMPH daily for 4 days. Changes in feeding behavior and expression levels of hypothalamic NPY, CART, cFos, cJun, phosphorylated JNK (pJNK), as well as those of anti-oxidative enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GP) and glutathione S-transferase (GST), were examined and compared. Following AMPH treatment, food intake and NPY expression decreased, whereas the other proteins expression and AP-1/DNA binding activity increased. Both cerebral cJun inhibition and ROS inhibition attenuated AMPH anorexia and modified detected protein, revealing a crucial role for AP-1 and ROS in regulating AMPH-induced appetite control. Moreover, both pJNK/CART and SOD/CART activities detected by double immunofluorescent staining increased in hypothalamic arcuate nucleus in AMPH-treated rats. The results suggested that pJNK/AP-1 signaling and endogenous anti-oxidants participated in regulating NPY/CART-mediated appetite control in rats treated with AMPH. These findings advance understanding of the molecular mechanism underlying the role of pJNK/AP-1 and oxidative stress in NPY/CART-mediated appetite suppression in AMPH-treated rats.

    更新日期:2019-09-10
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