[Analysis of efficacy and factors influencing sequential combination therapy with tenofovir alafenamide fumarate after treatment with entecavir in chronic hepatitis B patients with low-level viremia].

Objective: To observe the efficacy and factors influencing sequential or combined tenofovir alafenamide fumarate (TAF) after treatment with entecavir (ETV) in patients with chronic hepatitis B (CHB) with low-level viremia (LLV). Methods: 126 CHB cases treated with ETV antiviral therapy in the Department of Infectious Diseases of the First Affiliated Hospital of Nanchang University from January 2020-September 2022 were retrospectively collected. Patients were divided into a complete virologic response (CVR) group (n = 84) and a low-level viremia (LLV) group (n = 42) according to the HBV DNA level during treatment. Clinical characteristics and laboratory indicators of the two groups at baseline and 48 weeks were analyzed by univariate analysis. Patients in the LLV group were divided into three groups according to their continued antiviral treatment regimen until 96 weeks: continued use of ETV as a control group; replacement of TAF as a sequential group; and combination of ETV and TAF as a combined group. The data of the three groups of patients were analyzed by one-way analysis of variance for 48 weeks. HBV DNA negative conversion rate, HBeAg negative conversion rate, alanine aminotransferase (ALT), creatinine (Cr), and liver stiffness test (LSM) were compared among the three groups after 96 weeks of antiviral treatment. Multivariate logistic regression was used to analyze the independent factors influencing the occurrence of HBV DNA non-negative conversion in LLV patients at 96 weeks. Receiver operating characteristic curve (ROC) was used to evaluate the effectiveness of predicting the occurrence of HBV DNA non-negative conversion in LLV patients at 96 weeks. Kaplan-Meier was used to analyze the cumulative negative rate of DNA in LLV patients, and the Log-Rank test was used for comparison. HBV DNA and HBV DNA negative conversion rates during treatment were observed dynamically. Results: Univariate analysis showed statistically significant differences in age, BMI, HBeAg positivity rate, HBV DNA, HBsAg, ALT, AST, and LSM at baseline between the CVR group and the LLV group (P < 0.05). Univariate analysis of variance revealed no statistically significant difference among the three groups of LLV patients at 48 weeks (P > 0.05). HBV-DNA negative conversion rate in the sequential group and the combination group was significantly higher than that in the control group after 96 weeks of treatment (88.89% vs. 41.18%, 85.71% vs. 41.18%, χ (2) = 10.404, P = 0.006). HBeAg negative conversion rate was higher than that of the control group, with no statistically significant difference (P > 0.05).Compared with the control group, ALT, Cr, and LSM in the sequential group and the combined group were equally improved to varying degrees, with a statistically significant difference (P < 0.05). Subsequent use of ETV and HBV DNA at 48 weeks were independent risk factors for HBV DNA positivity at 96 weeks in LLV patients (P < 0.05). The AUC of HBV DNA at 48 weeks was 0.735 (95%CI: 0.578 ~ 0.891), the cut-off value was 2.63 log(10) IU/ml, and the sensitivity and specificity were 76.90% and 72.40%, respectively. DNA conversion rate was significantly lower in LLV patients receiving 48-week ETV and 48-week HBV DNA≥2.63 log10 IU/mL than in patients receiving sequential or combined TAF and 48-week HBV DNA < 2.63 log(10) IU/mL. HBV DNA negative conversion rates in the sequential group and combined group at 72 weeks, 84 weeks, and 96 weeks were higher than those in the control group during the period from 48 weeks to 96 weeks of continuous treatment, and the differences were statistically significant (P < 0.05). Conclusion: Sequential or combined TAF antiviral therapy could more effectively improve the 96-week CVR rate, as well as hepatic and renal function, and alleviate the degree of hepatic fibrosis in CHB patients with LLV following ETV treatment. Subsequent use of ETV and HBV DNA load at 48 weeks were independent predictors of HBV DNA positivity at 96 weeks in LLV patients.

[Alteration on hepatocyte nuclear factor 1α expressions and significance in the process of occurrence and development of liver inflammation and fibrosis in patients with chronic hepatitis B].

Objective: To investigate the relationship between the expression of hepatocyte nuclear factor-1 α (HNF-1α) and the occurrence and development of liver inflammation and fibrosis in liver tissues of patients with chronic hepatitis B. Methods: Sixty-four patients with chronic hepatitis B who were diagnosed and treated in our hospital from 2011 to 2018 were selected. All patients underwent ultrasound-guided aspiration liver biopsy. The pathological results of liver biopsy were collected for inflammation grading and fibrosis staging. The liver puncture biopsies was collected by paraffin sectioning. The expression of HNF1α in the liver tissue was detected by immunohistochemical staining. Mantel-Haenszel χ(2) test was used for bidirectional ordered grouping data, and Spearman's rank-correlation test was used for rank correlation analysis. Results: There were varying degrees of inflammatory necrosis and fibrosis in the liver tissues of patients with chronic hepatitis B. There was a linear relationship between the expression of HNF1α and the level of inflammation in liver tissues (χ (2)(MH) = 40.70, P < 0.05). The expression of HNF1α in liver tissues of patients with chronic hepatitis B was decreased with the increase of liver inflammation. The expression intensity of HNF1α was negatively correlated with the inflammation grade (r(s) = -0.815, P < 0.05). There was a linear relationship between the expressions of HNF1α and the degree and stage of liver fibrosis (χ (2)(MH) = 31.95, P < 0.05). The expression level of HNF1α in liver tissue was gradually decreased with the aggravation of liver fibrosis. The expression intensity of HNF1α was negatively correlated with fibrosis stage (r(s) = -0.713, P < 0.05). Conclusion: HNF1α is closely related to the occurrence and development of liver tissue inflammation and fibrosis, and is expected to be a sensitive indicator for evaluating the level of liver tissue inflammation and fibrosis in patients with chronic hepatitis B. In addition, its down-regulation may be involved in the process of occurrence and development of liver inflammation and liver fibrosis, and may become a new target for the treatment of chronic hepatitis B.

Pain cognition versus pain intensity in patients with endometriosis: toward personalized treatment.

OBJECTIVE: To explore how pain intensity and pain cognition are related to health-related quality of life (HRQoL) in women with endometriosis. DESIGN: Cross-sectional questionnaire-based survey. SETTING: Multidisciplinary referral center. PATIENT(S): Women with laparoscopically and/or magnetic resonance imaging-proven endometriosis (n = 50) and healthy control women (n = 42). INTERVENTION(S): For HRQoL, two questionnaires: the generic Short Form Health Survey (SF-36) and the Endometriosis Health Profile 30 (EHP-30). For pain cognition, three questionnaires: the Pain Catastrophizing Scale (PCS), the Pain Vigilance and Awareness Questionnaire (PVAQ), and the Pain Anxiety Symptoms Scale (PASS). For pain intensity, the verbal Numeric Rating Scale (NRS). MAIN OUTCOME MEASURE(S): Association between pain intensity and pain cognition with HRQoL in women with endometriosis, and the differences in HRQoL and pain cognition between women with endometriosis and healthy controls. RESULT(S): Health-related quality of life was statistically significantly impaired in women with endometriosis as compared with healthy control women. The variables of pain intensity and pain cognition were independent factors influencing the HRQoL of women with endometriosis. Patients with endometriosis had statistically significantly more negative pain cognition as compared with controls. They reported more pain anxiety and catastrophizing, and they were hypervigilant toward pain. CONCLUSION(S): Pain cognition is independently associated with the HRQoL in endometriosis patients. Clinicians should be aware of this phenomenon and may consider treating pain symptoms in a multidimensional, individualized way in which the psychological aspects are taken into account. In international guidelines on management of women with endometriosis more attention should be paid to the psychological aspects of care.

[Role and clinical significance of Th17/Treg balance in patients with severe exacerbation of hepatitis B].

OBJECTIVE: To investigate the role of Th17/Treg balance in immune mechanism in severe exacerbation of hepatitis B. METHODS: The clinical data of 41 patients with chronic hepatitis B were collected, and according to the conditions during hospitalization, these patients were divided into exacerbation group (19 patients) and improvement group (22 patients). On admission, at weeks 1 and 2 of treatment, and at the end of treatment, flow cytometry was used to measure the frequencies of Th17 and Treg cells in peripheral blood, and enzyme-linked immunosorbent assay was used to determine the serum levels of interleukin-17 (IL-17), interleukin-10 (IL-10), and transforming growth factor-ß (TGF-ß). The dynamic changes in the frequencies of Th17 and Treg cells were compared between the two groups, and the correlation between clinical indices for hepatitis and cytokines was analyzed. The t-test was used for comparison between groups, a one-way analysis of variance was used for comparison within one group across different time points, and Pearson correlation analysis was performed. RESULTS: With disease progression, the exacerbation group showed an increase in the frequency of Th17 cells and a relatively low frequency of Treg cells; compared with the improvement group, the exacerbation group had a higher frequency of Th17 cells and a lower frequency of Treg cells. Th17/Treg ratio gradually increased with exacerbation and decreased with improvement in conditions; in the exacerbation group and the improvement group, Th17/Treg ratio was positively correlated with total bilirubin and negatively correlated with prothrombin activity. In the exacerbation group and the improvement group, Th17 cells were positively correlated with IL-17, and Treg cells were positively correlated with IL-10 and TGF-ß. CONCLUSION: Th17 and Treg cells play important roles in severe exacerbation of hepatitis B, and Th17/Treg ratio may be used as an immunobiological marker for the judgment of severity during severe exacerbation of hepatitis B.

Reduced expression of miR-503 is associated with poor prognosis in cervical cancer.

OBJECTIVE: We wished to evaluate the association between expression of microRNA (miR) -503 and prognosis in patients with cervical cancer. PATIENTS AND METHODS: 96 paired specimens of cervical cancer and adjacent normal cervical epithelial tissues were obtained. qPCR was used to evaluate expression levels of miR-503. We analyzed the associations between miR-503 expression levels and clinicopathological parameters, as well as recurrence-free and overall survival with Kaplan-Meier survival curves and proportional hazards model. RESULTS: miR-503 levels were significantly (p < 0.001) lower in cervical cancer tissue compared with adjacent normal cervical epithelial tissue. We further observed significant associations of expression of this miR and recurrence of cervical cancer, lymph node metastasization, and International Federation of Gynecology and Obstetrics (FIGO) stage. In addition, in multivariate analysis, miR-503 expression level was found to be an independent prognostic factor for both recurrence-free and overall survival. CONCLUSIONS: Reduced expression of miR-503 is an independent prognostic factor in cervical cancer indicating poor prognosis.

Pharmaco-EEG Studies in Animals: An Overview of Contemporary Translational Applications.

The contemporary value of animal pharmaco-electroencephalography (p-EEG)-based applications are strongly interlinked with progress in recording and neuroscience analysis methodology. While p-EEG in humans and animals has been shown to be closely related in terms of underlying neuronal substrates, both translational and back-translational approaches are being used to address extrapolation issues and optimize the translational validity of preclinical animal p-EEG paradigms and data. Present applications build further on animal p-EEG and pharmaco-sleep EEG findings, but also on stimulation protocols, more specifically pharmaco-event-related potentials. Pharmaceutical research into novel treatments for neurological and psychiatric diseases has employed an increasing number of pharmacological as well as transgenic models to assess the potential therapeutic involvement of different neurochemical systems and novel drug targets as well as underlying neuronal connectivity and synaptic function. Consequently, p-EEG studies, now also readily applied in modeled animals, continue to have an important role in drug discovery and development, with progressively more emphasis on its potential as a central readout for target engagement and as a (translational) functional marker of neuronal circuit processes underlying normal and pathological brain functioning. In a similar vein as was done for human p-EEG studies, the contribution of animal p-EEG studies can further benefit by adherence to guidelines for methodological standardization, which are presently under construction by the International Pharmaco-EEG Society (IPEG).

Pharmaco-EEG Studies in Animals: A History-Based Introduction to Contemporary Translational Applications.

Current research on the effects of pharmacological agents on human neurophysiology finds its roots in animal research, which is also reflected in contemporary animal pharmaco-electroencephalography (p-EEG) applications. The contributions, present value and translational appreciation of animal p-EEG-based applications are strongly interlinked with progress in recording and neuroscience analysis methodology. After the pioneering years in the late 19th and early 20th century, animal p-EEG research flourished in the pharmaceutical industry in the early 1980s. However, around the turn of the millennium the emergence of structurally and functionally revealing imaging techniques and the increasing application of molecular biology caused a temporary reduction in the use of EEG as a window into the brain for the prediction of drug efficacy. Today, animal p-EEG is applied again for its biomarker potential - extensive databases of p-EEG and polysomnography studies in rats and mice hold EEG signatures of a broad collection of psychoactive reference and test compounds. A multitude of functional EEG measures has been investigated, ranging from simple spectral power and sleep-wake parameters to advanced neuronal connectivity and plasticity parameters. Compared to clinical p-EEG studies, where the level of vigilance can be well controlled, changes in sleep-waking behaviour are generally a prominent confounding variable in animal p-EEG studies and need to be dealt with. Contributions of rodent pharmaco-sleep EEG research are outlined to illustrate the value and limitations of such preclinical p-EEG data for pharmacodynamic and chronopharmacological drug profiling. Contemporary applications of p-EEG and pharmaco-sleep EEG recordings in animals provide a common and relatively inexpensive window into the functional brain early in the preclinical and clinical development of psychoactive drugs in comparison to other brain imaging techniques. They provide information on the impact of drugs on arousal and sleep architecture, assessing their neuropharmacological characteristics in vivo, including central exposure and information on kinetics. In view of the clear disadvantages as well as advantages of animal p-EEG as compared to clinical p-EEG, general statements about the usefulness of EEG as a biomarker to demonstrate the translatability of p-EEG effects should be made with caution, however, because they depend on the particular EEG or sleep parameter that is being studied. The contribution of animal p-EEG studies to the translational characterisation of centrally active drugs can be furthered by adherence to guidelines for methodological standardisation, which are presently under construction by the International Pharmaco-EEG Society (IPEG).

Guidelines for the recording and evaluation of pharmaco-sleep studies in man: the International Pharmaco-EEG Society (IPEG).

The International Pharmaco-EEG Society (IPEG) presents guidelines summarising the requirements for the recording and computerised evaluation of pharmaco-sleep data in man. Over the past years, technical and data-processing methods have advanced steadily, thus enhancing data quality and expanding the palette of sleep assessment tools that can be used to investigate the activity of drugs on the central nervous system (CNS), determine the time course of effects and pharmacodynamic properties of novel therapeutics, hence enabling the study of the pharmacokinetic/pharmacodynamic relationship, and evaluate the CNS penetration or toxicity of compounds. However, despite the presence of robust guidelines on the scoring of polysomnography -recordings, a review of the literature reveals inconsistent -aspects in the operating procedures from one study to another. While this fact does not invalidate results, the lack of standardisation constitutes a regrettable shortcoming, especially in the context of drug development programmes. The present guidelines are intended to assist investigators, who are using pharmaco-sleep measures in clinical research, in an effort to provide clear and concise recommendations and thereby to standardise methodology and facilitate comparability of data across laboratories.

Guidelines for the recording and evaluation of pharmaco-EEG data in man: the International Pharmaco-EEG Society (IPEG).

The International Pharmaco-EEG Society (IPEG) presents updated guidelines summarising the requirements for the recording and computerised evaluation of pharmaco-EEG data in man. Since the publication of the first pharmaco-EEG guidelines in 1982, technical and data processing methods have advanced steadily, thus enhancing data quality and expanding the palette of tools available to investigate the action of drugs on the central nervous system (CNS), determine the pharmacokinetic and pharmacodynamic properties of novel therapeutics and evaluate the CNS penetration or toxicity of compounds. However, a review of the literature reveals inconsistent operating procedures from one study to another. While this fact does not invalidate results per se, the lack of standardisation constitutes a regrettable shortcoming, especially in the context of drug development programmes. Moreover, this shortcoming hampers reliable comparisons between outcomes of studies from different laboratories and hence also prevents pooling of data which is a requirement for sufficiently powering the validation of novel analytical algorithms and EEG-based biomarkers. The present updated guidelines reflect the consensus of a global panel of EEG experts and are intended to assist investigators using pharmaco-EEG in clinical research, by providing clear and concise recommendations and thereby enabling standardisation of methodology and facilitating comparability of data across laboratories.

Synthesis and SAR studies of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl)acetamide vasopressin V1b receptor antagonists.

Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) (V(3)) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.

Rapid glucocorticoid receptor-mediated inhibition of hypothalamic-pituitary-adrenal ultradian activity in healthy males.

A complex dynamic ultradian rhythm underlies the hypothalamic-pituitary-adrenal (HPA) circadian rhythm. We have investigated in normal human male subjects the importance, site of action, and receptor-mediated processes involved in rapid basal corticosteroid feedback and its interaction with corticotrophin releasing hormone (CRH) drive. Pro-opiomelanocortin (POMC), ACTH, and cortisol were measured every 10 min from healthy males during the awakening period or late afternoon using an automated blood sampling system. Mathematical modeling into discrete pulses of activity revealed that intravenous infusion of the synthetic mixed glucocorticoid/mineralocorticoid agonist prednisolone produced rapid inhibition of ACTH and cortisol pulsatility within 30 min in the morning and afternoon. Any pulse that had commenced at the time of injection was unaffected, and subsequent pulsatility was inhibited. Prednisolone also inhibited ACTH and cortisol secretion in response to exogenous CRH stimulation, inferring rapid feedback inhibition at the anterior pituitary. Circulating POMC peptide concentrations were unaffected, suggesting that the rapid corticosteroid inhibitory effect specifically targeted ACTH secretion from pituitary corticotrophs. Prednisolone fast feedback was only reduced by glucocorticoid receptor antagonist pretreatment and not by mineralocorticoid receptor antagonism, suggesting a glucocorticoid receptor-mediated pathway. The intravenous prednisolone suppression test provides a powerful new tool to investigate HPA abnormalities underlying metabolic and psychiatric disease states.

SATB1 regulates SPARC expression in K562 cell line through binding to a specific sequence in the third intron.

Special AT-rich binding protein 1 (SATB1), a cell type-specific nuclear matrix attachment region (MAR) DNA-binding protein, tethers to a specific DNA sequence and regulates gene expression through chromatin remodeling and HDAC (histone deacetylase complex) recruitment. In this study, a SATB1 eukaryotic expression plasmid was transfected into the human erythroleukemia K562 cell line and individual clones that stably over-expressed the SATB1 protein were isolated. Microarray analysis revealed that hundreds of genes were either up- or down-regulated in the SATB1 over-expressing K562 cell lines. One of these was the extra-cellular matrix glycoprotein, SPARC (human secreted protein acidic and rich in cysteine). siRNA knock-down of SATB1 also reduced SPARC expression, which was consistent with elevated SPARC levels in the SATB1 over-expressing cell line. Bioinformatics software Mat-inspector showed that a 17bp DNA sequence in the third intron of SPARC possessed a high potential for SATB1 binding; a finding confirmed by Chromatin immunoprecipitation (ChIP) with anti-SATB1 antibody. Our results show for the first time that forced-expression of SATB1 in K562 cells triggers SPARC up-regulation by binding to a 17bp DNA sequence in the third intron.

VEGF-targeted RNA interference suppresses angiogenesis and tumor growth of retinoblastoma.

Vascular endothelial growth factor (VEGF) is one of the most important angiogenic growth factors for tumor angiogenesis which has been verified to be involved in neovascularization of retinoblastoma. Here, we sought to explore whether RNA interference (RNAi) targeting VEGF could inhibit retinoblastoma angiogenesis and tumor growth. Stable transfection of the two human retinoblastoma cell lines SO-RB50 and HXO-RB44 with VEGF-targeted small interfering RNA (siRNA) expression plasmid significantly inhibited VEGF expression determined by real-time polymerase chain reaction (PCR), enzyme-linked immunosorbent assay and Western blot, whereas the control transfection showed no effects. The chemically synthesized VEGF siRNA dramatically suppressed tumor angiogenesis (CD34 immunohistochemistry) and tumor growth in the SO-RB50 subcutaneous xenograft model. Significant downregulation of VEGF expression both on messenger RNA and protein levels in VEGF-siRNA-treated SO-RB50 subcutaneous xenograft was confirmed by real-time PCR and Western blot compared to control. Our data demonstrate the suppression function on angiogenesis and tumor growth of retinoblastoma by VEGF-targeted RNAi. This novel therapeutic strategy promises to play a part in the clinical management of retinoblastoma.

Psychomotor and memory effects of haloperidol, olanzapine, and paroxetine in healthy subjects after short-term administration.

RATIONALE: Impaired psychomotor function has been shown to be associated with clinical and functional outcome in schizophrenia. However, few studies have investigated the short-term effects of antipsychotics on the cognitive and psychomotor functions of this patient group. Because many confounding factors tend to influence the test results in patient research, this study investigates the drugs' effects in healthy volunteers. OBJECTIVES: The short-term effects of haloperidol (2.5 mg), olanzapine (10 mg), and paroxetine (20 mg) on psychomotor function in 15 healthy volunteers are compared with placebo and each other. METHODS: In a crossover design, the subjects completed a battery of psychomotor tasks assessing psychomotor speed, sensorimotor accuracy, visuospatial monitoring, and speed of information processing. In addition, peak velocity of saccadic eye movements and subscales of the visual analog scales were analyzed as the objective and subjective measures for sedation, respectively. Finally, the verbal memory test was used to assess the drugs' effects on memory. RESULTS: Apart from affecting the pursuit task where visuospatial monitoring, sensorimotor speed, and sensorimotor accuracy are measured simultaneously, haloperidol has been proven to be not associated with sedative nor with impairing effects on psychomotor function or verbal memory. In contrast, olanzapine had significant sedative effects. Moreover, the subjects displayed a significant impairment on all measures of psychomotor function and verbal memory, which was not attributable to the drug's sedative effects. After administration of paroxetine, no effects were found, with the exception of a single improvement in eye movement velocity. CONCLUSIONS: Short-term administration of olanzapine, and not of haloperidol, impedes several aspects of psychomotor function and verbal memory in healthy volunteers.

Acute effects of the ampakine farampator on memory and information processing in healthy elderly volunteers.

Ampakines act as positive allosteric modulators of AMPA-type glutamate receptors and facilitate hippocampal long-term potentiation (LTP), a mechanism associated with memory storage and consolidation. The present study investigated the acute effects of farampator, 1-(benzofurazan-5-ylcarbonyl) piperidine, on memory and information processes in healthy elderly volunteers. A double-blind, placebo-controlled, randomized, cross-over study was performed in 16 healthy, elderly volunteers (eight male, eight female; mean age 66.1, SD 4.5 years). All subjects received farampator (500 mg) and placebo. Testing took place 1 h after drug intake, which was around Tmax for farampator. Subjects performed tasks assessing episodic memory (wordlist learning and picture memory), working and short-term memory (N-back, symbol recall) and motor learning (maze task, pursuit rotor). Information processing was assessed with a tangled lines task, the symbol digit substitution test (SDST) and the continuous trail making test (CTMT). Farampator (500 mg) unequivocally improved short-term memory but appeared to impair episodic memory. Furthermore, it tended to decrease the number of switching errors in the CTMT. Drug-induced side effects (SEs) included headache, somnolence and nausea. Subjects with SEs had significantly higher plasma levels of farampator than subjects without SEs. Additional analyses revealed that in the farampator condition the group without SEs showed a significantly superior memory performance relative to the group with SEs. The positive results on short-term memory and the favorable trends in the trail making test (CTMT) are interesting in view of the development of ampakines in the treatment of Alzheimer's disease and schizophrenia.

Effects of antipsychotic and antidepressant drugs on action monitoring in healthy volunteers.

Humans need to monitor their actions continuously to detect errors as fast as possible and to adjust their performance to prevent future errors. This process of action monitoring can be investigated by measuring the error-related negativity (ERN), an ERP component elicited immediately after an error. In the current study, we investigated action monitoring after administration of the classic antipsychotic haloperidol (2.5 mg), the atypical antipsychotic olanzapine (10 mg), and the antidepressant paroxetine (20 mg), a selective serotonin reuptake inhibitor. Healthy volunteers (N = 14) were administered the three compounds and placebo in a randomized, double-blind, single-dose, four-way cross-over design. All participants performed a speeded two-choice reaction task, while event-related potentials and behavioral measurements were obtained. Both haloperidol and olanzapine significantly reduced ERN amplitudes. After paroxetine, the ERN was not different from placebo. N2 congruency effects were not affected by treatment condition. Only olanzapine demonstrated behavioral effects, namely a slowing of responses, an increase in error rates, and the absence of performance adjustments. The attenuated ERNs after the dopamine antagonist haloperidol are in line with the presumed role of dopamine in action monitoring. Haloperidol is thought to block dopaminergic signaling, thus reducing ERN amplitudes. On the other hand, the effects of olanzapine are mainly caused by its sedative side effects, leading to a decline in motivation and appraisal of errors. Finally, the absence of any effects after paroxetine suggests that serotonin transmission does not play a direct role in regulating mechanisms related to action monitoring.

Drug-induced stimulation and suppression of action monitoring in healthy volunteers.

RATIONALE: Action monitoring has been studied extensively by means of measuring the error-related negativity (ERN). The ERN is an event-related potential (ERP) elicited immediately after an erroneous response and is thought to originate in the anterior cingulate cortex (ACC). Although the ACC has a central role in the brain, only a few studies have been performed to investigate directly the effects of drugs on action monitoring. A recent theory argues that the mesencephalic dopamine system carries an error signal to the ACC, where it generates the ERN. METHODS: ERPs and behavioral measurements were obtained from 12 healthy volunteers performing an Eriksen Flankers task. On each of the 4 test days, the stimulant D-amphetamine, the sedative lorazepam, the antidepressant mirtazapine, or a placebo was orally administered in a double-blind, four-way crossover design. RESULTS: The indirect dopamine agonist amphetamine led to a strong enlargement of ERN amplitudes without affecting reaction times. Lorazepam and mirtazapine both showed slowing of responses, but only lorazepam led to reduced ERN amplitudes. CONCLUSIONS: Administration of amphetamine leads to stimulated action monitoring, reflected in increased ERN amplitudes. This result provides evidence for dopaminergic involvement in action monitoring and is in line with differences in ERN amplitude found in neuropsychiatric disorders also suggesting dopaminergic involvement. The different effects for lorazepam and mirtazapine are probably caused by the neurobiological characteristics of these two types of sedation. Action monitoring is suppressed after administration of lorazepam, because the GABAergic pathways directly inhibit ACC functioning, whereas the histaminergic pathways of mirtazapine do not innervate the ACC directly.