Publications by authors named "Ralf Regenthal"

39 Publications

A single dose of escitalopram blunts the neural response in the thalamus and caudate during monetary loss.

J Psychiatry Neurosci 2021 Apr 27;46(3):E319-E327. Epub 2021 Apr 27.

From the Emotion Neuroimaging Lab, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (Lewis, Zsido, Sacher); the International Max Planck Research School on Neuroscience of Communication: Function, Structure, and Plasticity, Leipzig, Germany (Lewis, Zsido); the Department of Psychiatry and Psychotherapy, Medical School, University of Tuebingen, Germany (Lewis); the Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (Mueller, Reinelt, Villringer); the Max Planck School of Cognition, Leipzig, Germany (Zsido); the Division of Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany (Regenthal); the Department of Psychology, School of Psychological Sciences, University of Haifa, Haifa, Israel (Okon-Singer); the Integrated Brain and Behavior Research Center (IBBR), University of Haifa, Haifa, Israel (Okon-Singer); the Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA (Forbes); and the Clinic for Cognitive Neurology, University of Leipzig, Leipzig, Germany (Villringer, Sacher).

Background: Selective serotonin reuptake inhibitors (SSRIs) show acute effects on the neural processes associated with negative affective bias in healthy people and people with depression. However, whether and how SSRIs also affect reward and punishment processing on a similarly rapid time scale remains unclear.

Methods: We investigated the effects of an acute and clinically relevant dose (20 mg) of the SSRI escitalopram on brain response during reward and punishment processing in 19 healthy participants. In a doubleblind, placebo-controlled study using functional MRI, participants performed a well-established monetary reward task at 3 time points: at baseline; after receiving placebo or escitalopram; and after receiving placebo or escitalopram following an 8-week washout period.

Results: Acute escitalopram administration reduced blood-oxygen-level-dependent (BOLD) response during punishment feedback in the right thalamus (family-wise error corrected [FWE] p = 0.013 at peak level) and the right caudate head (pFWE = 0.011 at peak level) compared to placebo. We did not detect any significant BOLD changes during reward feedback.

Limitations: We included only healthy participants, so interpretation of findings are limited to the healthy human brain and require future testing in patient populations. The paradigm we used was based on monetary stimuli, and results may not be generalizable to other forms of reward.

Conclusion: Our findings extend theories of rapid SSRI action on the neural processing of rewarding and aversive stimuli and suggest a specific and acute effect of escitalopram in the punishment neurocircuitry.
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http://dx.doi.org/10.1503/jpn.200121DOI Listing
April 2021

Expression of muscarinic acetylcholine receptors in turkey cardiac chambers.

Res Vet Sci 2021 May 16;136:602-608. Epub 2021 Apr 16.

Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, An den Tierkliniken 15, D-04103 Leipzig, Germany. Electronic address:

The aim of the present study was to characterize the specific binding sites for [N-methyl-H]-scopolamine ([H]-NMS), a radioligand for labeling muscarinic acetylcholine receptors (mAChRs), in membranes of four heart chambers obtained from adult male British United Turkey (BUT) Big 6 ("meat-type") and Cröllwitzer ("wild-type") turkeys. MAChR subtypes were examined by inhibiting [H]-NMS binding with subtype selective non-labelled receptor antagonists. In all left and right atria as well as left and right ventricles of both turkey breeds, the specific [H]-NMS binding was saturable, reversible and of high affinity (K range: 0.5-1.0 nM). The maximum receptor density (B) was not significantly different between the four cardiac chambers of BUT Big 6 turkeys, but a significant difference was found between atria and ventricles of Cröllwitzer turkeys. Moreover, significant lower B was found in the atria of Cröllwitzer turkeys than in the atria of BUT Big 6, while the ventricular B was significantly higher. In all cardiac chambers, unlabeled mAChR antagonists competed for specific [H]-NMS binding sites in a concentration-dependent manner, suggesting the presence of the M and M receptor subtypes, whereby the latter was the predominant subtype. The presence of the M subtype could not be excluded. In conclusion, there was a difference between BUT Big 6 ("meat-type") and Cröllwitzer ("wild-type") turkeys with regard to receptor density in heart chambers with dominant M and M receptor subtypes.
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http://dx.doi.org/10.1016/j.rvsc.2021.04.016DOI Listing
May 2021

Validation of an LC-MS/MS Method to Quantify the New TRPC6 Inhibitor SH045 (Larixyl -methylcarbamate) and Its Application in an Exploratory Pharmacokinetic Study in Mice.

Pharmaceuticals (Basel) 2021 Mar 13;14(3). Epub 2021 Mar 13.

Rudolf Boehm Institute for Pharmacology and Toxicology, Leipzig University, 04107 Leipzig, Germany.

TRPC6 (transient receptor potential cation channels; canonical subfamily C, member 6) is widespread localized in mammalian tissues like kidney and lung and associated with progressive proteinuria and pathophysiological pulmonary alterations, e.g., reperfusion edema or lung fibrosis. However, the understanding of TRPC6 channelopathies is still at the beginning stages. Recently, by chemical diversification of (+)-larixol originating from resin traditionally used for inhalation, its methylcarbamate congener, named SH045, was obtained and identified in functional assays as a highly potent, subtype-selective inhibitor of TRPC6. To pave the way for use of SH045 in animal disease models, this study aimed at developing a capable bioanalytical method and to provide exploratory pharmacokinetic data for this promising derivative. According to international guidelines, a robust and selective LC-MS/MS method based on MRM detection in positive ion mode was established and validated for quantification of SH045 in mice plasma, whereby linearity and accuracy were demonstrated for the range of 2-1600 ng/mL. Applying this method, the plasma concentration time course of SH045 following single intraperitoneal administration (20 mg/kg body weight) revealed a short half-life of 1.3 h. However, the pharmacological profile of SH045 is promising, as five hours after administration, plasma levels still remained sufficiently higher than published low nanomolar IC values. Summarizing, the LC-MS/MS method and exploratory pharmacokinetic data provide essential prerequisites for experimental pharmacological TRPC6 modulation and translational treatment of TRPC6 channelopathies.
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http://dx.doi.org/10.3390/ph14030259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000919PMC
March 2021

Locus coeruleus integrity and the effect of atomoxetine on response inhibition in Parkinson's disease.

Brain 2021 Mar 30. Epub 2021 Mar 30.

MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.

Cognitive decline is a common feature of Parkinson's disease, and many of these cognitive deficits fail to respond to dopaminergic therapy. Therefore, targeting other neuromodulatory systems represents an important therapeutic strategy. Among these, the locus coeruleus-noradrenaline system has been extensively implicated in response inhibition deficits. Restoring noradrenaline levels using the noradrenergic reuptake inhibitor atomoxetine can improve response inhibition in some patients with Parkinson's disease, but there is considerable heterogeneity in treatment response. Accurately predicting the patients who would benefit from therapies targeting this neurotransmitter system remains a critical goal, in order to design the necessary clinical trials with stratified patient selection to establish the therapeutic potential of atomoxetine. Here, we test the hypothesis that integrity of the noradrenergic locus coeruleus explains the variation in improvement of response inhibition following atomoxetine. In a double-blind placebo-controlled randomised crossover design, 19 people with Parkinson's disease completed an acute psychopharmacological challenge with 40 mg of oral atomoxetine or placebo. A stop-signal task was used to measure response inhibition, with stop-signal reaction times obtained through hierarchical Bayesian estimation of an ex-Gaussian race model. Twenty-six control subjects completed the same task without undergoing the drug manipulation. In a separate session, patients and controls underwent ultra-high field 7 T imaging of the locus coeruleus using a neuromelanin-sensitive magnetisation transfer sequence. The principal result was that atomoxetine improved stop-signal reaction times in those patients with lower locus coeruleus integrity. This was in the context of a general impairment in response inhibition, as patients on placebo had longer stop-signal reaction times compared to controls. We also found that the caudal portion of the locus coeruleus showed the largest neuromelanin signal decrease in the patients compared to controls. Our results highlight a link between the integrity of the noradrenergic locus coeruleus and response inhibition in Parkinson's disease patients. Furthermore, they demonstrate the importance of baseline noradrenergic state in determining the response to atomoxetine. We suggest that locus coeruleus neuromelanin imaging offers a marker of noradrenergic capacity that could be used to stratify patients in trials of noradrenergic therapy and to ultimately inform personalised treatment approaches.
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http://dx.doi.org/10.1093/brain/awab142DOI Listing
March 2021

Modulation of premotor cortex response to sequence motor learning during escitalopram intake.

J Cereb Blood Flow Metab 2021 Jun 4;41(6):1449-1462. Epub 2020 Nov 4.

Emotion Neuroimaging (EGG) Lab, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.

The contribution of selective serotonin reuptake inhibitors to motor learning by inducing motor cortical plasticity remains controversial given diverse findings from positive preclinical data to negative findings in recent clinical trials. To empirically address this translational disparity, we use functional magnetic resonance imaging in a double-blind, randomized controlled study to assess whether 20 mg escitalopram improves sequence-specific motor performance and modulates cortical motor response in 64 healthy female participants. We found decreased left premotor cortex responses during sequence-specific learning performance comparing single dose and steady escitalopram state. Escitalopram plasma levels negatively correlated with the premotor cortex response. We did not find evidence in support of improved motor performance after a week of escitalopram intake. These findings do not support the conclusion that one week escitalopram intake increases motor performance but could reflect early adaptive plasticity with improved neural processing underlying similar task performance when steady peripheral escitalopram levels are reached.
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http://dx.doi.org/10.1177/0271678X20965161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138331PMC
June 2021

Determination of atomoxetine or escitalopram in human plasma by HPLC: Applications in neuroscience research studies
.

Int J Clin Pharmacol Ther 2020 Aug;58(8):426-438

Background: Atomoxetine and escitalopram are potent and selective drugs approved for noradrenergic or serotonergic modulation of neuronal networks in attention-deficit hyperactivity disorder (ADHD) or depression, respectively. High-performance liquid chromatography (HPLC) methods still play an important role in the therapeutic drug monitoring (TDM) of psychopharmacological drugs, and coupled with tandem mass spectrometry are the gold standard for the quantification of drugs in biological matrices, but not available everywhere. The aim of this work was to develop and validate a HPLC method for neuroscientific studies using atomoxetine or escitalopram as a test drug.

Materials And Methods: A HPLC method from routine TDM determination of atomoxetine or citalopram in plasma was adapted and validated for use in neuroscientific research. Using photo diode array detection with UV absorption at 205 nm, the variation of internal standard within one chromatographic method enables separate drug monitoring for concentration-controlled explorative studies in healthy humans and patients with Parkinson's disease.

Results: The method described here was found to be linear in the range of 0.002 - 1.4 mg/L for atomoxetine and 0.0012 - 0.197 mg/L for escitalopram, with overall mean intra-day and inter-day imprecision and accuracy bias < 10% for both drugs. The method was successfully applied in concentration-controlled neuroimaging studies in populations of healthy humans and patients with Parkinson's disease.

Conclusion: A simple, sensitive, robust HPLC method capable of monitoring escitalopram and atomoxetine is presented and validated, as a useful tool for drug monitoring and the study of pharmacokinetics in neuroscientific study applications.
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http://dx.doi.org/10.5414/CP203705DOI Listing
August 2020

Presence and function of β-adrenergic receptors in primary equine bronchial epithelia cells.

Pulm Pharmacol Ther 2020 04 18;61:101897. Epub 2020 Jan 18.

University of Leipzig, Faculty of Veterinary Medicine, Institute of Pharmacology, Pharmacy and Toxicology, An den Tierkliniken 15, 04103, Leipzig, Germany. Electronic address:

The β-adrenergic receptor (β-AR) plays an important role in regulating a variety of cell and organ functions in different animal species and is an important target in asthma pathogenesis and therapy. The β-AR expression and function in equine bronchial epithelial cells (EBEC) were not known but innervation and significant decrease in receptor level were reported in the equine bronchial tissues from asthmatic horses. I-iodocyanopindolol (ICYP) binding studies were undertaken in primary freshly isolated and cultured EBEC to identify the presence of the β-ARs. The receptor distribution was assessed using subtype-selective β-AR antagonists (ICI 118 551 (β) and CGP 20712A (β). The β-AR function was confirmed by measuring the agonist-induced intracellular cAMP accumulation in freshly isolated and cultured EBEC. In both freshly isolated and cultured EBEC, the specific ICYP binding was saturable and of high affinity. The maximal receptor density (B) was 9763 ± 140 binding sites/cell (mean ± SEM, n = 7) and 10575 ± 194 binding sites/cell (mean ± SEM, n = 5) in freshly isolated and cultured EBEC, respectively. The receptor affinity to the ligand (K) was also not different between the two cell conditions. ICI 118.551 displaced ICYP with 25 000-fold higher affinity than CGP 20712A. Moreover, in both fresh isolated and cultured EBEC, cAMP-accumulation was stimulated with a rank-order of potency of isoproterenol > adrenaline > noradrenaline. These results highlight the β-AR to be a key subtype in both freshly isolated and cultured primary EBEC.
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http://dx.doi.org/10.1016/j.pupt.2020.101897DOI Listing
April 2020

Appropriate antibiotic prescribing among final-year medical students in Europe.

Int J Antimicrob Agents 2019 Sep 7;54(3):375-379. Epub 2019 May 7.

Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands; Research and Expertise Center in Pharmacotherapy Education (RECIPE), Amsterdam, The Netherlands.

Little is known about undergraduate education on antibiotic prescribing in Europe and even less about the antibiotic prescribing skills of nearly-graduated medical students. This study aimed to evaluate the antibiotic prescribing skills of final-year medical students across Europe and the education they received during medical training. In a cross-sectional study, final-year medical students from 17 medical schools in 15 European countries were asked to prescribe for two written case reports of infectious diseases (acute bronchitis and community-acquired pneumonia). The appropriateness of antimicrobial therapy was determined using a scoring form based on local guidelines. Teachers from each medical school were asked to complete a standardised questionnaire about the teaching and assessment of undergraduate education on antibiotic use. In total, 856 final-year medical students (95.6%) completed the assessment and 16 teachers (94.1%) completed the questionnaire. Overall, 52.7% (range 26-83%) of the 1.683 therapies prescribed were considered appropriate. The mean number of contact hours for undergraduate education on antimicrobials was 25.6 (range 2-90). Differences in education styles were found to have a significant impact on students' performance, with a problem-based learning style being associated with more appropriate antimicrobial prescribing than a traditional learning style (46.0% vs. 22.9%; P < 0.01). Although there are differences between medical schools, final-year medical students in Europe lack prescribing skills for two common infectious diseases, possibly because of inadequate undergraduate education on antibiotic use and general prescribing. To improve students' skills, interactive teaching methods such as prescribing for simulated and real patients should be used.
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http://dx.doi.org/10.1016/j.ijantimicag.2019.05.008DOI Listing
September 2019

Pharmacokinetic evaluation of a transdermal anastrozole-in-adhesive formulation.

Drug Des Devel Ther 2018 1;12:3653-3664. Epub 2018 Nov 1.

Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany.

Background And Objective: Anastrozole is a well-established active pharmaceutical ingredient (API) used for the treatment of hormone-sensitive breast cancer (BC) in postmenopausal women. However, treatment with the only available oral formulation is often associated with concentration-dependent serious side effects such as hot flashes, fatigue, muscle and joint pain, nausea, diarrhea, headache, and others. In contrast, a sustained-release system for the local application of anastrozole should minimize these serious adverse drug reactions.

Methods: Anastrozole-in-adhesive transdermal drug delivery systems (TDDS) were developed offering efficient loading, avoidance of inhomogeneity or crystallization of the drug, the desired controlled release kinetics, storage stability, easy handling, mechanical stability, and sufficient stickiness on the skin. In vitro continuous anastrozole release profiles were studied in Franz diffusion cells. In vivo, consecutive drug plasma kinetics from the final anastrozole transdermal system was tested in beagle dogs. For drug analysis, a specific validated liquid chromatography- mass spectrometry method using fragment ion detection was developed and validated.

Results: After efficient drug loading, a linear and sustained 65% drug release from the TDDS over 48 h was obtained. In vivo data showed a favorable anastrozole plasma concentration-time course, avoiding side effect-associated peak concentrations as obtained after oral administration but matching therapeutic plasma levels up to 72 h.

Conclusion: These results provide the basis for establishing the transdermal application of anastrozole with improved pharmacokinetics and drug safety as novel therapeutic approach and promising option to treat human BC by decreasing the high burden of unwanted side effects.
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http://dx.doi.org/10.2147/DDDT.S170764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219411PMC
March 2019

Dissociable effects of acute SSRI (escitalopram) on executive, learning and emotional functions in healthy humans.

Neuropsychopharmacology 2018 12 26;43(13):2645-2651. Epub 2018 Sep 26.

Department of Psychiatry, University of Cambridge, Cambridge, UK.

Serotonin is implicated in multiple executive functions including goal-directed learning, cognitive flexibility, response inhibition and emotional regulation. These functions are impaired in several psychiatric disorders, such as depression and obsessive-compulsive disorder. We tested the cognitive effects of the selective serotonin reuptake inhibitor escitalopram, using an acute and clinically relevant dose (20 mg), in 66 healthy male and female volunteers in a double-blind, placebo-controlled study. Participants performed a cognitive test battery including a probabilistic and reversal learning task, the CANTAB intra-dimensional/extra-dimensional shift test of cognitive flexibility, a response inhibition task with interleaved stop-signal and No-Go trials and tasks measuring emotional processing. We showed that acute escitalopram administration impaired learning and cognitive flexibility, but improved the ability to inhibit responses in stop-signal trials while leaving unaffected acute emotional processing. Our findings suggest a dissociation of effects of acute escitalopram on cognitive functions, possibly mediated by differential modulation of brain serotonin levels in distinct functional neural circuits.
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http://dx.doi.org/10.1038/s41386-018-0229-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224451PMC
December 2018

Search for an animal model to investigate selective pulmonary vasodilation.

Lab Anim 2017 Aug 25;51(4):376-387. Epub 2016 Nov 25.

1 Department of Anaesthesia and Intensive Care Medicine, Medical Faculty, University of Leipzig, Leipzig, Germany.

Pulmonary arterial hypertension is a life-threatening disease with a poor prognosis. Oral treatment with vasodilators is often limited by systemic hypotension. Inhalation of vasodilators offers the opportunity for selective pulmonary vasodilation. Testing selective pulmonary vasodilation by inhaled nitric oxide or alternative substances in animal models requires an increased pulmonary vascular tone. The aim of this study was to identify animal models that are suitable for investigating selective pulmonary vasodilation. To do so, a haemodynamic stable pulmonary hypertension was initiated, with a 30 min duration deemed to be a sufficient time interval before and after a possible intervention. In anaesthetized and mechanically-ventilated Sprague-Dawley rats pulmonary hypertension was induced either by acute hypoxia due to reduction of the inspired oxygen fraction from 0.21 to 0.1 ( n = 6), a fixed infusion rate of the thromboxane analogue U46619 (240 ng/min; n = 6) or a monocrotaline injection (MCT; 60 mg/kg applied 23 days before the investigation; n = 7). The animals were instrumented to measure right ventricular and systemic arterial pressures. Acute hypoxia caused a short, and only transient, increase of pulmonary artery pressure as well as profound systemic hypotension which suggested haemodynamic instability. U46619 infusion induced variable changes in the pulmonary and systemic vascular tone without sufficient stabilization within 30 min. MCT provoked sustained pulmonary hypertension with normal systemic pressure values and inhalation of nitric oxide caused selective pulmonary vasodilation. In conclusion, out of the three examined rat animal models only MCT-induced pulmonary hypertension is a solid and reliable model for investigating selective pulmonary vasodilation.
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http://dx.doi.org/10.1177/0023677216675384DOI Listing
August 2017

Atomoxetine restores the response inhibition network in Parkinson's disease.

Brain 2016 08 24;139(Pt 8):2235-48. Epub 2016 Jun 24.

1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK 2 Medical Research Council Cognition and Brain Sciences Unit, Cambridge, CB2 7EF, UK 4 Behavioural and Clinical Neuroscience Institute, Cambridge, CB2 3EB, UK

Parkinson's disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson's disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson's disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson's disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson's disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction time) following atomoxetine correlated with structural connectivity as measured by the fractional anisotropy in the white matter underlying the inferior frontal gyrus. Using multiple regression models, we examined the factors that influenced the individual differences in the response to atomoxetine: the reduction in stop-signal reaction time correlated with structural connectivity and baseline performance, while disease severity and drug plasma level predicted the change in fronto-striatal effective connectivity following atomoxetine. These results suggest that (i) atomoxetine increases sensitivity of the inferior frontal gyrus to afferent inputs from the pre-supplementary motor cortex; (ii) atomoxetine can enhance downstream modulation of frontal-subcortical connections for response inhibition; and (iii) the behavioural consequences of treatment are dependent on fronto-striatal structural connections. The individual differences in behavioural responses to atomoxetine highlight the need for patient stratification in future clinical trials of noradrenergic therapies for Parkinson's disease.
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http://dx.doi.org/10.1093/brain/aww138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958901PMC
August 2016

The effect of serum BDNF levels on central serotonin transporter availability in obese versus non-obese adults: A [(11)C]DASB positron emission tomography study.

Neuropharmacology 2016 11 22;110(Pt A):530-536. Epub 2016 Apr 22.

Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany; Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany. Electronic address:

Background: Serotonin (5-HT) and its neurotrophic support system, specifically brain-derived neurotrophic factor (BDNF), are thought to modulate energy homeostasis and susceptibility to obesity. Moreover, a polymorphism (5-HTTLPR) in the serotonin reuptake transporter (5-HTT) gene impairs its transcription, thereby altering serotonergic tone and potentially contributing to such susceptibility. This study aims to investigate the effect of BDNF, biallelic 5-HTTLPR, and central in-vivo 5-HTT availability in highly obese versus non-obese subjects using positron emission tomography (PET) and 5-HTT selective [(11)C]DASB.

Methods: Thirty-eight subjects, 24 obese, otherwise mentally and physically healthy, and 14 non-obese healthy controls were included in this study. Parametric images of binding potential were generated from PET data. Central 5-HTT availability, 5-HTTLPR genotype, and serum BDNF concentrations were analyzed, first in a volume of interest, then in a voxel-wise manner.

Results: Overall, our results showed an absence of a linear correlation between BDNF, in-vivo central 5-HTT availability, and body mass index (BMI). 5-HTTLPR genotyping revealed BDNF and hippocampal 5-HTT availability to be negatively correlated (r = -0.57, p = 0.007) in long allelic homozygotes. However, obese subjects exhibited opposing effects of BDNF levels on 5-HTT availability in the nucleus accumbens (NAcc) relative to our non-obese controls.

Conclusions: Our data did not confirm an overall correlation between serum BDNF, in-vivo central 5-HTT availability, 5-HTTLPR, and BMI. However, there is evidence that serotonergic tone linked to BDNF, specifically in the NAcc, is involved in the pathophysiology of obesity, although this needs further exploration over a wide range of reward-related eating behaviors.
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http://dx.doi.org/10.1016/j.neuropharm.2016.04.030DOI Listing
November 2016

Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures.

Hum Brain Mapp 2016 Mar 12;37(3):1026-37. Epub 2016 Jan 12.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.

Recent studies indicate that selective noradrenergic (atomoxetine) and serotonergic (citalopram) reuptake inhibitors may improve response inhibition in selected patients with Parkinson's disease, restoring behavioral performance and brain activity. We reassessed the behavioral efficacy of these drugs in a larger cohort and developed predictive models to identify patient responders. We used a double-blind randomized three-way crossover design to investigate stopping efficiency in 34 patients with idiopathic Parkinson's disease after 40 mg atomoxetine, 30 mg citalopram, or placebo. Diffusion-weighted and functional imaging measured microstructural properties and regional brain activations, respectively. We confirmed that Parkinson's disease impairs response inhibition. Overall, drug effects on response inhibition varied substantially across patients at both behavioral and brain activity levels. We therefore built binary classifiers with leave-one-out cross-validation (LOOCV) to predict patients' responses in terms of improved stopping efficiency. We identified two optimal models: (1) a "clinical" model that predicted the response of an individual patient with 77-79% accuracy for atomoxetine and citalopram, using clinically available information including age, cognitive status, and levodopa equivalent dose, and a simple diffusion-weighted imaging scan; and (2) a "mechanistic" model that explained the behavioral response with 85% accuracy for each drug, using drug-induced changes of brain activations in the striatum and presupplementary motor area from functional imaging. These data support growing evidence for the role of noradrenaline and serotonin in inhibitory control. Although noradrenergic and serotonergic drugs have highly variable effects in patients with Parkinson's disease, the individual patient's response to each drug can be predicted using a pattern of clinical and neuroimaging features.
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http://dx.doi.org/10.1002/hbm.23087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819701PMC
March 2016

Central serotonin transporter availability in highly obese individuals compared with non-obese controls: A [(11)C] DASB positron emission tomography study.

Eur J Nucl Med Mol Imaging 2016 Jun 18;43(6):1096-104. Epub 2015 Nov 18.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany.

Purpose: The role of the central serotonin (5-hydroxytryptamine, 5-HT) system in feeding has been extensively studied in animals with the 5-HT family of transporters (5-HTT) being identified as key molecules in the regulation of satiety and body weight. Aberrant 5-HT transmission has been implicated in the pathogenesis of human obesity by in vivo positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging techniques. However, results obtained thus far from studies of central 5-HTT availability have been inconsistent, which is thought to be brought about mainly by the low number of individuals with a high body mass index (BMI) previously used. The aim of this study was therefore to assess 5-HTT availability in the brains of highly obese otherwise healthy individuals compared with non-obese healthy controls.

Methods: We performed PET using the 5-HTT selective radiotracer [(11)C] DASB on 30 highly obese (BMI range between 35 and 55 kg/m(2)) and 15 age- and sex-matched non-obese volunteers (BMI range between 19 and 27 kg/m(2)) in a cross-sectional study design. The 5-HTT binding potential (BPND) was used as the outcome parameter.

Results: On a group level, there was no significant difference in 5-HTT BPND in various cortical and subcortical regions in individuals with the highest BMI compared with non-obese controls, while statistical models showed minor effects of age, sex, and the degree of depression on 5-HTT BPND.

Conclusion: The overall finding of a lack of significantly altered 5-HTT availability together with its high variance in obese individuals justifies the investigation of individual behavioral responses to external and internal cues which may further define distinct phenotypes and subgroups in human obesity.
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http://dx.doi.org/10.1007/s00259-015-3243-yDOI Listing
June 2016

Improving response inhibition systems in frontotemporal dementia with citalopram.

Brain 2015 Jul 21;138(Pt 7):1961-75. Epub 2015 May 21.

1 Department of Clinical Neurosciences, University of Cambridge, UK 2 Medical Research Council Cognition and Brain Sciences Unit, Cambridge, UK 5 Behavioural and Clinical Neuroscience Institute, Cambridge, UK.

Disinhibition is a cardinal feature of the behavioural variant of frontotemporal dementia, presenting as impulsive and impetuous behaviours that are often difficult to manage. The options for symptomatic treatments are limited, but a potential target for therapy is the restoration of serotonergic function, which is both deficient in behavioural variant frontotemporal dementia and closely associated with inhibitory control. Based on preclinical studies and psychopharmacological interventions in other disorders, we predicted that inhibition would be associated with the right inferior frontal gyrus and dependent on serotonin. Using magnetoencephalography and electroencephalography of a Go-NoGo paradigm, we investigated the neural basis of behavioural disinhibition in behavioural variant frontotemporal dementia and the effect of selective serotonin reuptake inhibition on the neural systems for response inhibition. In a randomized double-blinded placebo-controlled crossover design study, 12 patients received either a single 30 mg dose of citalopram or placebo. Twenty age-matched healthy controls underwent the same magnetoencephalography/electroencephalography protocol on one session without citalopram, providing normative data for this task. In the control group, successful NoGo trials evoked two established indices of successful response inhibition: the NoGo-N2 and NoGo-P3. Both of these components were significantly attenuated by behavioural variant frontotemporal dementia. Cortical sources associated with successful inhibition in control subjects were identified in the right inferior frontal gyrus and anterior temporal lobe, which have been strongly associated with behavioural inhibition in imaging and lesion studies. These sources were impaired by behavioural variant frontotemporal dementia. Critically, citalopram enhanced the NoGo-P3 signal in patients, relative to placebo treatment, and increased the evoked response in the right inferior frontal gyrus. Voxel-based morphometry confirmed significant atrophy of inferior frontal gyrus, alongside insular, orbitofrontal and temporal cortex in our patient cohort. Together, these data suggest that the dysfunctional prefrontal cortical systems underlying response inhibition deficits in behavioural variant frontotemporal dementia can be partially restored by increasing serotonergic neurotransmission. The results support a translational neuroscience approach to impulsive neurological disorders and indicate the potential for symptomatic treatment of behavioural variant frontotemporal dementia including serotonergic strategies to improve disinhibition.media-1vid110.1093/brain/awv133_video_abstractawv133_video_abstract.
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http://dx.doi.org/10.1093/brain/awv133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412666PMC
July 2015

Serotonergic modulation of intrinsic functional connectivity.

Curr Biol 2014 Oct 18;24(19):2314-8. Epub 2014 Sep 18.

Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, 04103 Leipzig, Germany; Clinic of Cognitive Neurology, University Hospital Leipzig, 04103 Leipzig, Germany; Berlin School of Mind and Brain, Mind and Brain Institute, Charité and Humboldt University, 10099 Berlin, Germany. Electronic address:

Serotonin functions as an essential neuromodulator that serves a multitude of roles, most prominently balancing mood. Serotonergic challenge has been observed to reduce intrinsic functional connectivity in brain regions implicated in mood regulation. However, the full scope of serotonergic action on functional connectivity in the human brain has not been explored. Here, we show evidence that a single dose of a serotonin reuptake inhibitor dramatically alters functional connectivity throughout the whole brain in healthy subjects (n = 22). Our network-centrality analysis reveals a widespread decrease in connectivity in most cortical and subcortical areas. In the cerebellum and thalamus, however, we find localized increases. These rapid and brain-encompassing connectivity changes linked to acute serotonin transporter blockade suggest a key role for the serotonin transporter in the modulation of the functional macroscale connectome.
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http://dx.doi.org/10.1016/j.cub.2014.08.024DOI Listing
October 2014

Fulminant thrombotic thrombocytopenic purpura (TTP): association with amphetamine consumption?

Ann Hematol 2015 Feb 4;94(2):337-8. Epub 2014 Jun 4.

Medical ICU, University Hospital Leipzig, Liebigstr. 20, 04103, Leipzig, Germany.

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http://dx.doi.org/10.1007/s00277-014-2125-xDOI Listing
February 2015

Targeting impulsivity in Parkinson's disease using atomoxetine.

Brain 2014 Jul 3;137(Pt 7):1986-97. Epub 2014 Jun 3.

2 Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK9 Department of Psychology, University of Cambridge, Cambridge, UK.

Noradrenergic dysfunction may play a significant role in cognition in Parkinson's disease due to the early degeneration of the locus coeruleus. Converging evidence from patient and animal studies points to the role of noradrenaline in dopaminergically insensitive aspects of the parkinsonian dysexecutive syndrome, yet the direct effects of noradrenergic enhancement have not to date been addressed. Our aim was to directly investigate these, focusing on impulsivity during response inhibition and decision making. To this end, we administered 40 mg atomoxetine, a selective noradrenaline re-uptake inhibitor to 25 patients with Parkinson's disease (12 female /13 male; 64.4 ± 6.9 years old) in a double blind, randomized, placebo controlled design. Patients completed an extensive battery of neuropsychological tests addressing response inhibition, decision-making, attention, planning and verbal short term memory. Atomoxetine improved stopping accuracy on the Stop Signal Task [F(1,19) = 4.51, P = 0.047] and reduced reflection impulsivity [F(1,9) = 7.86, P = 0.02] and risk taking [F(1,9) = 9.2, P = 0.01] in the context of gambling. The drug also conferred effects on performance as a function of its measured blood plasma concentration: it reduced reflection impulsivity during information sampling [adjusted R(2) = 0.23, F(1,16) = 5.83, P = 0.03] and improved problem solving on the One Touch Stockings of Cambridge [adjusted R(2) = 0.29, F(1,17) = 8.34, P = 0.01]. It also enhanced target sensitivity during sustained attention [F(1,9) = 5.33, P = 0.046]. The results of this exploratory study represent the basis of specific predictions in future investigations on the effects of atomoxetine in Parkinson's disease and support the hypothesis that targeting noradrenergic dysfunction may represent a new parallel avenue of therapy in some of the cognitive and behavioural deficits seen in the disorder.
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http://dx.doi.org/10.1093/brain/awu117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065022PMC
July 2014

Improving response inhibition in Parkinson's disease with atomoxetine.

Biol Psychiatry 2015 Apr 7;77(8):740-8. Epub 2014 Feb 7.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; Medical Research Council Cognition and Brain Sciences Unit, Cambridge, United Kingdom; Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom. Electronic address:

Background: Dopaminergic drugs remain the mainstay of Parkinson's disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm.

Methods: This pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging.

Results: Patients with Parkinson's disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity.

Conclusions: This study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinson's disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson's disease.
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http://dx.doi.org/10.1016/j.biopsych.2014.01.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384955PMC
April 2015

Selective serotonin reuptake inhibition modulates response inhibition in Parkinson's disease.

Brain 2014 Apr 27;137(Pt 4):1145-55. Epub 2014 Feb 27.

1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Impulsivity is common in Parkinson's disease even in the absence of impulse control disorders. It is likely to be multifactorial, including a dopaminergic 'overdose' and structural changes in the frontostriatal circuits for motor control. In addition, we proposed that changes in serotonergic projections to the forebrain also contribute to response inhibition in Parkinson's disease, based on preclinical animal and human studies. We therefore examined whether the selective serotonin reuptake inhibitor citalopram improves response inhibition, in terms of both behaviour and the efficiency of underlying neural mechanisms. This multimodal magnetic resonance imaging study used a double-blind randomized placebo-controlled crossover design with an integrated Stop-Signal and NoGo paradigm. Twenty-one patients with idiopathic Parkinson's disease (46-76 years old, 11 male, Hoehn and Yahr stage 1.5-3) received 30 mg citalopram or placebo in addition to their usual dopaminergic medication in two separate sessions. Twenty matched healthy control subjects (54-74 years old, 12 male) were tested without medication. The effects of disease and drug on behavioural performance and regional brain activity were analysed using general linear models. In addition, anatomical connectivity was examined using diffusion tensor imaging and tract-based spatial statistics. We confirmed that Parkinson's disease caused impairment in response inhibition, with longer Stop-Signal Reaction Time and more NoGo errors under placebo compared with controls, without affecting Go reaction times. This was associated with less stop-specific activation in the right inferior frontal cortex, but no significant difference in NoGo-related activation. Although there was no beneficial main effect of citalopram, it reduced Stop-Signal Reaction Time and NoGo errors, and enhanced inferior frontal activation, in patients with relatively more severe disease (higher Unified Parkinson's Disease Rating Scale motor score). The behavioural effect correlated with the citalopram-induced enhancement of prefrontal activation and the strength of preserved structural connectivity between the frontal and striatal regions. In conclusion, the behavioural effect of citalopram on response inhibition depends on individual differences in prefrontal cortical activation and frontostriatal connectivity. The correlation between disease severity and the effect of citalopram on response inhibition may be due to the progressive loss of forebrain serotonergic projections. These results contribute to a broader understanding of the critical roles of serotonin in regulating cognitive and behavioural control, as well as new strategies for patient stratification in clinical trials of serotonergic treatments in Parkinson's disease.
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http://dx.doi.org/10.1093/brain/awu032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959561PMC
April 2014

Altered serotonin transporter availability in patients with multiple sclerosis.

Eur J Nucl Med Mol Imaging 2014 May 22;41(5):827-35. Epub 2014 Feb 22.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany,

Purpose: Modulation of the immune system by the CNS may involve serotonergic regulation via the brain serotonin transporters (SERT). This regulation may be disturbed in patients with CNS disorders including multiple sclerosis (MS). Central serotonergic mechanisms have not been investigated in MS by in vivo imaging. The objective of the study was to assess the availability of SERT in antidepressant-naive patients with MS by means of PET.

Methods: Included in this study were 23 patients with MS and 22 matched healthy volunteers who were investigated with PET and the SERT-selective marker [(11)C]DASB, and distribution volume ratios were determined. Clinical assessment of the patients included the expanded disability status scale, the MS fatigue scale Würzburger Erschöpfungsinventar bei MS (WEIMuS) and the Beck Depression Inventory (BDI). The PET data were analysed with both volume-of-interest and voxel-based analyses to determine regional SERT availability.

Results: Patients had lower SERT availability in the cingulate cortex, the thalamus and the insula, and increased availability in the orbitofrontal cortex. Patients with relapsing/remitting MS tended to have lower SERT in the hippocampus, whereas patients with primary progressive disease showed increased SERT availability in prefrontal regions. There was a positive correlation between SERT availability in the insula and both depression and fatigue scores (r = 0.56 vs. BDI, p = 0.02; r = 0.49 vs. WEIMuS, p = 0.05).

Conclusion: Serotonergic neurotransmission in MS patients is altered in limbic and paralimbic regions as well as in the frontal cortex that this appears to contribute to psychiatric symptoms of MS.
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http://dx.doi.org/10.1007/s00259-013-2636-zDOI Listing
May 2014

A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment.

Brain 2013 Nov;136(Pt 11):3252-70

1 Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

Through the combined use of (18)F-fallypride positron emission tomography and magnetic resonance imaging this study examined the neural mechanisms underlying the attentional deficits associated with attention deficit/hyperactivity disorder and their potential reversal with a single therapeutic dose of methylphenidate. Sixteen adult patients with attention deficit/hyperactivity disorder and 16 matched healthy control subjects were positron emission tomography and magnetic resonance imaging scanned and tested on a computerized sustained attention task after oral methylphenidate (0.5 mg/kg) and placebo administration in a within-subject, double-blind, cross-over design. Although patients with attention deficit/hyperactivity disorder as a group showed significant attentional deficits and reduced grey matter volume in fronto-striato-cerebellar and limbic networks, they had equivalent D2/D3 receptor availability and equivalent increases in endogenous dopamine after methylphenidate treatment to that observed in healthy control subjects. However, poor attentional performers drawn from both the attention deficit/hyperactivity disorder and the control groups had significantly reduced left caudate dopamine activity. Methylphenidate significantly increased dopamine levels in all nigro-striatal regions, thereby normalizing dopamine levels in the left caudate in low performers. Behaviourally, methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis. This finding was accompanied by an equally performance-dependent effect of the drug on dopamine release in the midbrain, whereby low performers showed reduced dopamine release in this region. Collectively, these findings support a dimensional model of attentional deficits and underlying nigro-striatal dopaminergic mechanisms of attention deficit/hyperactivity disorder that extends into the healthy population. Moreover, they confer midbrain dopamine autoreceptors a hitherto neglected role in the therapeutic effects of oral methylphenidate in attention deficit/hyperactivity disorder. The absence of significant case-control differences in D2/D3 receptor availability (despite the observed relationships between dopamine activity and attention) suggests that dopamine dysregulation per se is unlikely to be the primary cause underlying attention deficit/hyperactivity disorder pathology in adults. This conclusion is reinforced by evidence of neuroanatomical changes in the same set of patients with attention deficit/hyperactivity disorder.
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http://dx.doi.org/10.1093/brain/awt263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4125626PMC
November 2013

Metabolic studies of the Amaryllidaceous alkaloids galantamine and lycorine based on electrochemical simulation in addition to in vivo and in vitro models.

Anal Chim Acta 2012 Dec 1;756:60-72. Epub 2012 Nov 1.

University of Münster, Institute of Inorganic and Analytical Chemistry and NRW Graduate School of Chemistry, Münster, Germany.

Alkaloids from the plant family of Amaryllidaceae, such as galantamine (GAL) and lycorine (LYC), are known to exhibit numerous promising biological and pharmacological activities like antibacterial, antiviral or anti-inflammatory effects. Nonetheless, studies on the biotransformation pathway are rare for this substance class, unless approval for use as medication exists. While GAL has become a prescription drug used to alleviate and delay the symptoms of Alzheimer's disease, LYC exhibits potential antitumor properties. However, it has also been linked to toxic effects resulting in nausea and emesis. Whereas there are few publications available describing the metabolic pathway of GAL in animals and humans, the metabolism of LYC is unknown. Therefore, this study is concerned with the investigation of the oxidative metabolism of GAL and LYC, which was achieved by means of three different approaches: electrochemical (EC) simulation coupled on-line to liquid chromatography (LC) with electrospray mass spectrometric (ESI-MS) detection was applied in addition to in vivo experiments in beagle dog analyzing plasma (BP) and in vitro incubations with rat liver microsomes (RLM). This way, it should be investigated if electrochemistry can be used to predict the oxidative metabolism of alkaloids. For GAL, the EC model was capable of predicting most metabolites observed during microsomal and plasma studies, including N-demethylated, dehydrogenated and oxygenated products or a combination of these. LYC was found to be metabolized far less than GAL in the animal-based approaches, but several EC oxidation products were generated. Some principal metabolic routes could successfully be correlated for this alkaloid as well, comprising dehydrogenation, dehydration to ungeremine and oxygenation reactions.
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http://dx.doi.org/10.1016/j.aca.2012.10.042DOI Listing
December 2012

In vivo assessment of antiemetic drugs and mechanism of lycorine-induced nausea and emesis.

Arch Toxicol 2011 Dec 31;85(12):1565-73. Epub 2011 May 31.

Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany.

Lycorine is the main alkaloid of many Amaryllidaceae and known to cause poisoning with still unknown mechanisms. Longer lasting toxicological core symptoms of nausea and emesis may become a burden for human and animal patients and may result in substantial loss of water and electrolytes. To optimise the only empirical symptomatic antiemetic drug treatment at present, it is important to elucidate the causative involved targets of lycorine-induced emesis. Therefore, in the current study, we have tested the actions of a various antiemetic drugs with selective receptor affinities on lycorine-induced nausea and emesis in vivo in dogs. Beagle dogs were pre-treated in a saline vehicle-controlled crossover and random design with diphenhydramine, maropitant, metoclopramide, ondansetron or scopolamine prior lycorine administration (2 mg/kg subcutaneously). In vivo effects were assessed by a scoring system for nausea and emesis as well as by the number and lag time of emetic events for at least 3 h. Moreover, plasma pharmacokinetic analysis was carried out for ondansetron before and after lycorine injection. The data show that histaminergic (H₁), muscarinic and dopaminergic (D₂) receptors are presumably not involved in lycorine-induced emetic effects. While ondansetron significantly reduced the number of emetic events, lycorine-induced emesis was completely blocked by maropitant. Only ondansetron also significantly decreased the level of nausea and was able to prolong the lag time until onset of emesis suggesting a preferential participation of 5-HT₃ receptors in lycorine-induced nausea. Thus, it is the first in vivo report evidencing that predominantly neurokinin-1 (NK₁) and to a lesser extent 5-hydroxytryptamine 3 (5-HT₃) receptors are involved in lycorine-induced emesis facilitating a target-oriented therapy.
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http://dx.doi.org/10.1007/s00204-011-0719-9DOI Listing
December 2011

The serotonin transporter availability in untreated early-onset and late-onset patients with obsessive-compulsive disorder.

Int J Neuropsychopharmacol 2011 Jun 14;14(5):606-17. Epub 2011 Jan 14.

Department of Nuclear Medicine, University of Leipzig, Germany.

The pathogenetic role of central serotonin transporters (SERT) in obsessive-compulsive disorder (OCD) has been investigated in vivo by positron emission tomography (PET) or single-photon emission computed tomography (SPECT) studies with inconsistent results. This might reflect methodological differences but possibly also the pathophysiological heterogeneity of the disorder, i.e. the age at onset of OCD. The aim of our study was to compare SERT availability in patients with OCD to healthy controls (HC) taking into account the onset type, other factors and covariates (e.g. SERT genotype, age, depression level, gender). We studied 19 drug-naive OCD patients (36±13 yr, eight females) with early onset (EO-OCD, n=6) or with late onset (LO-OCD, n=13), and 21 HC (38±8 yr, nine females) with PET and the SERT-selective radiotracer [11C]DASB. Statistical models indicated that a variety of covariates and their interaction influenced SERT availability measured by distribution volume ratios (DVR). These models revealed significant effects of onset type on DVR with lower values in LO-OCD (starting at age 18 yr) compared to EO-OCD and HC in limbic (e.g. the amygdala), paralimbic brain areas (the anterior cingulate cortex), the nucleus accumbens and striatal regions, as well as borderline significance in the thalamus and the hypothalamus. The putamen, nucleus accumbens and hypothalamus were found with significant interaction between two SERT gene polymorphisms (SERT-LPR and VNTR). These findings suggest that late but not early onset of OCD is associated with abnormally low SERT availability. In part, functional polymorphisms of the SERT gene might determine the differences.
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http://dx.doi.org/10.1017/S1461145710001604DOI Listing
June 2011

Dose-dependent emetic effects of the Amaryllidaceous alkaloid lycorine in beagle dogs.

Toxicon 2011 Jan 3;57(1):117-24. Epub 2010 Nov 3.

Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany.

Ingestions of plant material from Amaryllidaceae, especially the bulbs of daffodils, are known to be toxic, representing a persistent cause of poisoning in human and animals. Empiric data from case reports suggested, that the alkaloid lycorine could be the toxic constituent of the multi-component mixture responsible for symptoms like nausea and emesis. Systematic studies of the in vivo effects of the amaryllidaceaeous-type alkaloids are not available. Therefore, in an open, prospective, randomized and controlled trial we studied the dose-effect relationship of lycorine-induced nausea and emesis and the toxicokinetics of lycorine in beagle dogs. Subcutaneously administered lycorine-induced nausea and emesis starting at 0.5 mg/kg body weight reaching statistical significance at 1.0 mg/kg. The maximum emetic dose of lycorine (ED(100)) was 2 mg/kg body weight. There was a correlation between dose and nausea score as well as between dose and number of the induced emetic events. Nausea and emesis were short-lasting and occurred not later than 2.5 h post dose. Lycorine showed linear plasma kinetics with a mean elimination half-life of 0.67 and 0.3 h after single s.c. and i.v. administration, compatible with the clinical course of nausea and emesis. The mean oral bioavailability was calculated to be about 40%. Biochemical and haematological parameters of safety showed no pathological signs. The results provide evidence that lycorine can be considered as a main, if not the crucial constituent responsible for nausea and emesis in human and animals in poisoning due to ingestion of plant material of the Amaryllidaceae.
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http://dx.doi.org/10.1016/j.toxicon.2010.10.012DOI Listing
January 2011

Effects of modafinil and methylphenidate on visual attention capacity: a TVA-based study.

Psychopharmacology (Berl) 2010 Jun 30;210(3):317-29. Epub 2010 Mar 30.

Department of Psychology, Experimental Psychology, Ludwig Maximilian University, Munich, Germany.

Introduction: Theory of visual attention (TVA; Bundesen 1990) whole report tasks allow the independent measurement of visual perceptual processing speed and visual short-term memory (vSTM) storage capacity, unconfounded by motor speed. This study investigates how cognitive enhancing effects of psychostimulants depend on baseline performance and individual plasma levels.

Materials And Methods: Eighteen healthy volunteers (aged 20-35 years) received single oral doses of either 40 mg methylphenidate, 400 mg modafinil or placebo in a counterbalanced, double-blind crossover design. A whole report of visually presented letter arrays was performed 2.5-3.5 h after drug administration, and blood samples for plasma level analysis were taken.

Results: Methylphenidate and modafinil both enhanced perceptual processing speed in participants with low baseline (placebo) performance. These improvements correlated with subjective alertness. Furthermore, we observed differential plasma level-dependent effects of methylphenidate in lower and higher performing participants: higher plasma levels led to a greater improvement in low-performing participants and to decreasing improvement in high-performing participants. Modafinil enhanced visual short-term memory storage capacity in low-performing participants.

Conclusions: This is the first pharmacological investigation demonstrating the usefulness of a TVA task for high-resolution and repeated cognitive parameter estimation after cognitive-enhancing medication. Our results confirm previous findings of attentional capacity improvements in low performers and extend the baseline dependency model to methylphenidate. Plasma level-dependent effects of psychostimulants can be modelled on an inverted U-shaped dose-response relationship, which is highly relevant to predict cognitive enhancing and detrimental effects of psychostimulants in patients with cognitive deficits (e.g., attention deficit hyperactivity disorder) and healthy volunteers (e.g., self-medicating academics).
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http://dx.doi.org/10.1007/s00213-010-1823-xDOI Listing
June 2010

The dopamine D2 receptor antagonist sulpiride modulates striatal BOLD signal during the manipulation of information in working memory.

Psychopharmacology (Berl) 2009 Nov 12;207(1):35-45. Epub 2009 Aug 12.

Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.

Rationale: Dopamine (DA) plays an important role in working memory. However, the precise functions supported by different DA receptor subtypes in different neural regions remain unclear.

Objective: The present study used pharmacological, event-related fMRI to test the hypothesis that striatal dopamine is important for the manipulation of information in working memory.

Methods: Twenty healthy human subjects were scanned twice, once after placebo and once after sulpiride 400 mg, a selective DA D2 receptor antagonist, while performing a verbal working memory task requiring different levels of manipulation.

Results: Whilst there was no overall effect of sulpiride on task-dependent activation, individual variation in sulpiride plasma levels predicted the effect of working memory manipulation on activation in the putamen, suggesting a dose-dependent effect of DA antagonism on a striatally based manipulation process. These effects occurred in the context of a drug-induced improvement in performance on trials requiring the manipulation of information in working memory but not on simple retrieval trials. No significant drug effects were observed in the prefrontal cortex.

Conclusions: These results support models of dopamine function that posit a 'gating' function for dopamine D2 receptors in the striatum, which enables the flexible updating and manipulation of information in working memory.
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http://dx.doi.org/10.1007/s00213-009-1634-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764850PMC
November 2009