Publications by authors named "Thomas Steckler"

91 Publications

Pharmacology of Anxiety or Pharmacology of Elevated Plus Maze?

Biol Psychiatry 2021 Feb 18. Epub 2021 Feb 18.

Janssen Pharmaceutica N.V., Beerse, Belgium.

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http://dx.doi.org/10.1016/j.biopsych.2020.11.026DOI Listing
February 2021

The ARRIVE guidelines 2.0: updated guidelines for reporting animal research.

J Physiol 2020 09 14;598(18):3793-3801. Epub 2020 Jul 14.

Professor for Animal Welfare, Veterinary Public Health Institute, Vetsuisse Faculty, University of Bern, Bern, Switzerland.

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the 'ARRIVE Essential 10,' which constitutes the minimum requirement, and the 'Recommended Set,' which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
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http://dx.doi.org/10.1113/JP280389DOI Listing
September 2020

The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research.

Exp Physiol 2020 09 14;105(9):1459-1466. Epub 2020 Jul 14.

Professor for Animal Welfare, Veterinary Public Health Institute, Vetsuisse Faculty, University of Bern, Bern, Switzerland.

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the "ARRIVE Essential 10," which constitutes the minimum requirement, and the "Recommended Set," which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
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http://dx.doi.org/10.1113/EP088870DOI Listing
September 2020

Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0.

PLoS Biol 2020 07 14;18(7):e3000411. Epub 2020 Jul 14.

Veterinary Public Health Institute, Vetsuisse Faculty, University of Bern, Bern, Switzerland.

Improving the reproducibility of biomedical research is a major challenge. Transparent and accurate reporting is vital to this process; it allows readers to assess the reliability of the findings and repeat or build upon the work of other researchers. The ARRIVE guidelines (Animal Research: Reporting In Vivo Experiments) were developed in 2010 to help authors and journals identify the minimum information necessary to report in publications describing in vivo experiments. Despite widespread endorsement by the scientific community, the impact of ARRIVE on the transparency of reporting in animal research publications has been limited. We have revised the ARRIVE guidelines to update them and facilitate their use in practice. The revised guidelines are published alongside this paper. This explanation and elaboration document was developed as part of the revision. It provides further information about each of the 21 items in ARRIVE 2.0, including the rationale and supporting evidence for their inclusion in the guidelines, elaboration of details to report, and examples of good reporting from the published literature. This document also covers advice and best practice in the design and conduct of animal studies to support researchers in improving standards from the start of the experimental design process through to publication.
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http://dx.doi.org/10.1371/journal.pbio.3000411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360025PMC
July 2020

The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research.

PLoS Biol 2020 07 14;18(7):e3000410. Epub 2020 Jul 14.

Veterinary Public Health Institute, Vetsuisse Faculty, University of Bern, Bern, Switzerland.

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the "ARRIVE Essential 10," which constitutes the minimum requirement, and the "Recommended Set," which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration (E&E) document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
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http://dx.doi.org/10.1371/journal.pbio.3000410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360023PMC
July 2020

The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research.

J Cereb Blood Flow Metab 2020 09 14;40(9):1769-1777. Epub 2020 Jul 14.

Professor for Animal Welfare, Veterinary Public Health Institute, Vetsuisse Faculty, University of Bern, Bern, Switzerland.

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the "ARRIVE Essential 10," which constitutes the minimum requirement, and the "Recommended Set," which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
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http://dx.doi.org/10.1177/0271678X20943823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430098PMC
September 2020

The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research.

Br J Pharmacol 2020 08 14;177(16):3617-3624. Epub 2020 Jul 14.

Veterinary Public Health Institute, Vetsuisse Faculty, University of Bern, Bern, Switzerland.

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the "ARRIVE Essential 10," which constitutes the minimum requirement, and the "Recommended Set," which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration (E&E) document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
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http://dx.doi.org/10.1111/bph.15193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393194PMC
August 2020

The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research.

BMC Vet Res 2020 Jul 14;16(1):242. Epub 2020 Jul 14.

Veterinary Public Health Institute, Vetsuisse Faculty, University of Bern, Bern, Switzerland.

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the "ARRIVE Essential 10," which constitutes the minimum requirement, and the "Recommended Set," which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
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http://dx.doi.org/10.1186/s12917-020-02451-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359286PMC
July 2020

Be positive about negatives-recommendations for the publication of negative (or null) results.

Eur Neuropsychopharmacol 2019 12 18;29(12):1312-1320. Epub 2019 Nov 18.

Opiant Pharmaceuticals, Inc., Santa Monica, CA, USA.

Both positive and negative (null or neutral) results are essential for the progress of science and its self-correcting nature. However, there is general reluctance to publish negative results, and this may be due a range of factors (e.g., the widely held perception that negative results are more difficult to publish, the preference to publish positive findings that are more likely to generate citations and funding for additional research). It is particularly challenging to disclose negative results that are not consistent with previously published positive data, especially if the initial publication appeared in a high impact journal. Ideally, there should be both incentives and support to reduce the costs associated with investing efforts into preparing publications with negative results. We describe here a set of criteria that can help scientists, reviewers and editors to publish technically sound, scientifically high-impact negative (or null) results originating from rigorously designed and executed studies. Proposed criteria emphasize the importance of collaborative efforts and communication among scientists (also including the authors of original publications with positive results).
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http://dx.doi.org/10.1016/j.euroneuro.2019.10.007DOI Listing
December 2019

Good Research Practice: Lessons from Animal Care and Use.

Handb Exp Pharmacol 2020 ;257:367-382

Janssen Pharmaceutica NV, Beerse, Belgium.

Animal care and use play a pivotal role in the research process. Ethical concerns on the use of animals in research have promoted the creation of a legal framework in many geographical areas that researchers must comply with, and professional organizations continuously develop recommendations on specific areas of laboratory animal science. Scientific evidence demonstrates that many aspects of animal care and use which are beyond the legal requirements have direct impact on research results. Therefore, the review and oversight of animal care and use programs are essential to identify, define, control, and improve all of these aspects to promote the reproducibility, validity, and translatability of animal-based research outcomes. In this chapter, we summarize the ethical principles driving legislation and recommendations on animal care and use, as well as some of these laws and international recommendations. Examples of the impact of specific animal care and use aspects on research, as well as systems of internal and external oversight of animal care and use programs, are described.
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http://dx.doi.org/10.1007/164_2019_292DOI Listing
March 2020

Lacking quality in research: Is behavioral neuroscience affected more than other areas of biomedical science?

J Neurosci Methods 2018 04 28;300:4-9. Epub 2017 Oct 28.

Janssen Research & Development, Beerse, Belgium.

There are many reasons why novel therapeutics fail in clinical trials but these failures are often attributed to lacking quality of preclinical data. These problems are not limited to any specific therapeutic area, academic or industrial research and are due in large part to several generic factors influencing research quality (e.g., related to definition of pre-specified endpoints, principles of study design and analysis, biased reporting, and lack of proper training). Yet, neuroscience drug discovery is often said to be affected more than the other fields. Within neuroscience, behavioral studies are the most blamed for being poorly designed, underpowered and mis-reported and there are indeed several factors that may be rather unique for behavioral research, such as a multitude of environmental conditions that are difficult to control and that are often not reported, ethical concerns about in vivo research and the pressure to reduce animal numbers, contributing to under-powered studies, and the complexity of study design and analysis, creating too much room for post hoc data massaging and selective reporting. Also, the blood-brain barrier as a frequently neglected complicating factor has to be considered in CNS research. The importance of these factors is increasingly recognized and urgent efforts are needed to demonstrate that behavioral methods of preclinical neuroscience research deliver results that can be as robust as with the non-behavioral methods Until this goal is achieved, behavioral neuroscience and neuroscience in general may be losing young talent, CNS drug discovery may lack the needed investment and this field may indeed be amongst the most affected by the current preclinical data quality crisis.
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http://dx.doi.org/10.1016/j.jneumeth.2017.10.018DOI Listing
April 2018

Evaluating aged mice in three touchscreen tests that differ in visual demands: Impaired cognitive function and impaired visual abilities.

Behav Brain Res 2017 08 6;333:142-149. Epub 2017 Jul 6.

Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium.

Normal aging is often accompanied by reductions in cognitive abilities as well as impairments in visual acuity in men and mice. In preclinical models of human cognition this concomitance can make it difficult to assess the relative contributions of declined vision and cognitive ability on behavioral measures of cognition. To assess the influence of age on cognition and the impact of visual decline on the performance of touchscreen-based behavioral paradigms in mice, aged (11, 12, 16, 17, 19 and 21 months old) male C57BL/6J mice were compared to young (3 or 4 months old) male C57BL/6J mice using three tests of cognition as well as an assessment of visual acuity. Performance of a Visual Discrimination, Spatial Reversal, and an Automated Search Task were all affected by age. However, there was no relationship between reduced visual acuity and the observed performance impairments. Moreover, the visual acuity of animals with profound cognitive impairments overlapped with those showing normal cognitive ability. Despite the potential confound of impaired visual ability, it appears that the touchscreen approach might be particularly effective in studying age-related cognitive decline. This approach will increase the utility of aged mice as a model of decreased cognitive flexibility and may be particularly important for the study of age-related disorders such as Alzheimer's disease.
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http://dx.doi.org/10.1016/j.bbr.2017.06.053DOI Listing
August 2017

Metabolomic biosignature differentiates melancholic depressive patients from healthy controls.

BMC Genomics 2016 08 23;17:669. Epub 2016 Aug 23.

Department of Computer Science and Engineering, Center for Evolutionary Medicine and Informatics, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA.

Background: Major depressive disorder (MDD) is a heterogeneous disease at the level of clinical symptoms, and this heterogeneity is likely reflected at the level of biology. Two clinical subtypes within MDD that have garnered interest are "melancholic depression" and "anxious depression". Metabolomics enables us to characterize hundreds of small molecules that comprise the metabolome, and recent work suggests the blood metabolome may be able to inform treatment decisions for MDD, however work is at an early stage. Here we examine a metabolomics data set to (1) test whether clinically homogenous MDD subtypes are also more biologically homogeneous, and hence more predictiable, (2) devise a robust machine learning framework that preserves biological meaning, and (3) describe the metabolomic biosignature for melancholic depression.

Results: With the proposed computational system we achieves around 80 % classification accuracy, sensitivity and specificity for melancholic depression, but only ~72 % for anxious depression or MDD, suggesting the blood metabolome contains more information about melancholic depression.. We develop an ensemble feature selection framework (EFSF) in which features are first clustered, and learning then takes place on the cluster centroids, retaining information about correlated features during the feature selection process rather than discarding them as most machine learning methods will do. Analysis of the most discriminative feature clusters revealed differences in metabolic classes such as amino acids and lipids as well as pathways studied extensively in MDD such as the activation of cortisol in chronic stress.

Conclusions: We find the greater clinical homogeneity does indeed lead to better prediction based on biological measurements in the case of melancholic depression. Melancholic depression is shown to be associated with changes in amino acids, catecholamines, lipids, stress hormones, and immune-related metabolites. The proposed computational framework can be adapted to analyze data from many other biomedical applications where the data has similar characteristics.
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http://dx.doi.org/10.1186/s12864-016-2953-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994306PMC
August 2016

Do wholes become more than the sum of their parts in the rodent (Rattus Norvegicus) visual system? A test case with the configural superiority effect.

Eur J Neurosci 2016 10 22;44(8):2593-2599. Epub 2016 Aug 22.

Department of Neuroscience, Janssen Research and Development, Turnhoutseweg 30, Beerse, 2340, Belgium.

The rodent has been used to model various aspects of the human visual system, but it is unclear to what extent human visual perception can be modelled in the rodent. Research suggests rodents can perform invariant object recognition tasks in a manner comparable to humans. There is further evidence that rodents also make use of certain grouping cues, but when performing a shape discrimination they have a tendency to rely much more on local image cues than human participants. In the current work, we exploit the fact that humans sometimes discriminate better between whole shapes, rather than the parts from which they are constructed, to ask whether rodents show a classic Configural Superiority Effect. Using touchscreen-equipped operant boxes, rats were trained to discriminate 'part' or 'whole' images based off of those used by J. R. Pomerantz et al. () J Exp Psychol Hum Percept Perform, 3, 422-435. Here, we show that rats show no advantage for wholes and that they perform better when presented with simpler image parts, a pattern of effect opposite to what was seen in humans when highly comparable stimuli were used. These results add to our understanding of the similarities and differences between the human and rodent visual system, and suggest that the rodent visual system may not compute part whole relationships in a way comparable to humans. These results are significant from both a comparative anatomy perspective, and of particular relevance for those wishing to use rodents to model visuo-perceptual deficits associated with human psychiatric disorders.
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http://dx.doi.org/10.1111/ejn.13350DOI Listing
October 2016

Discovery and Characterization of AMPA Receptor Modulators Selective for TARP-γ8.

J Pharmacol Exp Ther 2016 May 17;357(2):394-414. Epub 2016 Mar 17.

Janssen Research and Development, LLC, Neuroscience Therapeutic Area, San Diego, California (M.P.M., N.W., S.R., M.K.A., B.M.S., C.L., B.L., R.M.W., J.A.M., C.D., S.Y., A.D.W., N.I.C., T.W.L.); and Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Neuroscience Therapeutic Area, Beerse, Belgium (L.V.D., T.S.).

Members of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA) subtype of ionotropic glutamate receptors mediate the majority of fast synaptic transmission within the mammalian brain and spinal cord, representing attractive targets for therapeutic intervention. Here, we describe novel AMPA receptor modulators that require the presence of the accessory protein CACNG8, also known as transmembrane AMPA receptor regulatory protein γ8 (TARP-γ8). Using calcium flux, radioligand binding, and electrophysiological assays of wild-type and mutant forms of TARP-γ8, we demonstrate that these compounds possess a novel mechanism of action consistent with a partial disruption of the interaction between the TARP and the pore-forming subunit of the channel. One of the molecules, 5-[2-chloro-6-(trifluoromethoxy)phenyl]-1,3-dihydrobenzimidazol-2-one (JNJ-55511118), had excellent pharmacokinetic properties and achieved high receptor occupancy following oral administration. This molecule showed strong, dose-dependent inhibition of neurotransmission within the hippocampus, and a strong anticonvulsant effect. At high levels of receptor occupancy in rodent in vivo models, JNJ-55511118 showed a strong reduction in certain bands on electroencephalogram, transient hyperlocomotion, no motor impairment on rotarod, and a mild impairment in learning and memory. JNJ-55511118 is a novel tool for reversible AMPA receptor inhibition, particularly within the hippocampus, with potential therapeutic utility as an anticonvulsant or neuroprotectant. The existence of a molecule with this mechanism of action demonstrates the possibility of pharmacological targeting of accessory proteins, increasing the potential number of druggable targets.
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http://dx.doi.org/10.1124/jpet.115.231712DOI Listing
May 2016

Editorial: Reporting guidelines for psychopharmacology.

Psychopharmacology (Berl) 2016 Apr;233(7):1131-4

Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.

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http://dx.doi.org/10.1007/s00213-016-4252-7DOI Listing
April 2016

Preliminary investigation of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives as a novel series of mGlu5 receptor positive allosteric modulators with efficacy in preclinical models of schizophrenia.

Bioorg Med Chem Lett 2016 Jan 28;26(2):429-434. Epub 2015 Nov 28.

Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain. Electronic address:

As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212, this letter details the investigation and challenges of a novel series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives. From these efforts, compound 4k emerged as a potent and selective mGlu5 PAM displaying overall attractive in vitro (pharmacological and ADMET) and PK profiles combined with in vivo efficacy in preclinical models of schizophrenia. However, further advancement of the compound was precluded due to severely limiting CNS-related side-effects confirming the previously reported association between excessive mGlu5 activation and target-related toxicities.
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http://dx.doi.org/10.1016/j.bmcl.2015.11.098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835042PMC
January 2016

Acyl dihydropyrazolo[1,5-a]pyrimidinones as metabotropic glutamate receptor 5 positive allosteric modulators.

Bioorg Med Chem Lett 2015 Nov 9;25(22):5115-20. Epub 2015 Oct 9.

Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address:

We report the optimization of a series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) from an acyl dihydropyrazolo[1,5-a]pyrimidinone class. Investigation of exocyclic amide transpositions with this unique 5,6-bicyclic core were conducted in attempt to modulate physicochemical properties and identify a suitable backup candidate with a reduced half-life. A potent and selective PAM, 1-(2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)ethanone (9a, VU0462807), was identified with superior solubility and efficacy in the acute amphetamine-induced hyperlocomotion (AHL) rat model with a minimum effective dose of 3mg/kg. Attempts to mitigate oxidative metabolism of the western phenoxy of 9a through extensive modification and profiling are described.
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http://dx.doi.org/10.1016/j.bmcl.2015.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634704PMC
November 2015

TrkB in the hippocampus and nucleus accumbens differentially modulates depression-like behavior in mice.

Behav Brain Res 2016 Jan 24;296:15-25. Epub 2015 Aug 24.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands; European Graduate School of Neuroscience (EURON), Maastricht University, Maastricht, The Netherlands. Electronic address:

Brain-derived neurotrophic factor (BDNF) exerts antidepressant-like effects in the hippocampus and pro-depressant effects in the nucleus accumbens (NAc). It is thought that downstream signaling of the BDNF receptor TrkB mediates the effects of BDNF in these brain structures. Here, we evaluate how TrkB regulates affective behavior in the hippocampus and NAc. We overexpressed TrkB by electroporating a non-viral plasmid in the NAc or hippocampus in mice. Depression- and anxiety-like behaviors were evaluated in the sucrose test (anhedonia), the forced swim test (despair) and the elevated zero maze (anxiety). Targeted brain tissue was biochemically analyzed to identify molecular mechanisms responsible for the observed behavior. Overexpressing TrkB in the NAc increased the number of young neuronal cells and decreased despair and basal corticosterone levels. TrkB overexpression in the hippocampus increased astrocyte production and activation of the transcription factor CREB, yet without altering affective behavior. Our data suggest antidepressant effects of BDNF-TrkB in the NAc, which could not be explained by activation of the transcription factors CREB or β-catenin. The effects TrkB has on depression-related behavior in different brain regions appear to critically depend on the targeted cell type.
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http://dx.doi.org/10.1016/j.bbr.2015.08.027DOI Listing
January 2016

Dissociable effects of NR2A and NR2B NMDA receptor antagonism on cognitive flexibility but not pattern separation.

Psychopharmacology (Berl) 2015 Nov 18;232(21-22):3991-4003. Epub 2015 Jul 18.

Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium.

Rationale: N-methyl-D-aspartate (NMDA) receptors play crucial roles in learning and memory, but the role of each NMDA receptor subtype in a specific cognitive process is unclear. Non-selective blockers of NMDA receptor are used to model the cognitive impairment in schizophrenia and Alzheimer's disease. Counter-intuitively selective NR2A and 2B NMDA receptor antagonists are thought to have pro-cognitive properties. These seemingly contrasting findings might in part be the result of different compounds and behavioral measures used across studies.

Objective: We compared the effect of NVP-AAM077 (NR2A antagonist), CP 101-606 (NR2B antagonist), and MK-801 (non-selective antagonist) in a series of touch screen tasks that can be used to measure spatial cognition and cognitive flexibility.

Methods: NVP-AAM077, CP 101-606, and MK-801 were administered prior to testing, in adult male Lister-hooded rats trained in tasks of location discrimination, paired associate learning (PAL), and trial unique non-match to location (TUNL).

Results: Results showed that MK-801 impaired performance on all the tasks. In contrast, CP 101-606 only impaired reversal learning in location discrimination and had minimal effect on working memory in TUNL and caused a modest improvement in accuracy in PAL and acquisition of a spatial discrimination. NVP-AAM077 had little effect on performance across tasks, although these data allude to a potential enhancement of acquisition of a spatial location and impairments in spatial reversal learning in a separation-dependent manner.

Conclusions: These data demonstrated that non-selective NMDA antagonism will disrupt numerous aspects of cognitive function. However, selective antagonism is capable of impairing or enhancing cognitive function in a task-dependent fashion.
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http://dx.doi.org/10.1007/s00213-015-4008-9DOI Listing
November 2015

Further optimization of the mGlu5 PAM clinical candidate VU0409551/JNJ-46778212: Progress and challenges towards a back-up compound.

Bioorg Med Chem Lett 2015 Sep 4;25(17):3515-9. Epub 2015 Jul 4.

Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address:

This Letter describes the progress and challenges in the continued optimization of the mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212. While many analogs addressed key areas for improvement, no one compound possessed the amalgamation of improvements needed within the (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanone scaffold to advance as a back-up clinical candidate. However, many analogs displayed excellent solubility and physiochemical properties, and were active in the amphetamine-induced hyperlocomotion (AHL) model. Moreover, the SAR was robust for this series of PAMs, and both polar and hydrogen-bond donors were found to be tolerated, leading to analogs with overall attractive profiles and good ligand efficiencies.
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http://dx.doi.org/10.1016/j.bmcl.2015.06.096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535329PMC
September 2015

Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia.

ACS Med Chem Lett 2015 Jun 20;6(6):716-20. Epub 2015 May 20.

Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States ; Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.

Herein, we report the structure-activity relationship of a novel series of (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones as potent, selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). On the basis of its robust in vitro potency and in vivo efficacy in multiple preclinical models of multiple domains of schizophrenia, coupled with a good DMPK profile and an acceptable therapeutic window, 17a (VU0409551/JNJ-46778212) was selected as a candidate for further development.
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http://dx.doi.org/10.1021/acsmedchemlett.5b00181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492464PMC
June 2015

The preclinical data forum network: A new ECNP initiative to improve data quality and robustness for (preclinical) neuroscience.

Eur Neuropsychopharmacol 2015 Oct 4;25(10):1803-7. Epub 2015 Jun 4.

Department of Pharmacology, Neuroscience Research, AbbVie, Ludwigshafen, Germany; Institute of Pharmacology, Pavlov Medical University, St. Petersburg, Russia.

Current limitations impeding on data reproducibility are often poor statistical design, underpowered studies, lack of robust data, lack of methodological detail, biased reporting and lack of open data sharing, coupled with wrong research incentives. To improve data reproducibility, robustness and quality for brain disease research, a Preclinical Data Forum Network was formed under the umbrella of the European College of Neuropsychopharmacology (ECNP). The goal of this network, members of which met for the first time in October 2014, is to establish a forum to collaborate in precompetitive space, to exchange and develop best practices, and to bring together the members from academia, pharmaceutical industry, publishers, journal editors, funding organizations, public/private partnerships and non-profit advocacy organizations. To address the most pertinent issues identified by the Network, it was decided to establish a data sharing platform that allows open exchange of information in the area of preclinical neuroscience and to develop an educational scientific program. It is also planned to reach out to other organizations to align initiatives to enhance efficiency, and to initiate activities to improve the clinical relevance of preclinical data. Those Network activities should contribute to scientific rigor and lead to robust and relevant translational data. Here we provide a synopsis of the proceedings from the inaugural meeting.
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http://dx.doi.org/10.1016/j.euroneuro.2015.05.011DOI Listing
October 2015

The subchronic phencyclidine rat model: relevance for the assessment of novel therapeutics for cognitive impairment associated with schizophrenia.

Psychopharmacology (Berl) 2015 Nov 14;232(21-22):4059-83. Epub 2015 Jun 14.

Neuroscience, Ophthalmology and Rare Diseases, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland.

Rationale: Current treatments for schizophrenia have modest, if any, efficacy on cognitive dysfunction, creating a need for novel therapies. Their development requires predictive animal models. The N-methyl-D-aspartate (NMDA) hypothesis of schizophrenia indicates the use of NMDA antagonists, like subchronic phencyclidine (scPCP) to model cognitive dysfunction in adult animals.

Objectives: The objective of this study was to assess the scPCP model by (1) reviewing published findings of scPCP-induced neurochemical changes and effects on cognitive tasks in adult rats and (2) comparing findings from a multi-site study to determine scPCP effects on standard and touchscreen cognitive tasks.

Methods: Across four research sites, the effects of scPCP (typically 5 mg/kg twice daily for 7 days, followed by at least 7-day washout) in adult male Lister Hooded rats were studied on novel object recognition (NOR) with 1-h delay, acquisition and reversal learning in Morris water maze and touchscreen-based visual discrimination.

Results: Literature findings showed that scPCP impaired attentional set-shifting (ASST) and NOR in several labs and induced a variety of neurochemical changes across different labs. In the multi-site study, scPCP impaired NOR, but not acquisition or reversal learning in touchscreen or water maze. Yet, this treatment regimen induced locomotor hypersensitivity to acute PCP until 13-week post-cessation.

Conclusions: The multi-site study confirmed that scPCP impaired NOR and ASST only and demonstrated the reproducibility and usefulness of the touchscreen approach. Our recommendation, prior to testing novel therapeutics in the scPCP model, is to be aware that further work is required to understand the neurochemical changes and specificity of the cognitive deficits.
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http://dx.doi.org/10.1007/s00213-015-3954-6DOI Listing
November 2015

Opposing effects of glutamatergic and GABAergic pharmacological manipulations on a visual perception task with relevance to schizophrenia.

Psychopharmacology (Berl) 2015 Nov 28;232(21-22):3967-76. Epub 2015 May 28.

Department of Neuroscience, Janssen Research and Development, 30 Turnhoutseweg, 2340, Beerse, Belgium.

Rationale: Numerous psychiatric disorders and neurodegenerative diseases have been associated with differences in visual perception, and it has been proposed that the treatment of these differences may represent a novel means to treat disorders like schizophrenia. Unfortunately, few methods exist to study visual perception in pre-clinical species.

Objective: The purpose of the present study was to adapt a task of visual integration by proximity with relevance to schizophrenia to a rodent touchscreen environment to determine the effects of glutamatergic and GABAergic compounds. In this way, we could evaluate the effects of common models of cognitive impairment, as well as the effects of net excitation versus inhibition, on a task of visual integration.

Method: Rats were trained to perform a visual discrimination where the stimuli were composed of rows of dots differing only in there horizontal and vertical proximity. Once stable performance had been achieved, animals were tested under the influence of glutamatergic or GABAergic drugs (ketamine, MK-801, PCP, memantine, chlordiazepoxide, or diazepam) while attempting to perform a visual discrimination with altered stimuli.

Results: Ketamine appeared to impair perceptual grouping in this paradigm, while the GABA agonist chlordiazepoxide enhanced grouping even in the presence of non-selective effects.

Conclusions: In general, these findings support the theory that NMDA antagonists may disrupt visual grouping by proximity and highlight a potential beneficial effect of enhanced GABA activity in perception. However, additional research will be required to confirm the stimulus selectivity of this effect, and the clinical significance of this approach.
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http://dx.doi.org/10.1007/s00213-015-3964-4DOI Listing
November 2015

Biased mGlu5-Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu5 Modulation of NMDAR Currents.

Neuron 2015 May 30;86(4):1029-1040. Epub 2015 Apr 30.

Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA. Electronic address:

Schizophrenia is associated with disruptions in N-methyl-D-aspartate glutamate receptor subtype (NMDAR)-mediated excitatory synaptic signaling. The metabotropic glutamate receptor subtype 5 (mGlu5) is a closely associated signaling partner with NMDARs and regulates NMDAR function in forebrain regions implicated in the pathology of schizophrenia. Efficacy of mGlu5 positive allosteric modulators (PAMs) in animal models of psychosis and cognition was previously attributed to potentiation of NMDAR function. To directly test this hypothesis, we identified VU0409551 as a novel mGlu5 PAM that exhibits distinct stimulus bias and selectively potentiates mGlu5 coupling to Gαq-mediated signaling but not mGlu5 modulation of NMDAR currents or NMDAR-dependent synaptic plasticity in the rat hippocampus. Interestingly, VU0409551 produced robust antipsychotic-like and cognition-enhancing activity in animal models. These data provide surprising new mechanistic insights into the actions of mGlu5 PAMs and suggest that modulation of NMDAR currents is not critical for in vivo efficacy. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.neuron.2015.03.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4443790PMC
May 2015

MK-801 and amphetamine result in dissociable profiles of cognitive impairment in a rodent paired associates learning task with relevance for schizophrenia.

Psychopharmacology (Berl) 2015 Nov 23;232(21-22):3911-20. Epub 2015 Apr 23.

Department of Neuroscience, Janssen Research and Development, 30 Turnhoutseweg, 2340, Beerse, Belgium.

Rationale: Paired associates learning (PAL) has been suggested to be predictive of functional outcomes in first episode psychosis and of conversion from mild cognitive impairment to Alzheimer's disease. An automated touch screen-based rodent PAL (rPAL) task has been developed and is sensitive to manipulations of the dopaminergic and glutamatergic system. Accordingly, rPAL when used with pharmacological models of schizophrenia, like NMDA receptor blockade with MK-801 or dopaminergic stimulation with amphetamine, may have utility as a translational model of cognitive impairment in schizophrenia.

Objective: The purpose of this study was to determine if amphetamine- and MK-801-induced impairment represent distinct models of cognitive impairment by testing their sensitivity to common antipsychotics and determine the relative contributions of D1 versus D2 receptors on performance of PAL.

Method: Rats were trained in rPAL and were then treated with MK-801, amphetamine, risperidone, haloperidol, quinpirole, SK-82958, or SCH-23390 alone and in combination.

Results: While both amphetamine and MK-801 caused clear impairments in accuracy, MK-801 induced a profound "perseverative" type behavior that was more pronounced when compared to amphetamine. Moreover, amphetamine-induced impairments, but not the effects of MK-801, could be reversed by antipsychotics as well as the D1 receptor antagonist SCH-23390, suggesting a role for both the D1 and D2 receptor in the amphetamine impairment model.

Conclusions: These data suggest that amphetamine and MK-801 represent dissociable models of impairment in PAL, dependent on different underlying neurobiology. The ability to distinguish dopaminergic versus glutamatergic effects on performance in rPAL makes it a unique and useful tool in the modeling of cognitive impairments in schizophrenia.
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http://dx.doi.org/10.1007/s00213-015-3934-xDOI Listing
November 2015

Strain-dependent effects on acquisition and reversal of visual and spatial tasks in a rat touchscreen battery of cognition.

Physiol Behav 2015 May 3;144:26-36. Epub 2015 Mar 3.

Janssen Research & Development, Janssen Pharmaceutica companies of J&J, Turnhoutseweg 30, 2340 Beerse, Belgium.

Aim: The use of touch-screen equipped operant boxes is an increasingly popular method for modeling human cognition in the rodent. A concern of this approach is that the dependence upon vision may limit the strains of rats that can be tested in the apparatus. This is of particular concern because of the increased availability of genetically modified rats that are disproportionately on an albino background and may have compromised vision. Here we test pigmented and albino strains of rats on three touch-screen tasks of learning and memory that may require different levels of visual ability. In tests where albino animals have similar levels of performance as the pigmented rats we also tested common pharmacological models of cognitive impairment to determine the generalizability of these challenges across strains. By doing this work we hope to determine the robustness of common models of pharmacological impairment in albino rats.

Methods: We tested four strains of rats (albino: Wistar and Sprague Dawley, pigmented: Long Evans and Lister Hooded) in three touchscreen-based tasks of cognition with differing visual requirements: visual discrimination (VD) acquisition and reversal learning, and the more spatial and less visually demanding, automated spatial search task (AST). Furthermore, we tested the effects of the muscarinic antagonist scopolamine and the non-competitive NMDAR antagonist MK801 on performance of the four strains in AST. Finally, visual acuity was also assessed via a movement detection test.

Results: The rate of acquisition (% correct) in albino rats was significantly slower than in pigmented rats. Wistar rats were significantly slower to acquire the task, and showed differences in reversal learning when compared to the pigmented strains. Moreover, SD rats performed so badly during the acquisition phase of the VD that they failed to reach inclusion criteria (80% correct responses over 3-sessions) for the reversal phase. In contrast, no effect of strain was found in AST. Some of these differences can likely be attributed to differences in visual acuity as albino animals appeared to have reduced visual acuity when compared to the pigmented animals as previously reported in the literature. Pharmacological challenge with scopolamine or MK801 induced dissociable effects between compounds, but generally comparable impairments in all four strains.

Conclusions: Albino animals showed a clear impairment on tasks that are dependent upon intact vision, while no impairment was observed in the visually less demanding spatial task. Despite a published report to the contrary, these results demonstrate that albino strains may not be appropriate for use in touchscreen tasks that are dependent upon a visual discrimination. Furthermore, the spatial search task showed distinct impairment profiles as a result of treatment with either MK-801 or scopolamine. While an interaction did exist between strain and treatment, the dissociation between MK-801 and scopolamine was consistent across 3 of 4 strains. These results highlight the importance of selecting the appropriate strain for use in tasks of visual learning and memory and also demonstrate the potential robustness of pharmacological models of cognitive impairment across strains.
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http://dx.doi.org/10.1016/j.physbeh.2015.03.001DOI Listing
May 2015