Improving Translational Relevance in Preclinical Psychopharmacology (iTRIPP).

Animal models are important in preclinical psychopharmacology to study mechanisms and potential treatments for psychiatric disorders. A working group of 14 volunteers, comprising an international team of researchers from academia and industry, convened in 2021 to discuss how to improve the translational relevance and interpretation of findings from animal models that are used in preclinical psychopharmacology. The following paper distils the outcomes of the working group's discussions into 10 key considerations for the planning and reporting of behavioural studies in animal models relevant to psychiatric disorders. These form the iTRIPP guidelines (Improving Translational Relevance In Preclinical Psychopharmacology). These guidelines reflect the key considerations that the group thinks will likely have substantial impact in terms of improving the translational relevance of behavioural studies in animal models that are used to study psychiatric disorders and their treatment. They are relevant to the research community when drafting and reviewing manuscripts, presentations and grant applications. The iTRIPP guidelines are intended to complement general recommendations for planning and reporting animal studies that have been published elsewhere, by enabling researchers to fully consider the most appropriate animal model for the research purpose and to interpret their findings appropriately. This in turn will increase the clinical benefit of such research and is therefore important not only for the scientific community but also for patients and the lay public.

Adrenoceptors: A Focus on Psychiatric Disorders and Their Treatments.

Research into the involvement of adrenoceptor subtypes in the cause(s) of psychiatric disorders is particularly challenging. This is partly because of difficulties in developing animal models that recapitulate the human condition but also because no evidence for any causal links has emerged from studies of patients. These, and other obstacles, are outlined in this chapter. Nevertheless, many drugs that are used to treat psychiatric disorders bind to adrenoceptors to some extent. Direct or indirect modulation of the function of specific adrenoceptor subtypes mediates all or part of the therapeutic actions of drugs in various psychiatric disorders. On the other hand, interactions with central or peripheral adrenoceptors can also explain their side effects. This chapter discusses both aspects of the field, focusing on disorders that are prevalent: depression, schizophrenia, anxiety, attention-deficit hyperactivity disorder, binge-eating disorder, and substance use disorder. In so doing, we highlight some unanswered questions that need to be resolved before it will be feasible to explain how changes in the function of any adrenoceptor subtype affect mood and behavior in humans and other animals.

Guidance for the use and reporting of anaesthetic agents in BJP manuscripts involving work with animals.

Scientists who plan to publish in the British Journal of Pharmacology (BJP) should read this article before undertaking studies utilising anaesthetics in mammalian animals. This editorial identifies certain gaps in the reporting of details on the use of anaesthetics in animal research studies published in the BJP. The editorial also provides guidance, based upon current best practices, for performing in vivo experiments that require anaesthesia. In addition, mechanisms of action and physiological impact of specific anaesthetic agents are discussed. Our goal is to identify best practices and to provide guidance on the information required for manuscripts submitted to the BJP that involve the use of anaesthetic agents in studies with experimental animals.

Planning experiments: Updated guidance on experimental design and analysis and their reporting III.

Scientists who plan to publish in British Journal of Pharmacology (BJP) must read this article before undertaking a study. This editorial provides guidance for the design of experiments. We have published previously two guidance documents on experimental design and analysis (Curtis et al., 2015; Curtis et al., 2018). This update clarifies and simplifies the requirements on design and analysis for BJP manuscripts. This editorial also details updated requirements following an audit and discussion on best practice by the BJP editorial board. Explanations for the requirements are provided in the previous articles. Here, we address new issues that have arisen in the course of handling manuscripts and emphasise three aspects of design that continue to present the greatest challenge to authors: randomisation, blinded analysis and balance of group sizes.

Animal Models of ADHD?

To describe animals that express abnormal behaviors as a model of Attention-Deficit Hyperactivity Disorder (ADHD) implies that the abnormalities are analogous to those expressed by ADHD patients. The diagnostic features of ADHD comprise inattentiveness, impulsivity, and hyperactivity and so these behaviors are fundamental for validation of any animal model of this disorder. Several experimental interventions such as neurotoxic lesion of neonatal rats with 6-hydroxydopamine (6-OHDA), genetic alterations, or selective inbreeding of rodents have produced animals that express each of these impairments to some extent. This article appraises the validity of claims that these procedures have produced a model of ADHD, which is essential if they are to be used to investigate the underlying cause(s) of ADHD and its abnormal neurobiology.

Prevention and management of intra-operative pain during caesarean section under neuraxial anaesthesia: a technical and interpersonal approach.

A woman who experiences pain during caesarean section under neuraxial anaesthesia is at risk of adverse psychological sequelae. Litigation arising from pain during caesarean section under neuraxial anaesthesia has replaced accidental awareness under general anaesthesia as the most common successful medicolegal claim against obstetric anaesthetists. Generic guidelines on caesarean section exist, but they do not provide specific recommendations for this area of anaesthetic practice. This guidance aims to offer pragmatic advice to support anaesthetists in caring for women during caesarean section. It emphasises the importance of non-technical skills, offers advice on best practice and aims to encourage standardisation. The guidance results from a collaborative effort by anaesthetists, psychologists and patients and has been developed to support clinicians and promote standardisation of practice in this area.

Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species.

BACKGROUND: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer's disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors. OBJECTIVE: To determine whether the high in vitro potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans. METHODS: The effect of LY3202626 versus vehicle on amyloid-ß (Aß) levels was evaluated in a series of in vitro assays, as well as in in vivo and multi-part clinical pharmacology studies. Aß levels were measured using analytical biochemistry assays in brain, plasma, and cerebrospinal fluid (CSF) of mice, dogs and humans. Nonclinical data were analyzed using an ANOVA followed by Tukey's post hoc test and clinical data used summary statistics. RESULTS: LY3202626 exhibited significant human BACE1 inhibition, with an IC50 of 0.615±0.101 nM in a fluorescence resonance energy transfer assay and an EC50 of 0.275±0.176 nM for lowering Aß1-40 and 0.228±0.244 nM for Aß1-42 in PDAPP neuronal cultures. In dogs, CSF Aß1hboxx concentrations were significantly reduced by ∼80% at 9 hours following a 1.5 mg/kg dose. In humans, CSF Aß1-42 was reduced by 73.1±7.96 % following administration of 6 mg QD. LY3202626 was found to freely cross the blood-brain barrier in dogs and humans. CONCLUSION: LY3202626 is a potent BACE1 inhibitor with high blood-brain barrier permeability. The favorable safety and pharmacokinetic/pharmacodynamic profile of LY3202626 supports further clinical development.

Celebrating 125 years of the synapse: from Sherrington to the present day.

This themed collection celebrates 125 years of the synapse through a series of reviews written by a team of international experts in the field. The first in the series explains Sherrington's contribution to the debate about the term 'synapse' and its function in neuronal signaling. The topics that follow cover recent developments in a wide range of topics: new technologies for research of synaptic structure; proteomics and the regulation of synaptic integrity and function; their role in the processing of information in thalamic neuronal circuits; and how genetic mutations can modify synaptic function in ways that can have profound effects on mood, cognition and behaviour.

Neuronal Signaling: A reflection on the Biochemical Society's newest journal and an exciting outlook on its next steps.

The inaugural Editor-in-Chief of Neuronal Signaling, Aideen M. Sullivan, reflects on the journal's journey so far and welcomes the new Editor-in-Chief, Clare Stanford, as she shares some of the exciting initiatives and plans for its future.

Some Reasons Why Preclinical Studies of Psychiatric Disorders Fail to Translate: What Can Be Rescued from the Misunderstanding and Misuse of Animal 'Models'?

The repeated failure of animal models to yield findings that translate into humans is a serious threat to the credibility of preclinical biomedical research. The use of animals in research that lacks translational validity is unacceptable in any ethical environment, and so this problem needs urgent attention. To reproduce any human illness in animals is a serious challenge, but this is especially the case for psychiatric disorders. Yet, many authors do not hesitate to describe their findings as a 'model' of such a disorder. More cautious scientists describe the behavioural phenotype as 'disorder-like', without specifying the way(s) in which the abnormal behaviour could be regarded as being analogous to any of the diagnostic features of the disorder in question. By way of discussing these problems, this article focuses on common, but flawed, assumptions that pervade preclinical research of depression and antidepressants. Particular attention is given to the difference between putative 'models' of this illness and predictive screens for candidate drug treatments, which is evidently widely misunderstood. However, the problems highlighted in this article are generic and afflict research of all psychiatric disorders. This dire situation will be resolved only when funders and journal editors take action to ensure that researchers interpret their findings in a less ambitious, but more realistic, evidence-based way that would parallel changes in research of the cause(s), diagnosis and treatment of psychiatric problems in humans.

Spectroscopic confirmation of a mature galaxy cluster at a redshift of 2.

Galaxy clusters are the most massive virialized structures in the Universe and are formed through the gravitational accretion of matter over cosmic time1. The discovery2 of an evolved galaxy cluster at redshift z = 2, corresponding to a look-back time of 10.4 billion years, provides an opportunity to study its properties. The galaxy cluster XLSSC 122 was originally detected as a faint, extended X-ray source in the XMM Large Scale Structure survey and was revealed to be coincident with a compact over-density of galaxies2 with photometric redshifts of 1.9 ± 0.2. Subsequent observations3 at millimetre wavelengths detected a Sunyaev-Zel'dovich decrement along the line of sight to XLSSC 122, thus confirming the existence of hot intracluster gas, while deep imaging spectroscopy from the European Space Agency's X-ray Multi-Mirror Mission (XMM-Newton) revealed4 an extended, X-ray-bright gaseous atmosphere with a virial temperature of 60 million Kelvin, enriched with metals to the same extent as are local clusters. Here we report optical spectroscopic observations of XLSSC 122 and identify 37 member galaxies at a mean redshift of 1.98, corresponding to a look-back time of 10.4 billion years. We use photometry to determine a mean, dust-free stellar age of 2.98 billion years, indicating that star formation commenced in these galaxies at a mean redshift of 12, when the Universe was only 370 million years old. The full range of inferred formation redshifts, including the effects of dust, covers the interval from 7 to 13. These observations confirm that XLSSC 122 is a remarkably mature galaxy cluster with both evolved stellar populations in the member galaxies and a hot, metal-rich gas composing the intracluster medium.