Animal and Translational Models for CNS Drug Discovery ||

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  • 457Copyright 2008, Elsevier Inc.

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    Animal and Translational Models for CNS Drug Discovery, Vol. 1 of 3: Psychiatric Disorders Robert McArthur and Franco Borsini (eds), Academic Press, 2008

    INTRODUCTION This series has provided a systematic overview of translational research in psychophar-macology that integrates the perspectives of academics, industrial pharmacologists, and clinicians, in therapeutic areas representing three broad therapeutic domains, neu-rological disorders, psychiatric disorders, and reward/impulse control disorders. An earlier attempt to systematize translational research in psychopharmacology summa-rized the scope of the endeavor as follows:

    The problem of using animal behavior to model human mental disorders is, explicitly or implicitly, the central preoccupation of psychopharmacology. The idea that psychiatric disorders might be modeled in animals provides the basis for a substantial proportion of current research; and research that does not employ behavioral models directly is usually justifi ed by reference to its eventual benefi ts, in terms of an understanding of the human brain and the development of more effective and safer therapies. 1

    In effect, the principle that translation from animals to humans is both possible and necessary underpins and justifi es the whole fi eld of preclinical psychopharmacology.

    The forerunner to the present series, Behavioural Models in Psychopharmacology: Academic, Theoretical and Industrial Perspectives 2 was intended to generalize an approach fi rst outlined in a more focused earlier review of animal models of depres-sion. 3 These publications introduced four signifi cant ideas: that drug screening tests should not be thought of as models and differ in their practical and evidential require-ments; that academics, industrial pharmacologists, and clinicians view preclinical behavioral models from different perspectives, based on their different professional aspirations; that it is important to establish, or at least, estimate, the validity of animal models of psychiatric disorders; and that this is best achieved by considering validity from different aspects that refl ect different bodies of evidence.

    In the 20 or so years since these ideas were fi rst introduced, they have achieved a wide degree of acceptance, and the fi rst two are very apparent in the structure and content

    Translational Models for the 21st Century: Reminiscence, Refl ections, and Some Recommendations Paul Willner 1 , Franco Borsini 2 and Robert A. McArthur 3

    1 Department of Psychology, Swansea University, Swansea, Wales, UK 2 sigma-tau S.p.A., Pomezia, Roma, Italy 3 McArthur and Associates GmbH, Ramsteinerstrasse, Basel, Switzerland


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  • 458 EPILOGUE Translational Models for the 21st Century

    of the present series. The three approaches to the validation of animal models that were outlined in these publications, using terms borrowed from the realm of psychomet-ric testing, were predictive validity ( performance in the test predicts performance in the condition being modeled ), face validity ( there are phenomenological similarities between the two ), and construct validity ( the model has a sound theoretical ratio-nale ). 2 This analysis has since become standard, as seen, for example, in recent reviews of animal models of anxiety 4 and schizophrenia. 5 Indeed, these principles are now so well established that many contributors to the present series begin their discussions by considering the face, predictive, and construct validity of the models used and being developed in their therapeutic areas. i The extent to which these concepts have become absorbed into the language of psychopharmacology is demonstrated by the fact that they are now almost always used without attribution to the original publications.

    Much has changed in terms of model development in the last 20 years; particularly in neurology. As has been discussed in the neurological therapeutic areas surveyed in this series, much of the work has been developed more recently, and it is noticeable that these chapters tend to have a different fl avor to those chapters surveying psychi-atric and reward defi cit disorders, being heavily dominated by genetic and genomic models. In psychiatry, on the other hand, while these areas have also been heavily infl uenced by the genomic revolution, in behavioral terms, models of depression, anxi-ety, schizophrenia, or substance abuse have seen relatively little development. That is not to say that there have not been developments in the procedures by which mod-els of depressed-like, anxious-like, schizophrenic-like or substance-abuse-like behav-iors can be assessed. Indeed, there is now a signifi cantly greater choice of procedures. However, the newer developments are largely more sophisticated variants on proce-dures that were well established prior to 1990.

    Schizophrenia represents perhaps the one major therapeutic area where a signifi -cant shift in emphasis has been evident over the past 20 years. From the discovery of neuroleptics in the early 1950s 6,7 and the establishment of the dopamine hypoth-esis of schizophrenia, 8 drug discovery and development of pharmaceuticals used to treat the positive, that is, psychotic, symptoms of schizophrenia have centered around impairment of excessive dopaminergic function. Effects of mesolimbic dopaminer-gic imbalance have been relatively straightforward to model, mainly using changes in locomotion. ii Notwithstanding the importance of dopamine in schizophrenia,

    i For further and detailed discussions regarding criteria of validity, the reader is invited to refer to discus-sions, for example, by Steckler et al ., Developing novel anxiolytics: Improving preclinical detection and clinical assessment; Large et al ., Developing therapeutics for bipolar disorder: From animal models to the clinic; Joel et al ., Animal models of obsessivecompulsive disorder: From bench to bedside via endophe-notypes and biomarkers, in Volume 1, Psychiatric Disorders ; Lindner et al ., Development, optimization and use of preclinical behavioral models to maximize the productivity of drug discovery for Alzheimers Disease; Merchant et al ., Animal models of Parkinsons Disease to aid drug discovery and development, in Volume 2, Neurologic Disorders ; Koob, The role of animal models in reward defi cit disorders: Views from academia; Markou et al ., Contribution of animal models and preclinical human studies to medication development for nicotine dependence, in Volume 3, Reward Defi cit Disorders . ii Please refer to Jones et al ., Developing new drugs for schizophrenia: From animals to the clinic, in Volume 1, Psychiatric Disorders . For further discussion regarding models and procedures in schizophre-nia research.

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  • 459Paul Willner, Franco Borsini and Robert A. McArthur

    awareness of the infl uence of other neurotransmitters such as serotonin, glutamate and GABA has led to considerable research into the role of these and their interac-tions with dopamine. 9,10 Pharmaceutical interest in glutamate in schizophrenia has been particularly fruitful with the development of the metabotropic glutamate 2/3 (mGlu 2/3 ) receptor agonist LY2140023, which appears to be as effective as olanzap-ine (Zyprexa) as an antipsychotic in a Phase II trial. 11,12 mGlu 2/3 receptor agonists have been discovered and characterized using classical locomotor activity procedures or pharmacological interaction studies, 1315 but it is interesting to note that they also show positive effects on newer procedures that have been developed to assess drug effects on models of negative (i.e., social withdrawal, lack of affect and drive, poverty of speech) and cognitive symptoms of schizophrenia. 15,16 Such procedures include sensory gating and pre-pulse inhibition, 17 sustained or focused attention, 18,19 and impaired social interaction. 20 Furthermore, greater awareness of neurodevelopmental and environmental factors of schizophrenia has led to the establishment of models such as neo-natal hippocampal lesions, 21 and to attempts to model effects of peri-partum complications as risk factors of schizophrenia. 22

    Stress as a predisposing factor, the role of the hypothalamo-pituitary-adrenal (HPA) axis and reactions to stress infl uenced by the environment and development, are themes discussed not only in the chapters of the Psychiatry volume, such as depres-sion, 23 anxiety, 24 bipolar disorders, 25 and attention defi cit hyperactivity disorder (ADHD), 26 but also the chapters representing the reward and impulse defi cit disorders; disorders that share a high psychiatric component. 2729 Consequently, major efforts have been made to model the effects of chronic stress and infl uences of development on psychiatric, reward defi cit, and impulse control disorders. Behavioral developments in these areas are concerned almost exclusively with the ways in which stressors are applied and their effects evaluated. The procedures used to evaluate these changes have not changed markedly in the past 20 years. However, the way in which these procedures are used has been greatly infl uenced by the endophenotypic approach to considering psychiatric disorders and how to model aspects of these disorders. 23,24 , iii Similarly, models of reward and impulse disorders continue to be dominated by self-administration and place conditioning procedures. There is certainly a greater use of more sophisticated procedures, such as second order or progressive ratio reinforce-ment schedules 30 , iv but the procedures themselves have been well established for decades. 31

    Nevertheless, despite the relatively minor changes in the behavioral methodologies, research in these traditional areas of translational modeling is markedly different from 20 years, ago, since they too have been transformed by the genomic revolution, which now dominates and largely determines directions of change, dwarfi ng developments in behavioral technologies. Almost every chapter in this series bears witness to the fact

    iii Please refer to McArthur and Borsini, preface to this volume, What do you mean by translational research? An enquiry through animal and translational models for CNS drug discovery, and references within for further discussion on endophenotypes and deconstructing behavioral syndromes. iv See also Koob, The role of animal models in reward defi cit disorders: Views from academia; and Rochas et al. , Development of medications for heroin and cocaine addiction and regulatory aspects of abuse liability testing in Volume 3, Reward Defi cits Disorders.

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  • 460 EPILOGUE Translational Models for the 21st Century

    that current research is highly productive in proposing new models of aspects of psy-chiatric and impulse control disorders that, like the new neurological models, are based almost exclusively on the use of genetically modifi ed animals. 32,33 Molecular biology has also had a huge impact on the understanding of intracellular processes, particu-larly in relation to those intracellular sequelae of transmitterreceptor interactions that result in changes in gene expression. These developments were driven in part by the recognition that successful pharmacotherapy for psychiatric disorders depression in particular often requires chronic drug treatment. Consequently, there is an increasing use in preclinical studies of chronic dosing strategies modeled on the time course of clinical action, leading to a search for the biochemical mechanisms that underlie slowly developing neuroadaptive changes and the identifi cation of a plethora of novel intra-cellular targets. 3438

    A similar dynamic is apparent in relation to the understanding of brain structure and function, which serves as the context for translational research. Twenty years ago, psychopharmacology was preoccupied almost exclusively with neurotransmitters; specifi cally the monoamines dopamine, norepinephrine and serotonin, acetylcholine and GABA, and their receptors. There had been a shift away from the original paradigm that saw the brain as a biochemical soup, with a recognition that the anatomical site of action was also a crucial consideration, but little attention was paid to the underlying neural circuitry. Over the past 20 years, progress in understanding neurotransmitters and their receptors has been slowly incremental, particularly in relation to glutamater-gic and peptidergic systems, as well as the cannabinoid systems, which represent the only major truly novel development. On the other hand, the understanding of brain circuitry has increased exponentially. The importance of dopamine and the mesolim-bic and nigrostriatal systems in terms of movement (Parkinsons) and mood (schizo-phrenia), helped focus research on a more neural systems approach. Subsequently, examination of the relationships and interactions between neurotransmitter and neu-romodulators within discrete neural circuits has helped to clarify neural substrates of behavioral processes, with the result that the basic operating principles of the brain are being increasingly well understood. 3941 The parallel development of cognitive neuro-science has been accompanied by technological innovations, most notably, brain scan-ning methodologies, which have promoted a substantial growth of studies in human participants that complement the traditional work in animal models.

    Over the past two decades, then, it is the dramatic developments in molecular biol-ogy and in behavioral and cognitive neuroscience, rather than developments in psycho-pharmacology itself, that have had the major impact on both the theory and practice of translational research, as exemplifi ed by the contributions that comprise the present series. And the fundamental dilemma of psychopharmacology was already apparent 20 years ago, and remains so today: that following an early golden age all of the invest-ment in academic and industrial research has produced tiny returns by way of novel pharmacotherapies. For 30, perhaps 40, years now, psychopharmacological research has not substantially changed the pharmacological armamentarium with which to treat dev-astating and life-threatening behavioral disorders. It has often been pointed out, but bears repeating, that it was 1958, now half a century ago, when the fi...


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