Genes, Brain and Behavior (2011) 10: 127–128 doi: 10.1111/j.1601-183X.2010.00642.x

Book review

Animal and translational models for CNS drugdiscovery Vol. 1. Psychiatric disorders. Vol. 2.Neurological disorders. Vol. 3. Reward deficitdisorders

R. A. McArthur and F. Borsini (eds)

Academic Press, Burlington, MA, USA, 2008. xliii + 483 pp.,xlv11 + 361 pp., xlii + 383 pp. $200.ISBN978-0-12-373861-5

Over the last decades, promising neuropsychiatric drugscoming from animal studies have often failed to showadequate efficacy in humans, showing a real discrepancybetween preclinical drug discovery and clinical application.Beyond a possible inadequacy of concepts, methods orprocedures in preclinical research, a major concern raisedis the possibility of an ontological gap between humansand other animal species. According to this reasoning,humans are unique and, therefore, any attempt to findhomology with animals is inevitably condemned to be adead end. This philosophical/epistemological issue is crucialbecause there is growing skepticism among some clinicians,including some industry managers, regarding not only theconceptual but also the pragmatic and operational valueof preclinical animal models. Despite this, the notion oftranslational research has rapidly taken the front of thescene in the last years, but without really convincing orsignificant breakthroughs. With their trilogy on ‘Animal andtranslational models for CNS drug discovery’, McArthurand Borsini present a fascinating updated overview of thetheoretical and practical facets of translational research.These books are neither a mere compilation of technicalor methodological chapters nor a simple refreshment of old-fashioned terminology. Rather, leading preclinical and clinicalinvestigators from both academia and industry provide acomprehensive discussion in which translational researchis defined from different angles but with a common goal,namely efficient drug discovery.

This brief review cannot provide a detailed overview ofall chapters but only give a flavor of what these booksare dealing with. For example, in the first volume, Millanstresses the cardinal issue of the boundary conditions in themodeling process to select the relevant items of a particularpsychiatric disorder. The ‘deconstruction’ of syndromes intoclusters of symptoms often leads to the identification ofa set of symptoms that are shared by several disorders.Therefore, it is important to design animal models for, not of,psychiatric disorders by exploiting a multi-modal approach byputting together the biological, genetic, developmental andenvironmental aspects of the pathology. Accordingly, Miczekemphasizes eight principles to guide translational research.Most of these are found on good common sense and not

revolutionary, but they remind us that it is not necessarilywhere the light is that we should seek our keys. In otherwords, despite the ontological difficulty already mentionedwe cannot avoid to capture core symptoms of psychiatricdisorders in our experimental models to ameliorate theirtranslational value. Subsequent chapters tackle specificconcerns for translational research in relation with particulartherapeutic areas. Most psychiatric disorders are covered.Very interestingly, to stimulate discussion in the therapeuticchapters, the editors have recruited authors coming fromdifferent domains of the drug discovery process. Thisstrategy has produced exciting chapters that offer interestingideas and helpful concepts to implement a ‘translationalattitude’ that should become a natural prerequisite for drugdiscovery research.

The second volume is dedicated to neurological disorders.The overall philosophy is the same, as translational researchis confronted with similar pitfalls. This is exacerbatedby the fact that a large number of compounds withpositive preclinical results have failed to exhibit significantefficacy in clinical trials. The reasons for this discrepancymay be the usual ones: patient heterogeneity, end-pointmeasures, pharmacokinetics and dosing, clinical trial design,etc. In addition, there is an increasing emphasis ondeveloping disease-modifying therapeutic agents instead ofsymptomatic treatments, which presupposes knowledge ofthe etiology of the neurodegenerative processes. Becauseof spectacular advances in genetics and molecular biology, aplethora of transgenic mice have been generated to modelall sorts of disorders. These models need to be validatedby behavioral outcomes which are mostly epitomized bycognitive impairments. In this context, readers involvedin preclinical research will find very useful information inSchneider’s chapter on design and conduct of clinical trialsto assess cognitive-enhancing drugs. The feedback of thesetrials will help to refine not only the development of animalmodels, but also the design of the experimental proceduresthat should be conducted in line with good laboratory practice(see chapter by Lindner et al.). This second volume coversmost of the neurological disorders including Alzheimer’s,Parkinson’s, Huntington, Amyotrophic Lateral Sclerosis, andepilepsy disorders.

Reward deficit disorders constitute the theme of the thirdvolume, which contains nine chapters covering the maindisorders such as alcohol or nicotine dependence, heroin andcocaine addiction, obesity, pathological gambling, and otherimpulsive disorders. Again the organization of the differentchapters gives us a broad view on the question including theway a governmental institution like the National Institute ofDrug Abuse handles scientific and clinical issues in concertwith societal concerns.

Because addiction is the common feature that emergesfrom this volume, we might think that reward deficit disordersinvolving substance abuse are easier to model. However,

© 2010 The Authors 127Genes, Brain and Behavior © 2010 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society

Book review

in reward deficit disorders, comorbidity may mask veryheterogeneous patient populations, hampering positive out-come of pharmacological treatments in clinical trials. Anyway,although psychological and social factors are core compo-nents of most of the reward deficit disorders, the overallfeeling emerging from these chapters is that translationalpsychopharmacological research has led to effective treat-ment for these complex disorders and opened ways to novel,promising and potentially even more effective treatments.

In conclusion, this trilogy covers most of the field of centralnervous system (CNS) drug discovery that should impactfuture translational research. The real originality of this ‘roundtable’ lies in the impression that there is now a communality

of concerns shared by the different actors involved not only indrug discovery but also in clinical research, patient treatmentand institutional funding organisms. In consequence, anyoneinterested in the field should read this appealing contributionto drug discovery research.

J. MicheauCentre de Neurosciences Integratives et CognitivesUniversite de Bordeaux andCentre National de la Recherche ScientifiqueTalence (Bordeaux), FranceE-mail: j.micheau@cnic.u-bordeaux1.fr

128 Genes, Brain and Behavior (2011) 10: 127–128