Antidepressants and the resilience to early-life stress in inbred mouse strains Elke Binder b* , Karim Malki a* , Jose L. Paya-Cano a , Cathy Fernandes a , Katherine J. Aitchison a , Aleksander A. Mathe ´ c , Frans Sluyter a and Leonard C. Schalkwyk a Rationale Selecting an effective treatment for patients with major depressive disorder is a perpetual problem for psychiatrists. It is of particular interest to explore the interaction between genetic predisposition and environmental factors. Objectives Mouse inbred strains vary in baseline performance in depression-related behaviour tests, which were originally validated as tests of antidepressant response. Therefore, we investigated interactions between environmental stress, genotype, and drug response in a multifactorial behaviour study. Method Our study design included four inbred mouse strains (129S1/SvlmJ, C57LB/6J, DBA/2J and FVB/NJ) of both sexes, two subjected to environmental manipulations (maternal separation and unpredictable chronic mild stress) and two representative of treatment with antidepressants (escitalopram and nortryptiline vs. vehicle). The mice treated with antidepressants were further divided into those administered acute (1 day) and subchronic (14 days) regimes, giving 144 experimental groups in all, each with at least seven animals. All animals were tested using the Porsolt forced-swim test (FST) and the hole-board test. Results Despite a 24-h maternal separation (MS) or a 14-day unpredictable chronic mild stress protocol, most animals seemed to be resilient to the stress induced. One compelling finding is the long-lasting, strain-specific effect of MS resulting in an increased depression-like behaviour in the Porsolt FST and elevated anxiety-related behaviour in the hole-board test seen in 129S1/SvImJ mice. Nortriptyline was effective in reversing the effect of MS in the FST in 129S1/SvlmJ male mice. Conclusion A single 24-h maternal separation of pups from their mother on postnatal day 9 is a sufficient insult to result in a depression-like phenotype in adult 129S1/SvImJ mice but not in C57LB/6 J, DBA/2 J, and FVB/NJ mice. Pharmacogenetics and Genomics 21:779–789  c 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Pharmacogenetics and Genomics 2011, 21:779–789 Keywords: antidepressants, depression, escitalopram, Genome-based Therapeutic Drugs for Depression, maternal deprivation, maternal separation, nortriptyline, pharmacogenetics a King’s College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, London, UK, b INSERM U862, Avenir group Physio- pathology of Energy Balance and Obesity, Universite ´ de Bordeaux 2, Bordeaux, France and c Karolinska Institutet-Clinical Neuroscience, Karolinska University, Hospital Huddinge, Stockholm, Sweden Correspondence to Leonard C. Schalkwyk, PhD, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Box P082 De Crespigny Park, London SE5 8AF, UK Tel: +44 0 207 848 0279; fax: +44 0 207 848 0866; e-mail: Leonard.schalkwyk@kcl.ac.uk *Elke Binder and Karim Malki have contributed equally to this study. Received 10 June 2011 Accepted 23 July 2011 Introduction The most popularly prescribed class of antidepressant drugs is the selective serotonin reuptake inhibitor (SSRI), represented in this study by the drug escitalo- pram. Individual response to SSRIs is highly hetero- geneous, with up to half of the treated patients finding no relief or only partial relief from their symptoms [1]. Moreover, many patients have reported low tolerabil- ity [2]. Therefore, a variety of alternative antidepressant drugs can be prescribed in the hope of increasing efficacy or tolerance. These include second-generation tricyclics, such as nortriptyline (a noradrenaline reuptake inhibitor). The genetic and environmental etiologies of individual differences moderating the response and tolerance to common antidepressant medications remain largely un- known. It is, therefore, important to investigate the behavioural differences in drug response in connection with environmental factors and genetic background. This will lead to better prediction of drug response and a reduction in the lag time produced by the current trial- and-error procedure. Various attempts have been made to generate animal models of depression [3]. One strategy is to use selectively bred lines of rats or mice [4,5] and another is to use proto- cols such as unpredictable chronic mild stress (UCMS) and maternal separation (MS) to induce depression- related behaviour in healthy animals. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pharmacogeneticsandgenomics.com). Original article 779 1744-6872  c 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/FPC.0b013e32834b3f35 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.