Two different putative genetic animal models of childhood depression—A review O. Malkesman a, *, A. Weller b a Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA b Department of Psychology and the Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel Contents 1. Introduction ..................................................................................................... 154 1.1. Childhood depression ........................................................................................ 154 1.2. Genetic animal models of depression ........................................................................... 154 2. Putative genetic animal models of childhood depression ................................................................. 155 2.1. Face validity ............................................................................................... 155 2.1.1. Swim test .......................................................................................... 155 2.1.2. Weight disorders .................................................................................... 155 2.1.3. Social play ......................................................................................... 156 2.1.4. Reward and childhood depression ...................................................................... 157 2.1.5. Anxiety and depression ............................................................................... 158 2.2. Construct validity ........................................................................................... 159 2.2.1. Monoamines and depression........................................................................... 159 2.2.2. Dehydroepiandrosterone (DHEA) and depression .......................................................... 160 Progress in Neurobiology 88 (2009) 153–169 ARTICLE INFO Article history: Received 27 August 2008 Received in revised form 27 January 2009 Accepted 12 March 2009 Keywords: Childhood depression Animal models FSL WKY Rats ABSTRACT Estimated prevalence of childhood and adolescent depression varies from 0.4% to 3% at the 0–12 age range and 3.3% to 12.4% at the 13–18 age range. Despite similarities in the clinical picture of major depression in children, adolescents, and adults, there are notable differences in the neurobiological correlates and treatment response of depressed patients in these different age cohorts. In contrast to adults, most depressed children fail to respond to antidepressants. The main aim of this paper is to review several studies which attempt to develop and examine genetic animal models for childhood depression, in order to enable a search for new, unique treatment approaches for depressed children. Two different ‘‘depressive-like’’ rat strains were studied: Flinders Sensitive Line (FSL) and their controls, Sprague–Dawley (SD) rats; and the Wistar Kyoto (WKY) strain and their controls, Wistar rats. The results suggest that prepubertal FSL and WKY rats exhibit different styles of depressive behavior, one co-morbid with ‘‘anxiety-like’’ behavior (WKY), and one that is not (FSL). These two profiles may model clinical characteristics that resemble two subgroups of depressed children. However, in general the data on the WKY rats would seem most consistent with a classic childhood depressive profile. The FSL profile may possibly be related to chronic stress, and its role as a potential model of childhood depression requires further support. These two different putative genetic animal models of childhood depression can help in the attempts to understand the neurobiological basis and to predict successful treatment strategies for different patterns of childhood psychopathology. Published by Elsevier Ltd. Abbreviations: 5HIAA, 5-hydroxyundoleactic acid; 5HT, 5-hydroxytriptamine; ACTH, adrenocorticotropic hormone; BDNF, brain derived neurotropic factor; CMS, chronic mild stress; CORT, corticosterone; CPP, conditioned place preference; CRF, corticotropin releasing factor; CRH, corticotropin releasing hormone; CSF, cerebrospinal fluid; DA, dopamine; DG, dentate gyrus; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; DOPA, 3,4-dihydroxy-phenylalanine; DOPAC, dihydroxypheny- lacetic acid; DSM, Diagnostic and Statistical Manual of Mental Disorders; EEG, electorencephalogram; FDA, Food and Drug Administration; FRL, Flinders Resistant Line; FSL, Flinders Sensitive Line; GAD, generalized anxiety disorder; HPA, hypothalamic–pituitary–adrenal; MMD, major depressive disorder; NA, noradrenaline; Nac, nucleus accumbens; NE, norepinephrine; PND, post natal day; PVN, paraventicular nucleus; REM, rapid eye movement; SD, Sprague–Dawley; SSRI, selective serotonin reuptake inhibitor; Trk, tyrosine kinase; TSH, thyroid stimulating hormone; VTA, ventral tegmental area; WKY, Wistar Kyoto. * Corresponding author. Tel.: +1 301 443 6541; fax: +1 301 480 0123. E-mail address: malkesmano@mail.nih.gov (O. Malkesman). Contents lists available at ScienceDirect Progress in Neurobiology journal homepage: www.elsevier.com/locate/pneurobio 0301-0082/$ – see front matter . Published by Elsevier Ltd. doi:10.1016/j.pneurobio.2009.03.003