Behavioural Brain Research 223 (2011) 169–175 Contents lists available at ScienceDirect Behavioural Brain Research j ourna l ho mepage: www.elsevier.com/locate/bbr Research report Serotonin transporter genotype x construction stress interaction in rats Pieter Schipper a,b , Lourens J.P. Nonkes b , Peter Karel b , Amanda J. Kiliaan a,b , Judith R. Homberg b,∗ a Department of Anatomy, Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands b Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands a r t i c l e i n f o Article history: Received 22 March 2011 Received in revised form 13 April 2011 Accepted 20 April 2011 Keywords: Serotonin transporter Knockout Construction Stress Emotion Cognition a b s t r a c t A well-known example for gene x environment interactions in psychiatry is the one involving the low activity (s) allelic variant of the serotonin transporter (5-HTT) promoter polymorphism (5-HTTLPR) that in the context of stress increases risk for depression. In analogy, 5-HTT knockout rodents are highly responsive to early life, but also adult external stressors, albeit conflicting data have been obtained. In our study on emotion and cognition using homozygous 5-HTT knockout (5-HTT -/- ) and wild-type (5-HTT +/+ ) rats we have been confronted with animal facility construction, which were asso- ciated with severe lifetime stress (noise and vibrations). To assess the impact of construction stress on well-established 5-HTT -/- rat phenotypes we conducted ad hoc analyses of 5-HTT -/- and 5-HTT +/+ rats that grew up before and during the construction. The reproductive capacity of the parents of the experimental 5-HTT +/- rats was significantly decreased. Further, 5-HTT -/- anxiety-related pheno- types in the elevated plus maze and social interaction tests were abolished after construction noise exposure, due to increased anxiety in 5-HTT +/+ rats and decreased anxiety in 5-HTT -/- rats (social interaction test only). In addition, reversal learning was improved in 5-HTT +/+ and, to a milder extent, decreased in 5-HTT -/- rats. Finally, construction stress genotype-independently increased behavioural despair in the forced swim test. In conclusion, severe construction stress induces 5-HTT genotype- dependent ‘for-better-and-for-worse’ effects. These data importantly contribute to the understanding of 5-HTT gene x environment interactions and show the risk of losing genotype effects by construction stress. © 2011 Elsevier B.V. All rights reserved. 1. Introduction In psychiatry it has been well established that both genetic and environmental factors shape brain and behaviour. Therefore, psychiatric genetics is devoted to unravel the nature of gene x environment interactions and their underlying mechanisms. One common genetic factor that strongly interacts with environmen- tal stimuli is the serotonin transporter (5-HTT) linked polymorphic region (5-HTTLPR). Caspi et al. [1] reported that individuals carrying the low activity short (s) allelic variant of the 5-HTTLPR, as opposed to the long (l) variant, were at risk to develop depression when exposed to adverse psychosocial stressors in early life. This obser- vation has been replicated in a recent meta-analysis [2], although a Abbreviations: 5-HTT, serotonin transporter; 5-HTT -/- , homozygous serotonin transporter knockout; 5-HTT -/+ , heterozygous serotonin transporter knockout; 5- HTT +/+ , wild-type; 5-HTTLPR, serotonin transporter-linked polymorphic region; s, 5-HTTLPR short allele. ∗ Corresponding author at: Radboud University Nijmegen Medical Centre, Geert Grooteplein 21 (route 126), 6525 EZ Nijmegen, The Netherlands, Tel.: +31 24 3610906; fax: +31 24 3541435. E-mail address: j.homberg@cns.umcn.nl (J.R. Homberg). previous meta-analysis was unable to find evidence for 5-HTTLPR x stress interactions [3]. Nonetheless, experiments with non-human primates and rodents by using designs with stronger internal valid- ity (control environmental stimuli) have confirmed the 5-HTTLPR gene x environment hypothesis [4–9]. Hence, 5-HTTLPR gene x environment interactions are robust, generalize across species, and therefore serve as an example for gene x environment interactions in psychiatry. While rodents do not bear an orthologue of the 5-HTTLPR, genetic ablation of the 5-HTT in mice and rats has been associ- ated with anxiety- and depression-like symptoms that resemble those seen in stressed 5-HTTLPR s-allele carriers [10]. There is increasing evidence that particularly heterozygous 5-HTT knockout (5-HTT +/- ) mice respond to prenatal, early life and adult psychoso- cial stress [11–13], as seen in s-allele carriers. Yet, it also has been documented that homozygous 5-HTT knockout (5-HTT -/- ) mice are most responsive to olfactory cues of unfamiliar males (signaling danger) during pregnancy and the lactating period, and loser expe- rience in a resident-intruder test during adulthood in anxiety tests [14,15]. Collectively these data indicate that 5-HTT genotype inter- acts with a variety of stressors across lifespan, but to fully establish the nature of 5-HTT GXE interactions in rodents additional studies are required. 0166-4328/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2011.04.037