Lipopolysaccharide-induced anhedonia is abolished in male serotonin transporter knockout rats: An intracranial self-stimulation study Floor van Heesch a,⇑ , Jolanda Prins a , Jan Pieter Konsman b , Koen G.C. Westphal a , Berend Olivier a , Aletta D. Kraneveld a , S. Mechiel Korte a a Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Faculty of Science, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands b Psychoneuroimmunology, Nutrition and Genetics, Victor Segalen Bordeaux 2 University, Bordeaux, France article info Article history: Received 21 September 2012 Received in revised form 4 December 2012 Accepted 19 December 2012 Available online 28 December 2012 Keywords: Serotonin transporter knockout Depression Anhedonia Lipopolysaccharide Intracranial self-stimulation Body weight abstract A growing body of evidence suggests that pro-inflammatory cytokines contribute to the pathogenesis of depression. Previously, it has been shown that cytokines (e.g. interferon-a therapy) induce major depres- sion in humans. In addition, administration of the cytokine-inducer lipopolysaccharide (LPS) provokes anhedonia (i.e. the inability to experience pleasure) in rodents. Furthermore, serum pro-inflammatory cytokine levels are increased in depressed patients. Nevertheless, the etiology of cytokine-induced depression is largely unknown. Previously, it has been shown that selective serotonin re-uptake inhibi- tors decrease serum pro-inflammatory cytokine levels and that pro-inflammatory cytokines increase activity of the serotonin transporter (SERT). The purpose of this study was to explore the effect of partial and complete lack of the SERT in LPS-induced anhedonia assessed in the intracranial self-stimulation (ICSS) paradigm. A single intraperitoneal injection of LPS was used to induce a pro-inflammatory immune response in male serotonin transporter wild type (SERT +/+ ), heterozygous (SERT +/À ) and knockout (SERT À/ À ) rats. Body weight and ICSS thresholds were measured daily. Although LPS reduced body weight in all genotypes, loss of body weight was less pronounced in SERT À/À compared to SERT +/+ rats. Remarkably, LPS-induced anhedonia was totally abolished in SERT À/À rats and as expected was still present in SERT +/+ and to a lesser extent in SERT +/À rats. Therefore, it is concluded that an intact SERT function is needed for pro-inflammatory cytokine-induced anhedonia and weight loss in rats. Ó 2013 Elsevier Inc. All rights reserved. 1. Introduction Major depressive disorder (MDD) is a complex disorder affect- ing 121 million people worldwide. Although, according to the World Health Organization depression is among the leading causes of disability, the exact etiology is largely unknown. Since the mid- seventies there is a growing body of evidence that reciprocal path- ways between immune, endocrine and central nervous system are not only involved in physical health, but also in mental health. In this respect, there is an increasing interest in the putative involve- ment of the immune system in depression, especially in depression due to a general medical condition (Dantzer, 2009; Dantzer et al., 2008; Konsman et al., 2002). This hypothesis is supported by the following findings: first of all, it was shown that the cytokines IFN-a and IL-2, used effectively as therapy for hepatitis C and can- cer, increase the risk for the development of depression (Capuron et al., 2004; Heinze et al., 2010; Renault et al., 1987). Secondly, although the possibility that cytokines are also related to major depression in the absence of a medical condition has been debated, a recent meta-analysis concludes that the pro-inflammatory cyto- kines TNF-a and IL-6 are increased in serum of depressed patients (Dowlati et al., 2010). Furthermore, it has been demonstrated that lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria that binds to toll-like receptor 4 (TRL4) leading to the rapid systemic release of pro-inflammatory cyto- kines, induces anhedonia in rats and mice as shown by increased thresholds in an intracranial self-stimulation (ICSS) paradigm (Borowski et al., 1998; Prins et al., 2011; van Heesch et al., 2012). Anhedonia is a core symptom of MDD and characterized by the inability to experience pleasure probably caused by reduced ability to experience reward. Selective serotonin reuptake inhibitors (SSRIs) are the most pre- scribed antidepressants worldwide. Therefore the role of serotonin (5-HT) and the serotonin transporter (SERT) have been studied intensively in depression and an important role for altered seroto- nergic neurotransmission in MDD has been proposed (Albert et al., 2012). The SERT regulates 5-HT availability in the synaptic cleft and is therefore important in 5-HT driven processes. It was shown that inhibition of SERT by SSRIs suppresses pro-inflammatory cyto- kine production by T helper 1 (T H1 ) cells in whole blood ex vivo (Diamond et al., 2006; Taler et al., 2007) and decreases serum 0889-1591/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bbi.2012.12.013 ⇑ Corresponding author. Tel.: +31 6 202 74 192; fax: +31 30 253 7900. E-mail address: F.vanHeesch@uu.nl (F. van Heesch). Brain, Behavior, and Immunity 29 (2013) 98–103 Contents lists available at SciVerse ScienceDirect Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi