Acute tryptophan depletion in C57BL/6 mice does not induce central serotonin reduction or affective behavioural changes Eva L. van Donkelaar a,e, *, Arjan Blokland b,e , Cindy K.J. Lieben a , Gunter Kenis a,e , Linda Ferrington c , Paul A.T. Kelly d , Harry W.M. Steinbusch a,e , Jos Prickaerts a,e a Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands b Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands c Centre for Cognitive and Neural Systems, University of Edinburgh, Edinburgh, United Kingdom d Cerebrovascular Research Laboratory, Centre for Cognitive and Neural Systems, University of Edinburgh, Edinburgh, United Kingdom e European Graduate School of Neuroscience (‘EURON’), The Netherlands Although depression is a heterogeneous disorder with complex molecular pathophysiological mechanisms, a dysfunctional ser- otonergic neurotransmitter system is widely accepted to be one of the main factors underlying the development of depressive symptomatology (Asberg et al., 1976a; Meltzer, 1990; Leonard, 2007). Direct evidence comes from human studies associating depressive symptoms with abnormal physiological parameters related to the serotonergic system (Risch and Nemeroff, 1992). Depressed patients often display disturbances in 5-HT metabolism (van Praag and de Haan, 1979) as indicated by decreased peripheral levels of tryptophan (TRP; Cowen et al., 1989), the dietary precursor of serotonin (5-hydroxytryptamine, 5-HT), and diminished levels of 5-hydroxyindoleacetic acid (5-HIAA; Asberg et al., 1976b), an inactive 5-HT degradation product. Drugs successfully used in the treatment of depression provide direct evidence for the important role of disrupted function of specific pre- and post-synaptic receptors underlying the impaired 5-HT neurotransmission linked to depressive symptomatology (Naugh- ton et al., 2000). Moreover, variations in genes that regulate the 5- HT system appear to play an important role in the probability of onset and recurrence of depressive episodes and other affective disorders (Caspi et al., 2003; Levinson, 2006). Therefore, the aetiology of depression is thought to be strongly related to specific factors that predispose subjects to a dysfunctional 5-HT system (Booij and Van der Does, 2007; Jans et al., 2007b). The implication of the 5-HT system and serotonergic vulner- ability in the onset of depressive symptomatology is being Neurochemistry International 56 (2010) 21–34 ARTICLE INFO Article history: Received 14 July 2009 Accepted 24 August 2009 Available online 28 August 2009 Keywords: Amino acids Anxiety Depression Mouse Plasma tryptophan Serotonergic challenge ABSTRACT Acute tryptophan depletion is extensively used to investigate the implication of serotonin in the onset of depressive disorders. In rats, it lowers peripheral tryptophan and decreases central serotonin concentrations. We aimed to establish the rat model of acute tryptophan depletion in the mouse for potential application as serotonin challenge tool in genetic mouse models of depression. Pharmaco- kinetic and behavioural effects of a tryptophan-free diet were examined in Swiss and C57BL/6 mice. Peripheral amino acids were measured and central tryptophan and serotonin concentrations were compared with anxiety and depression-like behaviour in the elevated zero-maze, forced swimming test or tail suspension test. While acute tryptophan depletion resulted in a 74% reduction of the plasma ratio tryptophan to the sum of other large neutral amino acids in Swiss mice 1 h after administration (2 Â 10 ml/kg, 30 min interval), there was only a 40% reduction in C57BL/6 mice. The latter did not show anxiety in the elevated zero-maze or increased immobility in the forced swimming test or tail suspension test. A higher dose (2 Â 20 ml/kg) with a longer interval (60 min) reduced the ratio with 68% in C57BL/6 mice, lowered hippocampal serotonin turnover and had no functional effect when tested in the elevated zero-maze and forced swimming test. These findings have important implications for the use of acute tryptophan depletion in general and in particular for its application in mice. Although in healthy mice no clear central serotonin or functional effects were observed, further research is indicated using mice with pre-existing serotonin dysfunction, as they might be more vulnerable to acute tryptophan depletion. ß 2009 Elsevier Ltd. All rights reserved. * Corresponding author at: Department of Neuroscience, Section Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Tel.: +31 43 3881021; fax: +31 43 3671096. E-mail address: eva.vandonkelaar@np.unimaas.nl (E.L. van Donkelaar). Contents lists available at ScienceDirect Neurochemistry International journal homepage: www.elsevier.com/locate/neuint 0197-0186/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuint.2009.08.010