Repeated Administration of D-Amphetamine Induces Distinct Alterations in Behavior and Metabolite Levels in 129Sv and Bl6 Mouse Strains

ORIGINAL RESEARCH published: 12 June 2018 doi: 10.3389/fnins.2018.00399 Repeated Administration of D-Amphetamine Induces Distinct Alterations in Behavior and Metabolite Levels in 129Sv and Bl6 Mouse Strains Taavi Vanaveski 1,2 , Jane Narvik 1,2*, Jürgen Innos 1,2 , Mari-Anne Philips 1,2 , Aigar Ottas 2,3 , Mario Plaas 2,4 , Liina Haring 2,5 , Mihkel Zilmer 2,3 and Eero Vasar 1,2 1 Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia, 2 Center of Excellence for Genomics and Translational Medicine, University of Tartu, Tartu, Estonia, 3 Department of Biochemistry, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia, 4 Psychiatry Clinic and Center of Excellence for Genomics and Translational Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia, 5 Psychiatry Clinic, Tartu University Hospital, Tartu, Estonia Edited by: Haim Einat, Academic College Tel Aviv-Yaffo, Israel Reviewed by: Brandon Warren, National Institute on Drug Abuse (NIDA), United States Shlomit Flaisher-Grinberg, Saint Francis University, United States *Correspondence: Jane Narvik Specialty section: This article was submitted to Neuropharmacology, a section of the journal Frontiers in Neuroscience Received: 02 April 2018 Accepted: 24 May 2018 Published: 12 June 2018 Citation: Vanaveski T, Narvik J, Innos J, Philips M-A, Ottas A, Plaas M, Haring L, Zilmer M and Vasar E (2018) Repeated Administration of D-Amphetamine Induces Distinct Alterations in Behavior and Metabolite Levels in 129Sv and Bl6 Mouse Strains. Front. Neurosci. 12:399. doi: 10.3389/fnins.2018.00399 The main goal of the study was to characterize the behavioral and metabolomic profiles of repeated administration (for 11 days) of d-amphetamine (AMPH, 3 mg/kg i. p.), indirect agonist of dopamine (DA), in widely used 129S6/SvEvTac (129Sv) and C57BL/6NTac (Bl6) mouse strains. Acute administration of AMPH (acute AMPH) induced significantly stronger motor stimulation in Bl6. However, repeated administration of AMPH (repeated AMPH) caused stronger motor sensitization in 129Sv compared acute AMPH. Body weight of 129Sv was reduced after repeated saline and AMPH, whereas no change occurred in Bl6. In the metabolomic study, acute AMPH induced an elevation of isoleucine and leucine, branched chain amino acids (BCAA), whereas the level of hexoses was reduced in Bl6. Both BCAAs and hexoses remained on level of acute AMPH after repeated AMPH in Bl6. Three biogenic amines [asymmetric dimethylarginine (ADMA), alpha-aminoadipic acid (alpha-AAA), kynurenine] were significantly reduced after repeated AMPH. Acute AMPH caused in 129Sv a significant reduction of valine, lysophosphatidylcholines (lysoPC a C16:0, lysoPC a C18:2, lysoPC a C20:4), phosphatidylcholine (PC) diacyls (PC aa C34:2, PC aa C36:2, PC aa C36:3, PC aa C36:4) and alkyl-acyls (PC ae C38:4, PC ae C40:4). However, repeated AMPH increased the levels of valine and isoleucine, long-chain acylcarnitines (C14, C14:1-OH, C16, C18:1), PC diacyls (PC aa C38:4, PC aa C38:6, PC aa C42:6), PC acyl-alkyls (PC ae C38:4, PC ae C40:4, PC ae C40:5, PC ae C40:6, PC ae C42:1, PC ae C42:3) and sphingolipids [SM(OH)C22:1, SM C24:0] compared to acute AMPH in 129Sv. Hexoses and kynurenine were reduced after repeated AMPH compared to saline in 129Sv. The established changes probably reflect a shift in energy metabolism toward lipid molecules in 129Sv because of reduced level of hexoses. Pooled data from both strains showed that the elevation of isoleucine and leucine was a prominent biomarker of AMPH-induced behavioral sensitization. Simultaneously a significant decline of hexoses, citrulline, ADMA, Frontiers in Neuroscience | www.frontiersin.org 1 June 2018 | Volume 12 | Article 399 Vanaveski et al. Amphetamine Induced Metabolomic Changes and kynurenine occurred. The reduced levels of kynurenine, ADMA, and citrulline likely reflect altered function of N-methyl-D-aspartate (NMDA) and NO systems caused by repeated AMPH. Altogether, 129Sv strain displays stronger sensitization toward AMPH and larger variance in metabolite levels than Bl6. Keywords: amphetamine, repeated administration, locomotor activity, behavioral sensitization, 129Sv strain, Bl6 strain, metabolomics, branched chain amino acids INTRODUCTION Freissmuth, 2015). AMPH exerts its actions through an increase in DA extracellular levels in the terminal and cell body regions of midbrain DA neurons, by causing reverse transport of DA and preventing its uptake via the DA transporter (Seiden et al., 1993; Sulzer et al., 1995). Repeated administration of AMPH has been used to model psychotic-like behavior in rodents (Ham et al., 2017). The majority of studies evaluating the development of AMPH-induced motor sensitization have been performed in rats. Repeated AMPH administration to adult rats produced robust sensitization toward AMPH, disrupted latent inhibition, and decreased attentional vigilance; this effect lasted for 90 days after the last injection (Murphy et al., 2001; Russig, 2002; Russig et al., 2003; Ham et al., 2017). Even though deficits in the attention set-shifting task were observed, spatial memory was not impaired in the Morris water maze, indicating that cognitive impairments in the model appear to be restricted to some prefrontal cortex dependent tasks (Stefani and Moghaddam, 2002; Featherstone et al., 2008). So far few studies have been performed to examine mouse strain differences in behavioral sensitization to AMPH (Phillips et al., 2008). In comparison to Bl6, DBA/2 mice were more receptive to the development of motor sensitization (Badiani et al., 1992; Phillips et al., 1994). Despite extensive biomedical comparisons of 129Sv and Bl6 strains, we could not find any comprehensive studies comparing the effects of repeated AMPH in these two strains. Therefore, we hypothesize that these two mouse strains respond differently to repeated AMPH in terms of behavior and metabolomics. Based on above described data of DBA/2 mice we expect that 129Sv mice display stronger sensitization toward AMPH-induced hyper-locomotion compared to Bl6 strain. Previously, we have found the significant differences in the blood metabolite levels in Bl6 and 129Sv mice (Narvik et al., 2018). Thus, we expected to see significant differences in metabolite levels between these two mouse strains in response to repeated AMPH as well, especially in the levels of hexoses and lipid metabolites that are necessary to fuel the strong locomotor response. First, we aimed to study the effect of repeated AMPH on the locomotor activity of 129Sv and Bl6 strains. Simultaneously, changes in body weight were evaluated during repeated administrations. To study the effect of AMPH, both 129Sv and Bl6 mice were divided into three groups (Figure 1). The control group received saline injections for 11 days, the acute group received 10 days of saline, (...truncated)