Sexually dimorphic dopaminergic dysfunction in a transgenic mouse model of Huntington's disease Thibault Renoir a, ⁎, Andrew Argyropoulos a,b , Caroline Chevarin c,d , Laurence Lanfumey c,d , Anthony J. Hannan a,b a Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Australia b Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Australia c Inserm UMR S894, F-75013 Paris, France d UPMC, University of Paris 06, UMR S894, F-75013 Paris, France abstract article info Article history: Received 16 June 2014 Received in revised form 2 October 2014 Accepted 6 October 2014 Available online 12 October 2014 Keywords: Huntington's disease Locomotor activity Dopamine Sex differences Bupropion Tandem repeat disorder Background: Using the R6/1 transgenic mouse model of Huntington's disease (HD), we have recently shown that acute administration with the dopamine–norepinephrine reuptake inhibitor bupropion was able to rescue depressive-like behaviours in female HD mice at 12 weeks of age. Objective: In this present study, we aimed to further investigate the dopamine system as well as specifically measure dopamine transporter (DAT) and D1 receptor function in female versus male R6/1 HD mice at a very early stage of the disease. Methods: We assessed the effects of acute administration of bupropion and the dopamine D1 receptor agonist SKF-8129 on spontaneous locomotor activity in 8-week-old HD and wild-type (WT) mice. We also measured dopamine levels in striatum via high performance liquid chromatography (HPLC). Results: We found that female (but not male) HD mice were hyposensitive to bupropion when compared to WT littermates. However, both female and male HD mice were less sensitive to SKF-81297 locomotor effects. We also found that striatal dopamine levels and dopamine turnover were reduced in HD animals, regardless of sex. Conclusion: Our present findings suggest that whereas only female HD mice exhibit an impaired response to bupropion, dopamine D1 receptor function is altered in both female and male HD animals. These data are the first in vivo evidence of impaired dopamine D1 receptor-dependent function in pre-motor symptomatic HD mice suggesting that this is a candidate target for early therapeutic interventions. © 2014 Elsevier Inc. All rights reserved. 1. Introduction Huntington's disease (HD) is an autosomal dominant neurodegener- ative disorder caused by an abnormal expansion of CAG repeats in exon 1 of the huntingtin gene (The Huntington's Disease Collaborative Research Group, 1993). HD encompasses a triad of psychiatric, cognitive and motor dysfunctions. The majority of HD mutation carriers experi- ence some psychopathology during their lifetime (van Duijn et al., 2014), including mood disturbances such as depression, anxiety and ir- ritability, which often start before the onset of motor symptoms (Pla et al., 2014). We have previously discovered that expression of the mu- tant huntingtin gene was sufficient to cause depression-like behaviours in an animal model of HD, R6/1 transgenic mice (Grote et al., 2005; Pang et al., 2009; Renoir et al., 2012). Another interesting finding was that female – and not male – R6/1 HD mice exhibited a depressive-like phe- notype (Pang et al., 2009; Renoir et al., 2011). We have previously identified dysregulation in serotonin signalling as possibly underlying the HD mutation-induced depression-like behaviours (Pang et al., 2009; Renoir et al., 2011). However, early neurochemical changes relat- ed to the dopamine (DA) system could also be the cause of the neuro- psychiatric symptoms preceding the locomotor impairment. Indeed, clinical data indicate that dopaminergic dysfunction is common in both symptomatic and pre-manifest HD gene carriers (Andrews et al., 1999; Ginovart et al., 1997; Pavese et al., 2010) suggesting that this early event in HD pathophysiology could contribute to neuropsychiatric disorders. Animal studies have also reported reduction in specific dopa- mine receptors in HD mice associated with the onset of locomotor symptoms (Bibb et al., 2000; Cha et al., 1998). Alterations in dopaminer- gic signalling may underlie early cognitive and affective dysfunction in HD (Cummings et al., 2006; Dallerac et al., 2011). However, there is yet to be a study assessing dopamine signalling function in female versus male HD mice at an early stage of the disease. In that context, the present study aimed to functionally investigate the dopaminergic system of asymptomatic R6/1 HD mice (8-week-old fe- male and male animals) measuring the effect of bupropion (a dopamine reuptake inhibitor) as well as the dopamine D1 receptor agonist, SKF- 81297, on locomotor activity. Pharmacology, Biochemistry and Behavior 127 (2014) 15–20 ⁎ Corresponding author at: Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, VIC 3010, Melbourne, Australia. Tel.: + 61 3 9035 6614; fax: + 61 3 9035 3107. E-mail addresses: thibault.renoir@unimelb.edu.au, tibo.renoir@gmail.com (T. Renoir). http://dx.doi.org/10.1016/j.pbb.2014.10.004 0091-3057/© 2014 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh