Sexually dimorphic dopaminergic dysfunction in a transgenic mouse model of Huntington's disease

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.