Antidepressant-like effect of the norepinephrine-dopamine reuptake inhibitor bupropion in a mouse model of Huntington's disease with dopaminergic dysfunction

Background: The pre-motor stages of Huntington's disease (HD) are commonly associated with psychiatric manifestations including depression. Recent clinical data indicate that dopaminergic dysfunction is common in both symptomatic and pre-manifest HD gene carriers. There is also increasing evidence implicating catecholamine dysfunction in the pathophysiology of depression. Objective: In this study, we aimed to functionally investigate the dopaminergic system in the R6/1 mouse model of HD prior to onset of motor symptoms. Methods: We assessed the effects of acute administration of bupropion (a dopamine-norepinephrine reuptake inhibitor) on spontaneous locomotor activity and depression-like behaviour (using the forced-swim test). Results: Here we show that the bupropion-induced increased locomotor activity found in wild-type animals was no longer observed in HD mice. We also found that acute administration with bupropion rescued depressive-like behaviours in HD animals, possibly through dopamine D2/D3 receptor mechanisms. Conclusion: Our present data are the first in vivo evidence of an impaired dopamine D1 receptor-dependent function in pre-motor symptomatic R6/1 HD mice. Moreover, our findings suggest clinical potential for bupropion to alleviate depressive symptoms in HD.