Dopamine-rich grafts alleviate deficits in contralateral response space induced by extensive dopamine depletion in rats

Abstract

Unilateral infusion of 6-hydroxydopamine into the nigro-striatal pathway in the rat is the most common dopamine lesion model of Parkinson's disease. In the present study, we explore the impact of near complete unilateral loss of dopamine along the nigro-striatal pathway and subsequent cell replacement therapy in a choice reaction time task in rats, with assessment of spatial responding towards either side of the body (ipsilateral or contralateral to the lesion) on alternate days. Results indicated a stable contralateral deficit in response accuracy, reaction times and motor function for 50 consecutive days of testing, with no signs of recovery or compensation. All lesioned rats developed a near-hole bias and displayed prolonged movement and reaction times when responses had to be directed towards a distal response location on the side of the body contralateral to the lesion, as well as a smaller ipsilateral impairment in response accuracy and movement times. Grafts of dopamine-rich tissue into the denervated striatum improved some, but not all, of the deficits induced by the lesion. Specifically, grafted rats performed at a similar level to control animals when assessed on the ipsilateral side, they demonstrated a partial restitution of their ability to respond to far contralateral stimuli, and they exhibited a marked reduction in the time to complete all lateralised responses on both sides. The present characterisation of the task and the effects of cell replacement via primary fetal mesencephalic tissue demonstrate restorative properties in alleviating the marked spatial response bias induced by unilateral loss of dopamine.