A Clinically Relevant Unilateral Rat Model of Parkinsonian Akinesia

In transplantation research on Parkinson's disease, behavioral evidence of graft-specific improved function is as necessary as anatomical or chemical data in evaluating the success of the procedure. The circling model of Ungerstedt has been widely adopted to provide such evidence, in part because it is so convenient and (relative to primate models) inexpensive. In this model 6-hydroxydopamine (6-OHDA) is used to deplete nigrostriatal dopamine (DA) unilaterally. A reduction of the contraversive circling induced by the DA receptor agonist apomorphine or of the ipsiversive circling induced by amphetamine has been useful as a screen to test the integrity of grafts. However, it would be more compelling if the model included akinesia, one of the most disruptive symptoms of the disease. In addition, the model should reflect the clinical finding that akinesia becomes increasingly resistant to DAergic agonists, particularly in the severe later stages of parkinsonism. In the unilateral 6-OHDA rat, DA-agonist induced circling is actually more vigorous when the depletion of DA is more severe. Moreover, during circling behavior all limbs make stepping movements, even the limbs contralateral to the DA depletion in an undrugged animal (thus, there is no obvious akinesia). In this study, we describe a method of examining behavior in unilateral 6-OHDA rats which addresses these concerns. When stepping behavior in the contralateral forelimb of unilateral 6-OHDA-treated rats was tested in isolation, severe and chronic akinesia was found in that limb. That is, when the hind-quarters and ipsilateral forelimb were raised off the ground so that the contralateral forelimb alone supported the weight of the animal, the contralateral forelimb failed to step. Occasional trembling could be observed in the limb, but no more than a few small steps were ever initiated.