EFFECT OF BILATERAL 6-OHDA LESIONS OF THE SUBSTANTIA-NIGRA ON LOCOMOTOR-ACTIVITY IN THE RAT

Previous parkinsonian rat models have utilized stereotactic 6-OHDA inj ections to completely lesion the dopaminergic mesostriatal system on o ne side. Recently, hemiparkinsonian rat models in which the mesolimbic system is left intact have been developed. The selective, partial les ion models better mimic the neuropathology of human parkinsonism in wh ich there is usually an incomplete destruction of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and a relative sparing o f ventral tegmental area (VTA) cell groups. However, such hemiparkinso nian models which possess dopaminergic asymmetry cannot demonstrate br adykinesia, one of the main symptoms in human parkinsonism. Meanwhile, bilateral lesions of the ascending forebrain dopaminergic system have been reported to induce severe aphagia, adipsia and akinesia. We, the refore, undertook development of a bilateral partial SNpc lesion model which also spares the VTA on both sides. We have investigated spontan eous locomotor activities as well as amphetamine, apomorphine and levo dopa induced activities during a subchronic period of up to 27 days af ter the bilateral lesion. Three activity parameters, i.e. horizontal a ctivity, vertical activity and distance traveled, were measured. The r elationship between dopamine neuron loss in the SNpc and changes in th e locomotor activity was analyzed. Spontaneous activity was significan tly decreased in animals with extensive (> 80%) SNpc lesions on both s ides. Animals with a > 95% lesion were severely aphagia and adipsia. R esponses to amphetamine and apomorphine were variable. It is possible that in some cases the bilateral SNpc neurons were not equally damaged , which could cause the enhanced rotational behavior. Bradykinetic rat s displayed on the average, a > 20% decline in horizontal activity, a > 40% decline in vertical activity and a > 30% decline in distance tra veled after the lesion. These bradykinetic rats consistently showed a marked increase in activity in response to levodopa therapy as observe d in human parkinsonian patients. The results indicate that rats with bilateral partial lesions of the SNpc may be useful for the evaluation of new therapeutic approaches for treating Parkinson's disease.