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 injections to completely lesion the dopaminergic mesostriatal system on one side. Recently, hemiparkinsonian rat models in which the mesolimbic system is left intact have been developed. The selective, partial lesion models better mimic the neuropathology of human parkinsonism in which there is usually an incomplete destruction of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and a relative sparing of ventral tegmental area (VTA) cell groups. However, such hemiparkinsonian models which possess dopaminergic asymmetry cannot demonstrate bradykinesia, 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, therefore, undertook development of a bilateral partial SNpc lesion model which also spares the VTA on both sides. We have investigated spontaneous locomotor activities as well as amphetamine, apomorphine and levodopa induced activities during a subchronic period of up to 27 days after the bilateral lesion. Three activity parameters, i.e. horizontal activity, vertical activity and distance traveled, were measured. The relationship between dopamine neuron loss in the SNpc and changes in the locomotor activity was analyzed. Spontaneous activity was significantly decreased in animals with extensive (> 80%) SNpc lesions on both sides. Animals with a > 95% lesion were severely aphagia and adipsia. Responses 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 rats displayed on the average, a > 20% decline in horizontal activity, a > 40% decline in vertical activity and a > 30% decline in distance traveled after the lesion. These bradykinetic rats consistently showed a marked increase in activity in response to levodopa therapy as observed 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.