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Keywords:

  • 6-hydroxydopamine;
  • bursting activity;
  • cortical oscillations;
  • Parkinsonism;
  • rat;
  • stepping test;
  • substantia nigra pars reticulata

Abstract

Severe chronic dopamine (DA) depletion increases the proportion of neurons in the basal ganglia that fire rhythmic bursts of action potential (LFO units) synchronously with the cortical oscillations. Here we report on how different levels of mesencephalic DA denervation affect substantia nigra pars reticulata (SNpr) neuronal activity in the rat and its relationship to akinesia (stepping test). Chronic nigrostriatal lesion induced with 0 (control group), 4, 6 or 8 µg of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle resulted in a dose-dependent decrease of tyrosine hydroxylase positive (TH+) neurons in the SN and ventral tegmental area (VTA). Although 4 µg of 6-OHDA reduced the number of TH+ neurons in the SN by ∼60%, both stepping test performance and SNpr neuronal activity remained indistinguishable from control animals. By contrast, animals that received 6 µg of 6-OHDA showed a marked reduction of TH+ cells in the SN (∼75%) and VTA (∼55%), a significant stepping test deficit and an increased proportion of LFO units. These changes were not dramatically enhanced with 8 µg 6-OHDA, a dose that induced an extensive DA lesion (> 95%) in the SN and ∼70% reduction of DA neurons in the VTA. These results suggest a threshold level of DA denervation for both the appearance of motor deficits and LFO units. Thus, the presence of LFO activity in the SNpr is not related to a complete nigrostriatal DA neuron depletion (ultimate stage parkinsonism); instead, it may reflect a functional disruption of cortico-basal ganglia dynamics associated with clinically relevant stages of the disease.