The pedunculopontine nucleus (PPN) and the subthalamic nucleus (STN) are reciprocally connected by excitatory projections. In the 6-hydroxydopamine (6-OHDA) rat model the PPN was found to be hyperactive. Similarly, the STN and the substantia nigra pars reticulata (SNr) showed increased activity in Parkinson's disease (PD) animal models. A lesion of the STN was shown to restore increased activity levels in the SNr of 6-OHDA-treated rats. As the STN and the PPN were reciprocally connected by excitatory projections and both structures were shown to be hyperactive in PD animal models, the present study was performed in order to investigate the changes in neuronal activity of the STN and SNr under urethane anesthesia after unilateral ibotenic acid lesioning of the PPN in animals with previous unilateral 6-OHDA lesions of the substantia nigra pars compacta (SNc). The firing rate of STN neurons significantly increased from 10.3 +/- 0.6 spikes/s (mean +/- SEM) to 17.8 +/- 1.8 spikes/s after SNc lesion and returned to normal levels of 10.8 +/- 0.7 spikes/s after additional lesion of the PPN. Similarly, the firing rate of SNr neurons significantly increased from 19.0 +/- 1.1 to 25.9 +/- 1.4 spikes/s after SNc lesion, the hyperactivity being reversed after additional PPN lesion to 16.8 +/- 1.2 spikes/s. The reversal of STN and SNr hyperactivity of 6-OHDA-treated rats by additional PPN lesion suggests an important modulatory influence of the PPN on STN activity. Moreover, these findings could indicate a new therapeutic strategy in PD by interventional modulation of the PPN.

The functional significance of the interhemispheric projections on the basal ganglia level is poorly understood. Insofar as the anatomical evidence for crossing projections between basal ganglia nuclei is sparse, whereas tracing studies demonstrated important crossing projections from the pedunculopontine nucleus (PPN) to the basal ganglia, it is suggested that the PPN might play a key role in interhemispheric regulation of basal ganglia activity. The present study was performed to assess changes in neuronal activity of ipsilateral and contralateral subthalamic nucleus (STN), substantia nigra pars reticulata (SNr), and PPN in the unilateral 6-hydroxydopamine (6-OHDA) rat model of advanced PD under urethane anesthesia. After unilateral lesioning of the SNc, the firing rate of contralateral STN neurons significantly increased from 10.9 +/- 1.0 spikes/sec (mean +/- SEM) to 16.3 +/- 1.5 spikes/sec. Similarly, the firing rate of contralateral SNr neurons significantly increased from 19.4 +/- 1.2 to 25.7 +/- 1.9 spikes/sec, and the firing rate of contralateral PPN neurons significantly increased from 10.6 +/- 0.8 to 13.9 +/- 1.1 spikes/sec. The observed activity changes in contralateral STN, SNr, and PPN are similar to those induced in the corresponding nuclei of the hemisphere ipsilateral to the nigrostriatal degeneration. Based on previous, predominantly anatomical data, the results of the present study suggest that the PPN on the lesioned side is at the origin of changes in the activity of STN and SNr on the contralateral hemisphere, because of its crossing efferent projections.

Recent data suggest a role for the pedunculopontine nucleus (PPN) in the pathophysiology of Parkinson's disease. Although there is anatomical evidence that the PPN and the basal ganglia are reciprocally connected, the functional importance of these connections is poorly understood. Lesioning of the PPN was shown to induce akinesia in primates, whereas in the 6-hydroxydopamine rat model the PPN was found to be hyperactive. As both nigrostriatal dopamine depletion and lesioning of the PPN were shown to induce akinesia and parkinsonism, the present study was performed in order to investigate the changes in neuronal activity of the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) after unilateral ibotenic acid lesioning of the PPN and after unilateral 6-hydroxydopamine lesioning of the substantia nigra pars compacta (SNc). The firing rate of STN neurones significantly increased from 10.2 +/- 6.2 (mean +/- SD) to 14.6 +/- 11.7 spikes/s after lesion of the PPN and to 18.6 +/- 14.5 spikes/s after lesion of the SNc. The activity of the SNr significantly increased from 19.6 +/- 10.5 to 28.7 +/- 13.4 spikes/s after PPN lesioning and to 23.5 +/- 10.8 spikes/s after SNc lesioning. Furthermore, PPN lesion decreased the number of spontaneously firing dopaminergic SNc cells, while having no effect on their firing rate. The results of our study show that lesion of the PPN leads to hyperactivity of the STN and SNr, similar to the changes induced by lesion of the SNc. Moreover, the decreased activity of SNc cells observed after PPN lesion might be at the origin of activity changes in the STN and SNr.