Behavioral responses to injections of muscimol into the subthalamic nucleus: temporal changes after nigrostriatal lesions.

Changes in cellular activity in the subthalamic nucleus are a cardinal feature of Parkinson's disease and occur in rodents after lesions of the nigrostriatal pathway, a model of Parkinson's disease. GABA-ergic neurons from the globus pallidus provide a major input to the subthalamic nucleus. Previous electrophysiological studies revealed temporal changes in the activity of pallidal neurons after nigrostriatal lesions in rats. However, little is known about the impact of these changes on GABAergic transmission in the subthalamic nucleus. We have examined the behavioral responses to a local administration of the GABA A agonist muscimol into the subthalamic nucleus. Muscimol (0.01 and 0.1 microg) induced orofacial dyskinesia in normal rats; this response was blunted 2 weeks but enhanced 2 months after a unilateral lesion of the nigrostriatal pathway. The early decrease in the behavioral response occurred at a time when increased expression of mRNA for glutamic acid decarboxylase, the enzyme of GABA synthesis, and burst firing have been reported in the globus pallidus, suggesting an adaptive post-synaptic response to increased GABAergic transmission in the subthalamic nucleus. In contrast, we now show that glutamic acid decarboxylase mRNA is unchanged in the globus pallidus at the later time point, when electrophysiological changes also subside in this region. The increased behavioral response at this later time point may reflect a decreased activity in GABAergic inputs to the subthalamic nucleus. The results show time-dependent changes in behavioral responses to GABA A receptor stimulation in the subthalamic nucleus which may reflect adaptive changes in postsynaptic inhibitory responses after dopaminergic lesions.