PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

点击翻译按钮获取中文摘要

The goal of this project is to elucidate the function of specific neuronal systems in regulating information processing in the basal ganglia in order to identify mechanisms which could be manipulated to prevent, correct and/or compensate for dysfunction involving these systems. In FY95, focus has been on processes underlying the effects of dopamine receptor subtypes on basal ganglia output. (1) Subthalamic nucleus: In vivo extracellular single unit recordings have shown, unexpectedly, that locally as well as systemically administered dopamine D1 agonists exert excitatory effects on the activity of subthalamic neurons. Systemic effects are blocked by local infusion with a D1 antagonist. D2/D3 agonists induce less change in subthalamic activity although tonic endogenous tone at D2/D3 receptors appears required for the D1-mediated effects. Autoradiographic techniques have demonstrated D2/D3 receptors in the subthalamic nucleus and D1 receptors on the ventral border adjacent to the cerebral peduncle; presumably located on terminals of excitatory cortical afferents. Thus, in addition to acting on striatopallidal and striatonigral neurons, dopaminergic agents also may exert functionally significant effects on basal ganglia output through actions on cortical inputs to the subthalamic nucleus. In animal models of Parkinson's disease, tonic activity in the subthalamic nucleus is enhanced and the responses to dopamine agonists is markedly altered. Nonselective dopamine agonist induces decreases in subthalamic activity in the lesioned rats as compared to increases in normal animals. Mechanisms are being investigated and may be relevant to the efficacy of pallidotomies in the treatment of Parkinson's disease. (2) Striatum: AP-1 transcription factor binding in rat striatal nuclear protein extract is enhanced in a synergistic manner after combined systemic administration of D1 and D2/D3 agonists. These results demonstrate that D1 and D2/D3 receptor-mediated synergistic interactions induce changes in striatal gene expression as well as neuronal activity but do not indicate where the receptor subtypes are localized. Infusing selective D1 and D2 agonists locally into the striatum in 6-OHDA-lesioned rats produces changes in Fos protein in the striatum; however, this does not coincide with alterations in basal ganglia output as measured by firing rates in the SNpr. Results indicate that D1 and D2 receptors in the striatum as well as D1 receptors at extrastriatal sites are necessary for mediating the changes in basal ganglia output associated with D1 and D2-D3 dopamine receptor stimulation.