Functional changes of the basal ganglia circuitry in Parkinson's disease

The basal ganglia circuitry processes the signals that flow from the cortex , allowing the correct execution of voluntary movements. In Parkinson's dis ease. the degeneration of dopaminergic neurons of the substantia nigra pars compacta triggers a cascade of functional changes affecting the whole basa l ganglia network. The most relevant alterations affect the output nuclei o f the circuit. the medial globus pallidus and substantia nigra pars reticul ata, which become hyperactive. Such hyperactivity is sustained by the enhan ced glutamatergic inputs that the output nuclei receive from the subthalami c nucleus. The mechanisms leading to the subthalamic disinhibition are stil l poorly understood. According to the current model of basal ganglia organi zation, the phenomenon is due to a decrease in the inhibitory control exert ed over the subthalamic nucleus by the lateral globus pallidus. Recent data , however. suggest that additional if not alternative mechanisms may underl ie subthalamic hyperactivity. In particular, given the reciprocal innervati on of the substantia nigra pars compacta and the subthalamic nucleus, the d opaminergic deficit might influence the subthalamic activity, directly. In addition. the increased excitatory drive to the dopaminergic nigral neurons originating from the hyperactive subthalamic nucleus might sustain the pro gression of the degenerative process. The identification of the role of the subthalamic nucleus and, more in general, of the glutamatergic mechanisms in the pathophysiology of Parkinson's disease might lead to a new approach in the pharmacological treatment of the disease. Current therapeutic strate gies rely on the use of L-DOPA and/or dopamine agonists to correct the dopa minergic deficit. Drugs capable of antagonizing the effects of glutamate mi ght represent, in the next future, a valuable tool for the development of n ew symptomatic and neuroprotective strategies for therapy of Parkinson's di sease. (C) 2000 Elsevier Science Ltd. All rights reserved.