The basal ganglia circuitry processes the signals that flow from the cortex, allowing
the correct execution of voluntary movements. In Parkinson's disease, the degeneration
of dopaminergic neurons of the substantia nigra pars compacta triggers a cascade of
functional changes affecting the whole basal ganglia network. The most relevant alterations
affect the output nuclei of the circuit, the medial globus pallidus and substantia
nigra pars reticulata, which become hyperactive. Such hyperactivity is sustained by
the enhanced glutamatergic inputs that the output nuclei receive from the subthalamic
nucleus. The mechanisms leading to the subthalamic disinhibition are still poorly
understood. According to the current model of basal ganglia organization, the phenomenon
is due to a decrease in the inhibitory control exerted over the subthalamic nucleus
by the lateral globus pallidus. Recent data, however, suggest that additional if not
alternative mechanisms may underlie subthalamic hyperactivity. In particular, given
the reciprocal innervation of the substantia nigra pars compacta and the subthalamic
nucleus, the dopaminergic 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 progression 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
strategies rely on the use of L-DOPA and/or dopamine agonists to correct the dopaminergic
deficit. Drugs capable of antagonizing the effects of glutamate might represent, in
the next future, a valuable tool for the development of new symptomatic and neuroprotective
strategies for therapy of Parkinson's disease.