It is likely that the static model of inhibitory and excitatory pathways and the parsing of a direct and an indirect pathway, as useful as it is as a mnemonic, does not account well for the dynamic activities of the basal ganglia. In particular, the electrical activity of the neurons in these systems oscillate and influence the frequency pattern of firing in other parts of the system, as well as bringing individual cells closer to firing. Another limitation of currently conceived models is that they do not account for the tremor of Parkinson disease. To further complicate matters, the various subtypes of dopamine receptors act in both excitatory and inhibitory ways under different circumstances depending on their location as discussed below.
The manner in which excessive or reduced activity of various components of the basal ganglia gives rise to hypokinetic and hyperkinetic movement disorders is discussed further on, under “Symptoms of Basal Ganglia Disease.”
A series of pharmacologic observations have considerably enhanced our understanding of basal ganglionic function and led to a rational treatment of Parkinson disease and other extrapyramidal syndromes. Whereas physiologists had for years failed to discover the functions of the basal ganglia by stimulation and crude ablation experiments, clinicians became aware that certain drugs, such as reserpine and the phenothiazines, could produce extrapyramidal syndromes (e.g., parkinsonism, choreoathetosis, dystonia). These observations stimulated the study of central nervous system (CNS) transmitter substances in general. The current view is that the integrated basal ganglionic control of movement can be best understood by considering, in the context of the anatomy described above, the physiologic effects of neurotransmitters that convey the signals between cortex, striatum, globus pallidus, subthalamic nucleus, substantia nigra, and thalamus.
The most important neurotransmitter substances from the point of view of basal ganglionic function are glutamate, GABA, dopamine, acetylcholine, and serotonin. A more complete account of this subject may be found in the reviews of Penney and Young, of Alexander and Crutcher, and of Rao.
The following is what is known with a fair degree of certainty. Glutamate is the neurotransmitter of the excitatory projections from the cortex to the striatum and of the excitatory neurons of the subthalamic nucleus. GABA is the inhibitory neurotransmitter of striatal, pallidal, and substantia nigra (pars reticulata) projection neurons.
Of the catecholamines, dopamine has the most pervasive role but its influence can be excitatory or inhibitory depending on the site of action and the subtype of dopamine receptor. Disturbances of dopamine signaling are essential abnormalities of several CNS disorders including parkinsonism, schizophrenia, attention deficit hyperactivity disorder, and drug abuse. Within the basal ganglia, the areas richest in dopamine are the substantia nigra, where it is synthesized in the nerve cell bodies of the pars compacta, and the termination of these fibers in the striatum. In the most simplified models, stimulation of the dopaminergic neurons of the substantia nigra induces a specific response in the striatum—namely, an inhibitory effect on the already low firing rate of neostriatal neurons.
However, the effects of dopamine have proved even more difficult to resolve, in large part because there are now five known types of postsynaptic dopamine receptors (D1 to D5), each with a particular anatomic distribution and pharmacologic action. This heterogeneity is exemplified in the excitatory effect of dopamine on the small spiny neurons of the putamen and an inhibitory effect on others. Viewed from the perspective of the direct and indirect pathways, dopamine enhances the activity of the former and inhibits the latter, resulting in a net disinhibition of thalamic nuclei and a release of cortical motor function.