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Progressive degeneration of neurons of the various nuclei of the basal ganglia leads to many clinical disorders manifesting in severe disabling motor, autonomic, and cognitive problems. The different nuclei of the basal ganglia, especially the striatum, are the sites of actions of diverse neurotransmitters and neuropeptides.1 Classic and modern neuroanatomical and neurochemical studies have enabled us to draw a working model of the circuits of the basal ganglia.24 Although very much simplified, these models have been valuable and have advanced our understanding of the molecular circuitries as well as the role played by the individual neurotransmitters and neuropeptides in the functions of the basal ganglia.

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This chapter reviews the information relevant to the patterns of organization of five major neurotransmitters, namely, dopamine, acetylcholine (ACh), glutamate, serotonin, and noradrenaline, and their receptors in the basal ganglia and briefly relates to the changes that occur in the diseases of the basal ganglia.

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The basal ganglia may be divided into several functional subcompartments. The primary input structures are the caudate, putamen, and the nucleus accumbens, which are collectively termed the “striatum.” The putamen processes the motor component of basal ganglia-thalamocortical circuits, whereas caudate and nucleus accumbens mediate cognitive, emotive, and limbic inputs. The spiny neurons, the principal input and output cells accounting for more than three quarters of the total striatal neuronal population, receive the excitatory synaptic inputs from neocortex as well as thalamus and the dopaminergic input from substantia nigra pars compacta (SNc).5 Two neurochemically and anatomically distinct populations of spiny neurons of the striatum project downstream to the globus pallidus internal segment (GPi) and substantia nigra pars reticulata (SNr), which are the basal ganglia output nuclei (GPi/SNr). A specific subpopulation of γ-aminobutyric acid (GABA)- and substance P-containing spiny neurons that project directly to the GPi and SNr forms the direct pathway. The indirect pathway arises from a separate subpopulation of spiny neurons that coexpress GABA and enkephalin and project to the external segment of globus pallidus (GPe).6 GPe sends a GABAergic projection to the subthalamus (STN), which in turn provides glutamatergic innervations of GPi/SNr. The high basal discharge of the GABAergic GPi neurons, the major output nucleus of the basal ganglia circuit, results in tonic inhibitory control over the nonmotor and motor thalamus, and the mesopontine tegmentum.

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This working model of basal ganglia circuits (Fig. 6–1) suggests that the basal activity of the pallidal neurons is kept in check by a balance of the direct inhibitory pathway tending to reduce basal ganglia output and the excitatory indirect pathway tending to increase the output. During normal movement, changes in the balance of the direct and indirect pathways reduce GPi/SNr inhibition of thalamus, allowing engagement of thalamocortical circuits necessary for the speed and guidance of movements. An imbalance of activity, however, in the direct and indirect pathways can perturb the normal degree of GPi/SNr inhibition of thalamocortical activity, producing either hypokinetic or hyperkinetic ...

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