These experiments re-examined the notion that reduced activity in the external pallidal segment (GPe) results in the abnormalities of neuronal discharge in the subthalamic nucleus (STN) and the internal pallidal segment (GPi) and in the development of parkinsonian motor signs. Extracellular recording in two rhesus monkeys, which had been rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), revealed that the average neuronal discharge rate decreased in GPe but increased in STN and GPi. After MPTP, neurons in all three nuclei tended to discharge in oscillatory bursts. In addition, GABA release in STN (measured with microdialysis) was reduced, indicative of reduced activity along the GPe-STN pathway. Finally, the concentration of glutamic acid dehydrogenase (GAD; measured with autoimmunoradiography) was increased in GPe and GPi, likely reflecting increased striatal input and increased activity of local axon collaterals, respectively. Surprisingly, GAD protein in STN remained unchanged, indicating that the usual assumption that GAD levels are determined primarily by the overall activity of GABAergic elements may be too simplistic. The results from the MPTP-treated animals were compared with results obtained in a second group of three animals with ibotenic acid lesions of GPe. GPe lesions resulted in increased discharge in STN and GPi, comparable with the changes seen after MPTP but did not induce oscillatory bursting and had no behavioral effects. The results indicate that a mere reduction of GPe activity does not produce parkinsonism. Other changes, such as altered discharge patterns in STN and GPi, may play an important role in the generation of parkinsonism.

Kliem MA, Maidment NT, Ackerson LC, Chen S, Smith Y, Wichmann T. Activation of nigral and pallidal dopamine D1-like receptors modulates basal ganglia outflow in monkeys. J Neurophysiol 98: 1489-1500, 2007. First published July 18, 2007; doi:10.1152/jn.00171.2007. Studies of the effects of dopamine in the basal ganglia have focused on the striatum, whereas the functions of dopamine released in the internal pallidal segment (GPi) or in the substantia nigra pars reticulata (SNr) have received less attention. Anatomic and biochemical investigations have demonstrated the presence of dopamine D1-like receptors (D1LRs) in GPi and SNr, which are primarily located on axons and axon terminals of the GABAergic striatopallidal and striatonigral afferents. Our experiments assessed the effects of D1LR ligands in GPi and SNr on local ␥-aminobutyric acid (GABA) levels and neuronal activity in these nuclei in rhesus monkeys. Microinjections of the D1LR receptor agonist SKF82958 into GPi and SNr significantly reduced discharge rates in GPi and SNr, whereas injections of the D1LR antagonist SCH23390 increased firing in the majority of GPi neurons. D1LR activation also increased bursting and oscillations in neuronal discharge in the 3-to 15-Hz band in both structures, whereas D1LR blockade had the opposite effects in GPi. Microdialysis measurements of GABA concentrations in GPi and SNr showed that the D1LR agonist increased the level of the transmitter. Both findings are compatible with the hypothesis that D1LR activation leads to GABA release from striatopallidal or striatonigral afferents, which may secondarily reduce firing of basal ganglia output neurons. The antagonist experiments suggest that a dopaminergic "tone" exists in GPi. Our results support the finding that D1LR activation may have powerful effects on GPi and SNr neurons and may mediate some of the effects of dopamine replacement therapies in Parkinson's disease.

No abstract

The motor symptoms of Parkinson’s disease (PD) are commonly attributed to striatal dopamine loss, but reduced dopamine innervation of basal ganglia output nuclei, the internal globus pallidus (GPi) and the substantia nigra pars reticulata (SNr) may also contribute to symptoms and signs of PD. Both structures express dopamine D1 and D5 receptors under normal conditions, and we have recently demonstrated that their local activation reduces neuronal discharge rates and enhances bursts and oscillatory activity in both nuclei of normal monkeys [M.A. Kliem et al. (2007) J. Neurophysiol., 89, 1489–1500]. Here, we determined the ultrastructural localization and function of D1-like receptors in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian monkeys. In both normal and MPTP-treated monkeys, most of the D1 and D5 receptor immunoreactivity was associated with unmyelinated axons, but we also found significant postsynaptic D5 receptor immunostaining in dendrites of GPi and SNr neurons. A significant proportion of axonal D1 immunostaining was bound to the plasma membrane in both normal and MPTP-treated monkeys. Local microinjections of the D1 / D5 receptor agonist SKF82958 significantly reduced discharge rates in GPi and SNr neurons, while they increased burst firing and oscillatory activity in the 3–15-Hz band in SNr, but not in GPi, of parkinsonian monkeys. Together with our recent findings from normal monkeys, these data provide evidence that functional D1 / D5 receptors are expressed in GPi and SNr in both normal and parkinsonian states, and that their activation by endogenous dopamine (under normal conditions) or dopamine receptor agonists (in parkinsonism) may regulate basal ganglia outflow.

The basal ganglia participate in motor functions and are implicated in the pathophysiology of movement disorders. It has been shown in primates that the activity of many neurons in one of the basal ganglia output nuclei, the internal segment of the globus pallidus, changes with active or passive movements. The involvement of the second major output nucleus, the substantia nigra pars reticulata (SNr), in movement is less well established. In this study, the electrophysiologic activity of SNr neurons was studied in two awake Rhesus monkeys while the animals were examined and while they performed elbow movements in two different motor tasks ( n = 261 cells). Responses to examination were uncommon and subtle. Twenty-one percent of neurons responded to the target step in a step tracking task, mostly with anticipatory responses, although some cells showed directional, movement-related activity. In a delayed-response task, 17% of cells showed anticipatory activity to an instruction cue preceding the target jump, 11% responded directly to the cue, and 11% showed long-lasting postcue activity. Movement-related responses were seen in 21% in this task. Reward responses occurred in 10% of neurons. Responses to more than one event were common. The results demonstrate that few neurons in the SNr respond directly to passive or active movements, but a large proportion shows responses that may be related to memory, attention, or movement preparation. While internal pallidal segment neurons may be preferentially concerned with controlling elemental movement parameters, neurons in the SNr may be more involved in higher motor functions or nonmotor aspects of behavior.