A Direct Role of Dopamine in the Rat Subthalamic Nucleus and an Adjacent Intrapeduncular Area

Brown, Lucy L.; Markman, Maynard H.; Wolfson, Leslie; Dvorkin, B.; Warner, Carolyn L.; Katzman, Robert

doi:10.1126/science.505015

Cited by 79 publications

(31 citation statements)

References 21 publications

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“…The change in SNr Glu levels after dopaminergic denervation may be attributable to an effect restricted to the STN or related structures. Many studies have reported direct dopaminergic innervation of the STN (Brown et al, 1979;Meibach and Katzman, 1979;Campbell et al, 1985;Hassani et al, 1997;Smith et al, 1998), which may control STN neuron activity directly or via presynaptic modulation of neurotransmitter release (Kreiss et al, 1997;Ni et al, 2001;Shen et al, 2003;Cragg et al, 2004). The level of GABA in the SNr also increased in hemiparkinsonian rats.…”

Section: Changes In Basal Glu and Gaba Level Induced By Snc Lesioningmentioning

confidence: 82%

Pallidal Origin of GABA Release within the Substantia Nigra Pars Reticulata during High-Frequency Stimulation of the Subthalamic Nucleus

Windels

Carcenac²,

Poupard³

et al. 2005

J. Neurosci.

119

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High-frequency stimulation of the subthalamic nucleus (HFS-STN) is an effective treatment for alleviating the motor symptoms of parkinsonian patients. However, the neurochemical basis of its effects remains unknown. We showed previously that 1 h of HFS-STN in normal rats increases extracellular glutamate (Glu) level in the output nuclei of the STN, the globus pallidus (GP), and the substantia nigra pars reticulata (SNr), consistent with an increase in the activity of STN neurons. HFS-STN also increases GABA levels in the SNr, but the origin of this increase is unclear. We investigated the effectiveness of HFS-STN for improving Parkinson's disease symptoms, using intracerebral microdialysis to determine the extracellular Glu and GABA levels of the GP and SNr in response to HFS-STN in anesthetized hemiparkinsonian rats [6-hydroxydopamine lesion of the substantia nigra pars compacta (SNc)]. Basal levels of Glu and GABA in the GP and SNr were significantly higher in hemiparkinsonian than in intact rats. HFS-STN did not affect extracellular Glu level in the SNr of hemiparkinsonian rats but doubled the level of GABA. Ibotenic acid lesion of the GP abolished the increase in GABA levels in the SNr induced by HFS-STN in SNc-lesioned rats. These results provide neurochemical confirmation of the hyperactivity of the STN after dopaminergic denervation and suggest that the therapeutic effects of HFS-STN may result partly from the stimulation of pallidonigral fibers, thereby revealing a potential role for pallidal GABA in the inhibition of basal ganglial output structures during HFS-STN.

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Section: Changes In Basal Glu and Gaba Level Induced By Snc Lesioningmentioning

confidence: 82%

Pallidal Origin of GABA Release within the Substantia Nigra Pars Reticulata during High-Frequency Stimulation of the Subthalamic Nucleus

Windels

Carcenac²,

Poupard³

et al. 2005

J. Neurosci.

119

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“…Brain regions that receive dopaminergic inputs predominantly from the ventral tegmental area did not show L-dopa-induced increases in glucose utilization to the same degree as those areas that are innervated by the substantia nigra. Because the results obtained with the ['4C]dGlc method are not limited to the primary sites of action of the drug, it is not possible to conclude from these results whether the increases in glucose utilization seen in the subthalamic nucleus and the globus pallidus result from activation of dopaminergic receptors intrinsic to these areas (19)(20)(21) or are a result of dopaminergic activation of the striatum with consequent increased activity in pathways projecting from the striatum to the globus pallidus and subthalamic nucleus.…”

Section: Discussionmentioning

confidence: 98%

Local cerebral metabolic effects of L-dopa therapy in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in monkeys.

Porrino¹,

Burns²,

Crane³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

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The quantitative 2-deoxy['4C]glucose autoradiographic method was used to map the distribution of alterations in local cerebral glucose utilization that accompanies clinically effective chronic L-dopa therapy of rhesus monkeys made parkinsonian by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This pattern of changes was compared to the effects of a similar treatment regimen in normal monkeys. L-Dopa (100 mg with 10 mg carbidopa) was administered orally to normal and parkinsonian monkeys 3 times daily for 60-120 days prior to measurement of local cerebral glucose utilization. In parkinsonian monkeys treated with L-dopa, signs and symptoms of parkinsonism were controlled or suppressed, and widespread increases in glucose utilization were seen throughout the brain. Cerebral metabolic activity was increased both in areas rich in dopaminergic receptors, such as the caudate and putamen, and in nondopaminergic areas involved in motor functions. In many structures the rates of glucose utilization in L-dopatreated parkinsonian monkeys were increased to levels that far exceeded rates measured in normal monkeys. In sharp contrast, similar treatment with L-dopa in normal monkeys had little if any effect on local cerebral glucose utilization. L-Dopa, then, appears to have an action in animals with selective lesions of the substantia nigra pars compacta produced by MPTP that is distinctly different from its effects in the normal monkey.L-Dopa (3,4-dihydroxy-L-phenylalanine) is the most effective and commonly prescribed drug for the treatment ofParkinson disease. Treatment with this dopamine precursor diminishes the severity of many signs and symptoms of Parkinson disease, including bradykinesia, tremor, and rigidity, and often restores relatively normal motor function (1). Although its mechanisms of action are not fully understood, it is generally assumed that L-dopa enters the brain and is converted to dopamine, which then interacts with dopamine receptors to produce the therapeutic effects (2). A further implicit assumption is that the site of this action is in the striatum, which in Parkinson disease is depleted of dopamine as a result of the degeneration of the dopaminergic nigrostriatal pathway.In humans (3, 4) and nonhuman primates (5-8), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a typical parkinsonian syndrome, characterized by akinesia, rigidity, tremor, and flexed posture, that can be ameliorated by L-dopa treatment. MPTP administration causes almost complete and relatively selective destruction of the dopaminecontaining cells of the substantia nigra pars compacta and consequent depletion of dopamine and dopamine metabolites within the striatum (5-8). Because both the behavioral and the neuropathological characteristics of MPTP-induced parkinsonism in primates resemble human idiopathic Parkinson disease so closely, it appears that this syndrome provides an almost ideal animal model with which to study the effects of L-dopa treatment.The autoradiographic 2-deoxy['...

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“…Hassani ( 1996) has similarly shown that OPe lesions result in only marginally significant STN hyperactivity. In contrast, dopaminergic lesions directly in the STN, which contains D 1 & D2 receptors (Brown et al, 1979; Martres eta!., 1985), result in five times the STN hyperactivity induced by OPe lesions alone (Hassani, 1996). Thus, the GPe-STN projection may be weak relative to the GPe-GPi/SNr projection.…”

mentioning

confidence: 99%

How laminar frontal cortex and basal ganglia circuits interact to control planned and reactive saccades

Brown

Bullock

Grossberg³

2004

Neural Networks

248

281

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A Direct Role of Dopamine in the Rat Subthalamic Nucleus and an Adjacent Intrapeduncular Area

Cited by 79 publications

References 21 publications

Pallidal Origin of GABA Release within the Substantia Nigra Pars Reticulata during High-Frequency Stimulation of the Subthalamic Nucleus

Pallidal Origin of GABA Release within the Substantia Nigra Pars Reticulata during High-Frequency Stimulation of the Subthalamic Nucleus

Local cerebral metabolic effects of L-dopa therapy in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in monkeys.

How laminar frontal cortex and basal ganglia circuits interact to control planned and reactive saccades

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