Synaptic release of dopamine in the subthalamic nucleus (original) (raw)
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The Journal of Comparative Neurology, 2000
The existence of a dopaminergic innervation of the subthalamic nucleus (STN) has been demonstrated in rats but has remained controversial in primates. The aim of the present study was first to demonstrate the existence of a dopaminergic innervation of the STN in monkeys using tracing methods and then to quantify the loss of dopaminergic fibers in the parkinsonian state in monkeys and humans. Following injection of Fluoro-Gold into the STN of a vervet monkey (Cercopithecus aethiops), retrogradely labeled neurons were found to be scattered in all dopaminergic areas of the mesencephalon. Injection of biotin dextran amine into dopaminergic areas A8 and A9 of two monkeys resulted in anterogradely labeled axons located throughout the whole extent of the STN. Labeled axons that also expressed tyrosine hydroxylase (TH) were reconstructed from serial sections. Some terminal axonal arborizations had profuse branching and occupied much of the STN, and others were restricted to small portions of the nucleus. In TH-immunoreactive sections, numerous sparse, fine, and varicose TH-positive fibers were observed in the STN of normal monkeys and humans. Quantification of these TH-positive fibers revealed a 51% loss of TH-positive fibers in MPTP-intoxicated monkeys and a 65% loss in Parkinson's disease patients compared with their respective controls. These findings demonstrate the existence of a dopaminergic innervation of the STN in primates. The loss of dopaminergic innervation in MPTP-intoxicated monkeys and in Parkinson's disease patients may directly affect the activity of STN neurons and could participate in the hyperactivity of the structure.
Dopaminergic innervation of the human striatum in Parkinson's disease
Movement Disorders, 2005
In Parkinson's disease (PD), dopaminergic input to the caudate nucleus and a band of putaminal tissue abutting the external globus pallidus seems well preserved on immunohistochemical staining for the dopamine transporter. Counting of dopaminergic terminals showed that terminal density in these regions in PD was the same as that in controls, which indicates that input is truly preserved and not a consequence of a compensatory upregulation of metabolism in a reduced pool of surviving terminals. When the branching pattern of dopaminergic axons coursing through the globus pallidus was examined, we found no evidence for increased axonal sprouting in PD that might have contributed to preservation of dopaminergic input to the putamen or caudate nucleus. Although terminal counting indicated that anatomic input was preserved to parts of the striatum, dopamine uptake site density in these regions was reduced significantly. This suggests that the impact of disease in these areas is more profound than was thought previously.
Journal of Neuroscience, 2007
This study examined the cellular changes produced in the striatum by chronic L-DOPA treatment and prolonged subthalamic nucleus high-frequency stimulation (STN-HFS) applied separately, successively, or in association, in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease (PD). Only animals showing severe L-DOPA-induced dyskinesias (LIDs) were included, and STN-HFS was applied for 5 d at an intensity efficient for alleviating akinesia without inducing dyskinesias. L-DOPA treatment alone induced FosB/⌬FosB immunoreactivity, exacerbated the postlesional increase in preproenkephalin, reversed the decrease in preprotachykinin, and markedly increased mRNA levels of preprodynorphin and of the glial glutamate transporter GLT1, which were respectively decreased and unaffected by the dopamine lesion. STN-HFS did not affect per se the postlesion changes in any of these markers. However, when applied in association with L-DOPA treatment, it potentiated the positive modulation exerted by L-DOPA on all of the markers examined and tended to exacerbate LIDs. After 5 d of L-DOPA withdrawal, the only persisting drug-induced responses were an elevation in preprodynorphin mRNA levels and in the number of FosB/⌬FosB-immunoreactive neurons. Selective additional increases in these two markers were measured when STN-HFS was applied subsequently to L-DOPA treatment. These data provide the first evidence that STN-HFS exacerbates the responsiveness of striatal cells to L-DOPA medication and suggest that STN-HFS acts specifically through an L-DOPAmodulated signal transduction pathway associated with LIDs in the striatum. They point to striatal cells as a primary site for the complex interactions between these two therapeutic approaches in PD and argue against a direct anti-dyskinetic action of STN-HFS.
Journal of Neuroscience, 2012
The symptoms of Parkinson's disease (PD) are related to changes in the frequency and pattern of activity in the reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN). In idiopathic and experimental PD the GPe and STN exhibit hypo-and hyper-activity, respectively, and abnormal synchronous rhythmic burst firing. Following lesion of midbrain dopamine neurons abnormal STN activity emerges slowly and intensifies gradually until it stabilizes after 2-3 weeks. Alterations in cellular/network properties may therefore underlie the expression of abnormal firing. Because the GPe powerfully regulates the frequency, pattern and synchronization of STN activity, electrophysiological, molecular and anatomical measures of GPe-STN transmission were compared in the STN of control and 6hydroxydopamine-lesioned rats and mice. Following dopamine depletion: 1) the frequency (but not the amplitude) of mIPSCs increased by ~70%; 2) the amplitude of evoked IPSCs and isoguvacine-evoked current increased by ~60% and ~70%, respectively; 3) mRNA encoding α1, β2 and γ2 GABA A receptor subunits increased by 15-30%; 4) the density of postsynaptic gephyrin and γ2 subunit co-immunoreactive structures increased by ~40%, whereas the density of vesicular GABA transporter and bassoon co-immunoreactive axon terminals was unchanged; 5) the number of ultrastructurally defined synapses per GPe-STN axon terminal doubled with no alteration in terminal/synapse size or target preference. Thus, loss of dopamine leads, through an increase in the number of synaptic connections per GPe-STN axon terminal, to substantial strengthening of the GPe-STN pathway. This adaptation may oppose hyperactivity but could also contribute to abnormal firing patterns in the parkinsonian STN.
Journal of Chemical Neuroanatomy, 2008
The striatum harbors a population of dopaminergic interneurons that increases in number in animal models of Parkinson's disease (PD), presumably to compensate for dopamine (DA) depletion. The purpose of the present study was to determine the fate of striatal dopaminergic neurons in parkinsonian monkeys in which striatal DA depletion had been alleviated by systemic administration of L-dopa. The number of striatal dopaminergic neurons, visualized with tyrosine hydroxylase (TH) immunohistochemistry, was measured in three groups of cynomolgus (Macaca fascicularis) monkeys: (1) normal untreated monkeys; (2) monkeys rendered parkinsonian following systemic injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), but otherwise untreated; and (3) MPTP-intoxicated monkeys that received oral L-dopa on a chronic basis. In agreement with previous studies, the number of striatal TH-positive (TH+) neurons in L-dopa-free parkinsonian monkeys was significantly higher (p < 0.05) than in normal (non-parkinsonian) monkeys. However, this increase was abolished in parkinsonian monkeys that received L-dopa treatment. In fact, the number of striatal TH+ neurons in L-dopa-treated parkinsonian monkeys was not significantly different (p > 0.05) from values obtained in normal monkeys. These findings suggest that the DA concentration regulates the numerical density of this ectopic neuronal population, a phenomenon that is more likely the result of a shift in the phenotype of preexistent striatal interneurons rather than the recruitment of newborn neurons that would eventually develop a DA phenotype. Our data also reinforce the hypothesis that striatal TH+ neurons act as local DA source and, as such, are part of a compensatory mechanism that could be artificially enhanced to alleviate or delay PD symptoms.
Journal of Neuroscience, 2009
Nicola, Saleem M. and Robert C. Malenka. Modulation of synulants . In contrast, the dorsal aptic transmission by dopamine and norepinephrine in ventral but striatum is required for the execution of planned motor behavnot dorsal striatum. J. Neurophysiol. 79: 1768-1776, 1998. Alior (Graybiel et al. 1994 and is implicated in the pathophysithough the ventral striatum (nucleus accumbens; NAc) and dorsal ology of Parkinson's disease and Huntington's chorea. Both striatum are associated with different behaviors, these structures nuclei may be involved in psychiatric diseases such as schizoare anatomically and physiologically similar. In particular, dopaphrenia (Swerdlow and Koob 1987). minergic afferents from the midbrain appear to be essential for the One element that is common to almost all hypotheses that normal functioning of both nuclei. Although a number of studies attempt to explain the behavioral functions of the NAc and have examined the effects of dopamine on the physiology of NAc or striatal cells, results have varied, and few studies have compared striatum is the paramount importance of the midbrain dopadirectly the actions of dopamine on both of these nuclei. Here we minergic projection. Despite convincing behavioral evidence use slice preparations of the NAc and dorsal striatum to compare of the importance of dopamine (DA), however, little is how synaptic transmission in these nuclei is modulated by catecholknown about the physiological actions of DA on neurons in amines. As previously reported, dopamine depressed excitatory these structures. Recently, we and others have shown that postsynaptic potentials (EPSPs) and inhibitory postsynaptic potenin the NAc, DA presynaptically depresses both excitatory tials (IPSPs) in the NAc. Surprisingly, however, neither EPSPs nor (Harvey and Lacey 1996; Nicola et al. 1996; Pennartz et al. IPSPs in the dorsal striatum were affected by dopamine. Similarly, 1992) and inhibitory (Nicola and Malenka 1997) synaptic norepinephrine depressed excitatory synaptic transmission in the transmission by activation of a D1-like DA receptor. Similar
Dopamine Systems in Parkinson's Disease and L-DOPA-induced Dyskinesia What Goes Wrong?
s disease (PD) is a neurological disorder characterized by a progressive degeneration of dopaminergic neurons located in the substantia nigra pars compacta (SNc). 1 Dopaminergic neurons of the SNc send their axons along the nigrostriatal pathway to the striatum, where dopamine (DA) acts to modulate post-synaptic signaling. The striatum comprises a heterogeneous population of neurons that receives input from a number of regions, including motor and sensory cortices, and under the influence of DA utilizes this information to guide motor