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The role of astrocytes in Parkinson's disease is still not well understood. This work studied the astrocytic response to the dopaminergic denervation. Rats were injected in the lateral ventricles with 6-hydroxydopamine (25μg), inducing a dopaminergic denervation of the striatum not accompanied by non-selective tissue damage. The dopaminergic debris were found within spheroids (free-spheroids) which retained some proteins of dopaminergic neurons (e.g., tyrosine hydroxylase, the dopamine transporter protein, and APP) but not others (e.g., α-synuclein). Free-spheroids showed the initial (LC3-autophagosomes) but not the late (Lamp1/Lamp2-lysosomes) components of autophagy (incomplete autophagy), preparing their autophagosomes for an external phagocytosis (accumulation of phosphatidylserine). Free-spheroids were penetrated by astrocyte processes (fenestrated-spheroids) which made them immunoreactive for GFAP and S100β, and which had some elements needed to continue the debris degradation (Lamp1/Lamp2). Finally, proteins normally found in neurons (TH, DAT and α-synuclein) were observed within astrocytes 2-5 days after the dopaminergic degeneration, suggesting that the intracellular contents of degenerated cells had been transferred to astrocytes. Taken together, present data suggest phagocytosis as a physiological role of striatal astrocytes, a role which could be critical for cleaning striatal debris during the initial stages of Parkinson's disease.

Despite evidence suggesting the interaction among glutamate (GLU), dopamine (DA) and ascorbic acid (AA) in the striatum, their actions are often studied separately. Microdialysis was used here to quantify the extracellular interaction among GLU-DA-AA in the striatum of rats, an interaction which was compared with those studied in the substantia nigra (SN). Perfusion of GLU by reverse microdialysis increased DA and decreased 3,4-dihydroxyphenylacetic acid (DOPAC) in the extracellular medium of the striatum, but increased both DA and DOPAC in the SN. The increase of extracellular DA-concentration induced by the local DA-perfusion decreased the extracellular level of GLU and glutamine, an effect that, as suggested by the GLU and glutamine increase observed after the haloperidol administration, probably involves the D2 dopamine receptor. Local administration of AA increased the extracellular DA, decreased DOPAC and had no effect on GLU and glutamine. Present data suggest that, in the striatum, GLU-release inhibits DA-uptake, DA-release inhibits GLU-release, and AA-release prevents DA-oxidation increasing its extracellular diffusion. These effects were different in the SN where GLU probably promoted the DA-release instead of inhibiting the DA-uptake as presumably occurred in the striatum. Present data denote a marked GLU-DA-AA interaction in the striatum, which might be relevant for the pharmacological control of basal ganglia disorders., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The influence of nigrostriatal cell firing on the dopamine transporter (DAT) activity of the rat striatum was studied in vivo with amperometric methods. Data were obtained after preventing dopamine (DA) release with alpha-methyl-L-tyrosine and replenishing extracellular DA with local injections. The DA cell stimulation, which under basal conditions increased extracellular DA, decreased DA after this pre-treatment, suggesting that firing activity facilitates the DA cell uptake of DA under these circumstances (drain response). Cocaine and GBR13069 markedly decreased the drain response, suggesting that it is dependent on DAT activation. Data obtained after haloperidol and apomorphine administration showed that the drain response was facilitated by pre-synaptic DA receptor stimulation but that receptors are not a necessary requirement. Two components in the drain response were observed, one with a short latency and duration that needed high-frequency stimuli, and the other with a long latency and duration that was even induced by low-frequency stimuli. This is the first evidence showing that DAT can be activated by the firing activity in nigrostriatal cells in a direct way and without the participation of pre-synaptic DA receptors.

In contrast to the relatively high attention paid to the structural heterogeneity of striatal dopamine (DA) innervation, little attention has been focused on the possible striatal heterogeneity for release and uptake of DA. By using amperometric methods, we found striatal regions showing a DA decrease during the medial forebrain bundle stimulation (drain areas) near to other zones that showed an increase in DA concentration (fountain areas). Both areas were intermixed to form a tridimensional matrix to regulate DA concentration throughout the striatum (fountain-drain matrix). The response to electrical stimuli of different amplitudes and durations and to different drugs (alpha-methyl-l-tyrosine, cocaine, gamma-butyrolactone, and haloperidol) suggests that regional differences for both DA release/DA uptake and DA cell firing autoregulation are behind the striatal fountain-drain matrix. The high diversity of DA activity observed in the striatum is a new framework for analyzing experimental and clinical phenomena.

It is generally considered that Parkinson's disease is induced by specific agents that degenerate a clearly defined population of dopaminergic neurons. Data commented in this review suggest that this assumption is not as clear as is often thought and that aging may be critical for Parkinson's disease. Neurons degenerating in Parkinson's disease also degenerate in normal aging, and the different agents involved in the etiology of this illness are also involved in aging. Senescence is a wider phenomenon affecting cells all over the body, whereas Parkinson's disease seems to be restricted to certain brain centers and cell populations. However, reviewed data suggest that Parkinson's disease may be a local expression of aging on cell populations which, by their characteristics (high number of synaptic terminals and mitochondria, unmyelinated axons, etc.), are highly vulnerable to the agents promoting aging. The development of new knowledge about Parkinson's disease could be accelerated if the research on aging and Parkinson's disease were planned together, and the perspective provided by gerontology gains relevance in this field. [ABSTRACT FROM AUTHOR]

Available data show marked similarities for the degeneration of dopamine cells in Parkinson's disease (PD) and aging. The etio-pathogenic agents involved are very similar in both cases, and include free radicals, different mitochondrial disturbances, alterations of the mitophagy and the ubiquitin-proteasome system. Proteins involved in PD such as α-synuclein, UCH-L1, PINK1 or DJ-1, are also involved in aging. The anomalous behavior of astrocytes, microglia and stem cells of the subventricular zone (SVZ) also changes similarly in aging brains and PD. Present data suggest that PD could be the expression of aging on a cell population with high vulnerability to aging. The future knowledge of mechanisms involved in aging could be critical for both understanding the etiology of PD and developing etiologic treatments to prevent the onset of this neurodegenerative illness and to control its progression. [ABSTRACT FROM AUTHOR]

An over-stimulation of nigral glutamate ( GLU) receptors has been proposed as a cause of the progression of the dopamine ( DA) cell degeneration (excitotoxicity) which characterizes Parkinson's disease. The possible toxic action of striatal GLU (retrograde excitotoxicity) on these cells, and on other neurons which innervate the striatum and which also degenerate in Parkinson's disease (thalamostriatal cells of the intralaminar thalamic nuclei), is still practically unexplored. The retrograde excitotoxicity of striatal GLU on DAergic mesostriatal and GLUergic thalamostriatal cells was tested here by studying these cells 6 weeks after striatal perfusion of GLU by reverse microdialysis. GLU perfusion induced the striatal denervation of thalamic inputs (as revealed by vesicular glutamate transporter 2) and the remote degeneration of intralaminar neurons. In both centres, these effects were accompanied by microglial activation. Similar responses were not observed for nigrostriatal neurons, which showed no dopaminergic striatal denervation, no microglial activation in the substantia nigra and no changes in the number of dopaminergic cells in the substantia nigra. The inhibition of DAergic transmission increased the extrasynaptic GLU levels in the striatum (evaluated by microdialysis), an effect observed after the local administration of agonists and antagonists of DAergic transmission, and after the peripheral administration of levodopa (which increased the DA and decreased the GLU levels in the striatum of rats with an experimental DAergic denervation of this centre). The data presented show that striatal GLU induced a retrograde excitotoxicity which did not affect all striatal inputs in the same way and which could be involved in the cell degeneration of the intralaminar nuclei of the thalamus generally observed in Parkinson's disease. [ABSTRACT FROM AUTHOR]