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  • 1
    ISSN: 1432-1106
    Keywords: Dopamine ; Neuropeptide Y ; Somatostatin ; Tachykinin ; Cholecystokinin ; In situ hybridization ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In situ hybridization was used to study the expression of prepro-neuropeptide Y (NPY), preprosomatostatin (SOM), preprotachykinin (PPT) and preprocholecystokinin (CCK) mRNA in caudate-putamen and frontoparietal cortex of rat brain with unilateral lesion of midbrain dopamine neurons. Neurons expressing NPY and SOM mRNA showed a similar distribution and the expression of both NPY and SOM appears to be regulated by dopamine in a similar fashion. Following a dopamine deafferentation, the numerical density of both NPY and SOM mRNA producing neurons almost doubled in the lesioned caudate-putamen with no change in the average grain density over positive neurons. Hence, in the intact caudate-putamen dopamine appears to suppress expression of these two neuropeptide genes leading to an activation of both NPY and SOM mRNA expression in many non- or low-expressing neurons when the level of dopamine is decreased. In the fronto-parietal cortex, on the other hand, dopamine appears to stimulate NPY and SOM gene expression. Thus, in the absence of dopamine about half of the NPY positive neurons disappeared. However, for SOM the number of positive neurons did not change, but rather most positive neurons appeared to have down-regulated their SOM mRNA expression. No evidence was found for a change in CCK mRNA expression by the dopamine deafferentation, while PPT mRNA expression decreased in the deafferented caudate-putamen. Consequently, dopamine exerts dissimilar effects on the expression of different neuropeptide genes, that in turn do not respond in the same way in different brain regions.
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  • 2
    ISSN: 1432-1106
    Keywords: Basal ganglia ; Dopamine ; Dynorphin ; Substance P ; 6-hydroxy-dopamine ; Ibotenic acid ; Rotational behaviour ; Intracerebral dialysis technique ; Feedback regulation ; Efferent pathways
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the present study the functional role of the striato-nigral dynorphin and substance P pathways in rat brain has been studied using the rotational behavioural model and an intracerebral dialysis technique complemented with brain lesions and immunohistochemical analysis. Attempts were made to evaluate whether these striato-nigral neurons have a feed-back modulatory action on the dopaminergic nigro-striatal system, or whether they represent an outflow pathway conveying motor information from the striatum. Unilateral injection of dynorphin A into the substantia nigra reticulata of naive rats induced contralateral rotational behaviour. This effect was dose-dependent and mimicked by the kappa-opioid receptor agonist, U50,488H. Intranigral injection of substance P, as well as substance K, also produced dose-dependent contralateral rotational behaviour. Unilateral injections of ibotenic acid into various sites of the striatum were used to destroy the striato-nigral pathways. The lesions produced a depletion of dynorphin- and substance P-like immunoreactivity in the pars reticulata of the substantia nigra ipsilateral to the lesion and markedly affected the behavioural responses to intranigral peptide injections. Dynorphin A more potently induced contralateral rotation in the lesioned compared to naive non-lesioned rats, suggesting development of supersensitivity for this peptide. Substance P on the other hand, was markedly less potent in inducing rotation in lesioned animals. The rotational responses to both dynorphin A and substance P were potentiated by injection of amphetamine 1 h later, suggesting that both peptides act via nigro-striatal dopamine neurons. However, in rats with unilateral nigro-striatal dopamine denervation, produced with 6-hydroxy-dopamine, dynorphin A retained its potency to induce rotational behaviour; substance P was again much less potent. Thus, both the ibotenic acid and 6-hydroxy-dopamine lesions differently affect the action of dynorphin A and substance P in the zona reticulata of the substantia nigra. The data suggests that substance P requires an intact dopamine pathway to produce the rotational response, while dynorphin A does not. Direct evidence that behavioural activation produced by dynorphin A is not dependent upon dopamine stimulation was obtained by intrastriatal dialysis experiments in which changes in striatal dopamine release were measured following intranigral injection of dynorphin A or substance P. Intranigral dynorphin A in fact reduced, while substance P increased the release of dopamine. It is concluded that the dynorphin and substance P striatonigral pathways have different functions. Thus, substance P in the striato-nigral pathway may have a role in a positive feed-back loop regulating the firing of nigro-striatal dopamine neurons, while dynorphin might be important in negative feed-back control. The rotational behaviour produced by DYN A is probably due to direct stimulation of receptors located on nigro-thalamic and nigro-tectal pathways.
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  • 3
    ISSN: 1432-1106
    Keywords: Dopamine ; Glutamic acid decarboxylase ; In situ hybridization ; Basal ganglia ; Fronto-parietal cortex
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In situ hybridization histochemistry and RNA blots were used to study the expression of glutamic acid decarboxylase (GAD) mRNA in rats with or without a unilateral lesion of midbrain dopamine neurons. Two populations of GAD mRNA positive neurons were found in the intact caudate-putamen, substantia nigra and fronto-parietal cortex. In caudate-putamen, only one out of ten of the GAD mRNA positive neurons expressed high levels, while in substantia nigra every second of the positive neurons expressed high levels of GAD mRNA. Relatively few, but intensively labelled neurons were found in the intact fronto-parietal cerebral cortex. In addition, one out of six of the GAD mRNA positive neurons in the fronto-parietal cortex showed a low labeling. On the ipsilateral side, the forebrain dopamine deafferentation induced an increase in the number of neurons expressing high levels of GAD mRNA in caudateputamen, and a decrease in fronto-parietal cortex. A smaller decrease was also seen in substantia nigra. However, the total number of GAD mRNA positive neurons were not significantly changed in any of these brain regions. The changes in the levels of GAD mRNA after the dopamine lesion were confirmed by RNA blot analysis. Hence, midbrain dopamine neurons appear to control neuronal expression of GAD mRNA by a tonic down-regulation in a fraction of GAD mRNA positive neurons in caudate-putamen, and a tonic up-regulation in a fraction of GAD mRNA positive neurons in fronto-parietal cortex and substantia nigra.
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  • 4
    ISSN: 1432-2072
    Keywords: Methylxanthines ; Dopamine ; Adenosine ; Benzodiazepine ; Neurotransmitter ; Neuromodulator
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Like the dopamine agonist apomorphine, the methylxanthines caffeine, theophylline and theobromine produced dose-dependent contralateral rotation in rats with unilateral 6-hydroxydopamine denervation, a response considered to be dependent upon dopamine receptors rendered supersensitive. This response was also observed after the injection of the substances into the denervated striatum. Indeed, intrastriatal administration of caffeine into the dopamine denervated striatum produced, dose-dependently (1.0–50.0 μg/μl), contralateral rotation. However, while apomorphine produced ipsilateral rotation in rats with unilateral striatal kainic acid lesions, a response considered to be dependent upon normosensitive dopamine receptors, neither caffeine nor theophylline produced rotational responses. As for apomorphine, the rotational behaviour elicited by caffeine (15.0 mg/kg SC) and theophylline (25.0 mg/kg SC) was inhibited by the dopamine antagonistscis-(Z)flupentixol, haloperidol and sulpiride. Nevertheless, despite the fact thatcis-(Z)flupentixol was the most potent inhibitor of the caffeine response, no more than 50% inhibition was produced with doses as high as 1.0–10.0 mg/kg SC ofcis-(Z)flupentixol. Pretreatment with alpha methyl-p-tyrosine inhibited the rotational response produced by caffeine in 6-OHDA-lesioned animals, but did not significantly modify the apomorphine response. Furthermore, the benzodiazepine diazepam produced a dose-dependent inhibition of the caffeine rotation, but again, the apomorphine response, although qualitatively modified, was not significantly inhibited.
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  • 5
    ISSN: 1432-2072
    Keywords: 6-Hydroxydopamine ; Neonatal ; Unilateral ; Microdialysis ; Amphetamine ; Dopamine ; Serotonin ; Acetylcholine ; Adenosine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 6-hydroxydopamine (6-OHDA, 100 µg in 5 µl) was injected into the right ventricle of 3-day-old Sprague-Dawley rats in order to produce a unilateral dopamine (DA) lesion. At adult stage, the rats were implanted with microdialysis probes into the left and right striata. On the injected side, basal extracellular levels of DA were reduced by 〉65%, as compared to the contralateral side or to the levels found in vehicle-injected rats. Extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were reduced by 〉95%, while acetylcholine (ACh) was decreased by 〉50%.d-Amphetamine (2 mg/kg SC) produced a 10-fold increase in extracellular DA levels in the striatum contralateral to the 6-OHDA-injected side, while on the ipsilateral side, DA levels were not affected byd-amphetamine.d-Amphetamine produced an increase (〉2 fold) in extracellular ACh levels, on both ipsilateral and contralateral sides. Choline and adenosine levels were unaffected by any of the experimental conditions. Thus, neonatal unilateral ICV administration of 6-OHDA produced an ipsilateral decrease in striatal extracellular DA, DOPAC and HVA levels, compared to the contralateral side. A reduction of extracellular ACh levels was also observed on the 6-OHDA-injected side. The DA releasing effect ofd-amphetamine was abolished on the 6-OHDA-injected side, but not that on ACh levels, indicating that striatal DA and AChd-amphetamine-induced release are produced by independent mechanisms in the meonatally unilateral 6-OHDA-treated animals. As a whole the present study gives evidence showing that neonatal unilateral ICV treatment with 6-OHDA produces a predominantly unilateral lesion of the mesencephalic DA systems.
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  • 6
    ISSN: 1438-2199
    Keywords: Amino acids ; Glutamate ; Aspartate ; Dopamine ; Cholecystokinin ; Microdialysis ; Basal Ganglia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Extracellular levels of cholecystokinin (CCK), dopamine (DA), glutamate (Glu) and aspartate (Asp) were simultaneously monitored in the frontoparietal cortex and the striatum of halothane-anaesthetized rats using in vivo microdialysis. Under basal conditions, cortical and striatal CCK levels were 3.11 ± 0.39 pM and 2.76 ± 0.15 pM, respectively. Local KCl (10−1 M) and bicuculline (10−4 M) co-application in cortex or striatum increased the CCK levels 18-fold and 26-fold, respectively. The DA level in striatum was 3.78 ± 0.28 nM and the local perfusion with KCl + bicuculline led to a 45-fold increase. The cortical and striatal outputs of Glu were of the order of 2 · 10−6 M and Asp levels were around 6 · 10−7 M. Local stimulation with KCl (10−1 M) and bicuculline (10−4 M) caused a small increase (2 fold) in cortical and striatal levels of Glu and Asp. The addition of KCl (10−1 M) and bicuculline (10−4 M) to the cortical perfusion medium did not modify CCK, DA or Glu concentrations in striatum. These results demonstrate that CCK, DA, Glu and Asp may be simultaneously monitored in vivo and support the idea that their extracellular levels recovered in the microdialysis perfusates could be derived from neuronal pools.
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  • 7
    ISSN: 1438-2199
    Keywords: Keywords: Amino acids ; Basal ganglia ; Dopamine ; Nitric oxide ; Excitatory amino acids ; Organotypic culture ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary. The nigrostriatal and mesolimbic systems of the rat have been re-constructed using the organotypic culture model, whereby neonatal brain tissue is grown in vitro for approximately one month. The nigrostriatal cultures consisted of tissue from the substantia nigra, dorsal striatum and frontoparietal cortex; while the mesolimbic cultures included the ventral tegmental area, ventral striatum and cingulate cortex. The cultures were grown at 35°C in normal atmosphere, using a tube-roller device placed in a cell incubator and changing the medium every 3–4 days. The in vitro development was evaluated with an inverted microscope equipped with a variable relief contrast function. Samples were taken directly from the medium in the culture tube and analysed for several amino acids with HPLC. After a month the cultures were fixed and processed for immunohistochemistry. High levels of glutamate and aspartate were observed every time the medium was changed, but the levels rapidly decreased reaching a steady state after approximately 24 h. A decrease in the levels was also observed along development, reaching stable values (∼2 μM and ∼0.12 μM for glutamate and aspartate, respectively) at approximately two weeks, but only when the cultures showed an apparently healthy development. The levels were approximately 10 times higher in deteriorating or apparently damaged cultures. Glutamine levels were in the mM range and remained stable along the entire experiment. No differences were observed among nigrostriatal and mesolimbic cultures. Immunohistochemistry confirmed the impressions obtained from microscopic and biochemical analysis along the in vitro development, revealing apparently healthy neuronal systems with characteristics similar to those observed in vivo, when tyrosine hydroxylase and nitric oxide synthase, markers for dopamine and nitric oxide containing neurons, respectively, were analysed. In the substantia nigra, nitric oxide synthase-positive networks surrounded tyrosine hydroxylase-positive neurons, while in the striatum nitric oxide synthase dendrites were surrounded by tyrosine hydroxylase-positive nerve terminals, suggesting a reciprocal interaction among dopamine and nitric oxide containing neurons. Thus, the organotypic model appears to capture many of the neurochemical and morphological features seen in vivo, providing a valuable model for studying in detail the neurocircuitries of the brain.
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  • 8
    ISSN: 1438-2199
    Keywords: Amino acids ; Dopamine ; Acetylcholine ; Glutamate ; Aspartate ; Gamma-aminobutyric acid (GABA) ; Striatum ; Microdialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The neuronal origin of extracellular levels of dopamine (DA), acetylcholine (ACh), glutamate (Glu), aspartate (Asp) and gamma-aminobutyric acid (GABA) simultaneously collected from the neostriatum of halothane anaesthetized rats with in vivo microdialysis was studied. The following criteria were applied (1) sensitivity to K+-depolarization; (2) sensitivity to inhibition of synaptic inactivation mechanisms; (3) sensitivity to extracellular Ca2+; (4) neuroanatomical regionality; sensitivity to selective lesions and (5) sensitivity to chemical stimulation of the characterized pathways. It was found that: (1) Extracellular DA levels found in perfusates collected from the neostriatum fulfills all the above criteria and therefore the changes in extracellular DA levels measured with microdialysis reflect actual release from functionally active nerve terminals, and so reflect ongoing synaptic transmission. (2) Changes in neostriatal ACh levels reflect neuronal activity, provided that a ACh-esterase inhibitor is present in the perfusion medium. (3) Extracellular Glu, Asp and GABA could be measured in different perfusion media in the rat neostriatum and probably reflect metabolic as well as synaptic release. However, (4) the majority of the extracellular GABA levels found in perfusates collected from the neostriatum may reflect neuronal release, since GABA levels were increased, in a Ca2+-dependent manner, by K+-depolarization, and could be selectively decreased by an intrinsic neostriatal lesion. (5) It was not possible to clearly distinguish between the neuronal and the metabolic pools of Glu and Asp, since neostriatal Glu and Asp levels were only slightly increased by K+-depolarization, and no changes were seen after decortication. A blocker of Glu re-uptake, DHKA, had to be included in the perfusion medium in order to monitor the effect of K+-depolarization on Glu and Asp levels. Under this condition, it was found (6) that neostriatal Glu and Asp levels were significantly increased by K+-depolarization, although only increases in the Glu levels were sensitive to Ca2+ in the perfusion medium, suggesting that Glu but not Asp is released from vesicular pools. (7) Evidence is provided that selective stimulations of nigral DA cell bodies may lead to changes in release patterns from DA terminals in the ipsilateral neostriatum, which are in turn followed by discrete changes in extracellular levels of GABA and Glu in the same region. Finally, some methodological considerations are presented to clarify the contribution of neuronal release to extracellular levels of amino acid neurotransmitters in the rat neostriatum.
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