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  • 1
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Norepinephrine, clonidine, and phenylephrine increased the electrically evoked release of endogenous acetylcholine in cortical slices taken from morphine-tolerant guinea pigs. This effect was α1adrenoreceptor mediated and was opposite to the α2-adrenoreceptor-mediated inhibition of acetylcholine release, normally elicited by norepinephrine and clonidine. In the presence of prazosin, clonidine recovered its normal inhibitory properties, suggesting that morphine tolerance induced the appearance of an α1adrenoreceptor-mediated response that overshadowed, but did not cancel, the still present α2-adrenoreceptor inhibitory control. The attempt to prove the presence of α-adrenoreceptors on the nerve endings by testing the effect of norepinephrine in synaptosomal preparations (preloaded with [3H]choline and de-polarized with KCL and veratridine) was unsuccessful. Therefore the problem of the exact location of this excitatory input remains to be solved. These results confirm previous findings reporting the increase in cortical acetylcholine release induced by the α-adrenoreceptor agonists in morphine-tolerant, freely moving guinea pigs and demonstrate that opiate tolerance inverts the direction of the noradrenergic modulation even in the isolated intracortical cholinergic structures.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 757 (1995), S. 0 
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 36 (1981), S. 0 
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The release processes of endogenous Acetylcholine (ACh), γ-aminobutyric acid (GABA), glutamate (Glu) and glutamine (GLN) were studied in superfused guinea-pig caudatal slices. Basal ACh release remained constant for up to 2 h, while the basal release of GABA, Glu and GLN declined to half or less of its initial values after 1 h of superfusion. Electrical stimulation increased the ACh release by 700–800% and that of GABA by 80% whereas it decreased the output of Glu by 50% and failed to modify the GLN efflux. KCl (25 mM) increased the output of ACh by 400%, that of GABA by approximately 500% and decreased that of Glu by 40%. Substituting of CaCl2 by MgCl2 in the superfusion medium reduced the basal ACh release by 70% whereas no differences were observed in the basal efflux of GABA, Glu and GLN. Under these conditions, no evoked release of ACh or of GABA was detected, following electrical or KCl stimulation. Tetrodotoxin 5 × 10-7 M decreased the basal ACh release by 60% and increased the GABA efflux by 40%. The toxin abolished the stimulus-evoked ACh efflux but scarcely affected that of GABA. These results are consistent with a possible neurotransmitter role of ACh and GABA in the striatum and show some differences in the ionic mechanisms underlying GABA and ACh release.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-1106
    Keywords: MPTP ; Dopamine ; Degeneration ; Mouse ; Protection ; Uptake ; Immunocytochemistry ; Image analysis ; Biochemistry ; Substantia nigra ; Neostriatum
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Based on the observations that the psychostimulant drug amphetamine in combination with physiotherapy can promote recovery of brain function after brain injury, we have studied the ability of the vigilance promoting drug Modafinil to counteract 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-(MPTP)-induced degeneration of the nigrostriatal dopamine (DA) neurons of the black mouse. MPTP was given s.c. in a dose of 40 mg/kg and the mice were sacrificed 2 weeks later. The effects of acute and chronic treatment with Modafinil were studied on MPTP-induced DA neurotoxicity. The substantia nigra and neostriatum were taken to both biochemical and histochemical analysis of presynaptic parameters of the nigrostriatal DA neurons, the latter in combination with image analysis. In separate experiments in rats in vivo tests for DA uptake blocking activity were made using intrastriatal microdialysis to study superfusate levels of DA and its metabolites and the 4-α-dimethylmetatyramine (H77/77) model to test for a possible ability of Modafinil to protect against H77/77-induced depletion of forebrain DA stores. Chronic treatment with Modafinil in doses of 10 to 100 mg/kg counteracted the MPTP-induced disappearance of nigral TH IR nerve cell body profiles and neostriatal TH IR nerve terminal profiles as evaluated after 2 weeks with image analysis. Chronic treatment with Modafinil (10–100 mg/kg) also dose-dependently counteracted the MPTP-induced disappearance of striatal DA uptake binding sites as evaluated at the same time interval. Also in the dose range 10–100 mg/kg Modafinil counteracts the MPTP-induced depletion of DA stores both in the neostriatum and the substantia nigra. In the acute experiments Modafinil (30 mg/kg) protected against the MPTP-induced depletion of striatal DA, dihydrophenylacetic acid (DOPAC) and homovanillic acid (HVA) levels both when given 15 min before, at the same time and 3 h following the MPTP injection. In the substantia nigra, however, these protective actions of Modafinil were only observed when the drug was coadministered with MPTP. Experiments with microdialysis in intact rats failed to demonstrate any increases of superfusate DA levels in neostriatum with 30 mg/kg of Modafinil. Modafinil in high doses of 2 × 50 mg/kg, however, significantly counteracted the H77/77 induced DA depletion of striatal DA stores. Thus, morphological and biochemical evidence has been obtained that Modafinil in the dose range 10–100 mg/kg protects against MPTP-induced degeneration of the nigrostriatal DA neurons of the black mouse. The results also indicate that the protective action of Modafinil is not caused by monoamine oxidase inhibition or by DA uptake inhibition, although the latter action may contribute in the highest dose used (100 mg/kg). Instead, it is hypothesized that its protective action may be related to actions on GABAergic mechanisms as evidenced by reduced cortical GABA outflow in doses of 3–30 mg/kg (Tanganelli et al. 1991) and/or to other unknown mechanisms.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-1106
    Keywords: Endothelin-1 ; Striatum ; Ischemia ; Microdialysis ; Cerebral blood flow ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have studied the ability of the vigilance-promoting drug modafinil to counteract the ischemic lesion produced by a unilateral microinjection of endothelin-1 (ET-1) in the neostriatum of the rat using a combined morphometrical, biochemical, cardiovascular and behavioral analysis. ET-1 was injected unilaterally into the neostriatum. The ET-1-induced lesion volume, which was determined by a computer-assisted morphometrical analysis, was reduced by the 7-day modafinil treatment (10, 30, and 100 mg/kg i.p.) in a dose-related way. Modafinil also produced a dose-related counteraction of the ET-1-induced increase of perfusate lactate levels, as determined by intrastriatal microdialysis without affec ting the ET-1 induced reduction of striatal blood flow, as determined by laser-Doppler flowmetry. The ipsilateral rotational behavior induced by apomorphine in the ET-1-lesioned rats was reduced dose-dependently by modafinil treatment. Thus, morphological, neurochemical, and behavioral evidence that the putative ischemic striatal injury induced by microinjection of ET-1 in the rat neostriatum is counteracted in a dose-dependent way by modafinil treatment has been obtained. The mechanism does not appear to involve an increase in striatal blood flow. It is instead speculated that its powerful preventive action in striatal ischemic injury may be related to a reduced anaerobic metabolism.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 318 (1982), S. 253-258 
    ISSN: 1432-1912
    Keywords: Nerve endings ; ACh release ; GABA agonists and antagonists ; Tetrodotoxin ; Presynaptic GABA receptors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of GABA on acetylcholine (ACh) release was investigated on superfused slices of guinea-pig cerebral cortex (CC), caudate nucleus (CN), tuberculum olfactorium and brain stem. GABA (1–6×10−3 mol/l) increased the spontaneous and KCl-evoked ACh overflow in CC and CN, reduced the electrically-evoked release in all areas tested (most evidently in CC and CN) and lowered the threshold of electric stimulation-induced ACh release in CC. These effects were also caused by 3-amino-1-propane sulphonic acid (1×10−3mol/l) and ethanolamine-O-sulphate (2×10−4mol/l), were reduced by bicuculline (1×10−4mol/l) and fully antagonized by picrotoxin (8×10−5mol/l), but they were not influenced by phentolamine, methysergide, spiroperidol or strychnine. Tetrodotoxin (TTX) (5×10−7mol/l) blocked the facilitation of spontaneous ACh release by GABA only when the slices were perfused with normal Krebs solution, but not when perfused with a KCl-enriched medium. These results suggest that GABA affects the cholinergic transmitter release through bicuculline- and picrotoxin-sensitive receptors, showing low affinity toward the agonist. Moreover GABA modulation of resting ACh release requires action potentials only in normal [K+]0, but not in high [K+]0, suggesting that GABA-receptive sites are located at cholinergic terminals.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 328 (1984), S. 119-126 
    ISSN: 1432-1912
    Keywords: ACh release ; tritium efflux ; Morphine ; GABA ; Brain slices
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Superfused slices of guinea-pig cerebral cortex (CC), caudate nucleus (CN) and thalamus (Th) were used to compare i) the resting and electrically-evoked release of endogenous acetylcholine (ACh) in the presence of physostigmine (Phys) and ii) the resting and electrically-evoked tritium efflux (after preloading with 3H choline) in the absence or in the presence of Phys and hemicholinium (HC-3). In addition, the effect of GABA, morphine and their antagonists on both effluxes was investigated. 1) By matching the ACh and tritium outflow on a molar basis, an average ratio of 100: 2–4 was found. When expressed as a percentage of tissue content, the ACh release at 2 Hz (2 min) was 4.1 in CN, 0.92 in CC and 0.44 in Th. Lower percent values in the same rank order, were found for tritium outflow with Phys. Thus, CN has the highest secretory activity. 2) Tritium evoked outflow in the presence of Phys was nearly halved in comparison with the normal values (without Phys). Therefore, the autoreceptor-mediated negative feed-back seems to be similar in the three areas. 3) Tritium evoked outflow in the presence of HC-3 was more than doubled in Th (less so in CC and CN) in comparison with the normal values. A second stimulation at 2 Hz (2 min) gave rise to the same outflow in Th while an evident fall in radiolabel efflux was found in CN. Therefore the blockade of high affinity choline uptake plays a different role in Th and CN. 4) The ratio between two subsequent periods of stimulation at 2 Hz for 2 min (at the 45th and 75th min, St2/St1) ranged as a rule between 0.75 and 1 for ACh and tritium. However, when the evoked outflow of ACh and tritium was tested during St2 at different rates (1–2–5–10 Hz), a three-times greater increase of ACh with respect tritium was found, as a function of the stimulation frequency. This suggests an inverse relationship between specific radioactivity of released transmitter and second stimulus intensity, above all when Phys and HC-3 are not present. 5) GABA 0.3–0.6 mM, added before St2, inhibited the evoked ACh and tritium efflux in CC and CN and increased the resting release in a dose-dependent manner. Conversely, picrotoxin, which prevented GABA effect, increased the evoked ACh release but not tritium efflux. Morphine 30 μM also inhibited the evoked ACh and tritium efflux from Th slices. However, the drug in the presence of naloxone enhanced ACh release but not tritium outflow. 6) In conclusion, the two methods give results only in part superimposable. Tritium method allows drug-induced inhibition to be seen more readly than facilitation. This fact may depend on the reduction of ACh specific radioactivity in St2, whenever drug treatment enhances the release process, thus involving less labelled (or more diluted) neurotransmitter stores.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 324 (1983), S. 34-37 
    ISSN: 1432-1912
    Keywords: ACh release ; Presynaptic GABA receptors ; Diazepam-antagonism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The acetylcholine (ACh) release was studied in superfused, electrically-stimulated slices of guinea-pig cerebral cortex. Muscimol and 4,5,6,7-tetrahydroisoxazolo (5-4-c)-pyridin-3-ol (THIP), as well as exogenous GABA, reduced the electrically-evoked ACh release and enhanced its spontaneous outflow. Picrotoxin antagonized these effects. In addition, picrotoxin and ethanolamine-O-sulphate (EOS) caused opposite changes in transmitter outflow, suggesting the existence of an endogenous GABAergic control on the cholinergic nerve endings. Neither flurazepam 6.6×10−6–3.3×10−5 mol/l nor diazepam 3.3×10−6–3.3×10−5 mol/l by themselves affected ACh release. Diazepam prevented GABA-, muscimol- and EOS-induced changes in spontaneous and 1 Hz-evoked outflow. Ro 15-1788 3.3×10−6 mol/l abolished diazepam antagonism vs exogenous GABA. The ineffectiveness of flurazepam and diazepam on normal release (i.e. the lack of potentiation vs the endogenous GABAergic control) supports the view that “synaptic” GABA receptors acting upon the cholinergic nerve endings are not coupled with Benzodiazepine receptors. The unexpected diazepam antagonism vs exogenous GABA and GABA-like compounds can be explained with an unusual Diazepam negative cooperation with “extrasynaptic” GABA receptors, possibly present on the cholinergic terminals. Thus, the rule of benzodiazepine-GABA synergism does not seem always tenable, at least at certain pre-synaptic sites.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-1912
    Keywords: Acetylcholine ; GABA ; 5-HT ; 5-HT2 receptors ; Metabolism ; Cortical cup ; Modafinil ; Release
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effects of modafmil on acetylcholine and GABA outflow from the cerebral cortex of awake freely moving guinea pigs provided with an epidural cup were studied. In the dose range of 3–30 mg/kg s. c. modafmil produced a dose dependent significant inhibition of GABA outflow without influencing cortical acetylcholine release. Methysergide (2 mg/kg, i.p.) and ketanserin (0.5 mg/kg, i. p.) but not prazosin (0.14 mg/kg, i. p.) counteracted the inhibitory action of modafinil on cortical GABA outflow. Modafinil both acutely and chronically in the same dose range increased striatal 5-HIAA levels and 5-HT utilization in the rat (acute) and mouse (chronic). The action on cortical GABA release may be dependent on activity at 5-HT2 receptors, since the action of modafmil in this respect is blocked by the non-selective 5-HT antagonist methysergide and the 5-HT2 antagonist ketanserin. The involvement of 5-HT mechanisms in the inhibitory action of modafmil on cortical GABA release is also suggested by the findings that 5-HT metabolism may become increased by modafmil at least in the striatum. The reduction of cortical GABA outflow via 5-HTZ receptors by modafmil is probably related to some of its actions on the central nervous system including behavioural effects.
    Type of Medium: Electronic Resource
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