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  • GABAB antagonists  (2)
  • Muscimol  (2)
  • 1
    Digitale Medien
    Digitale Medien
    Potential involvement of a baclofen-sensitive autoreceptor in the modulation of the release of endogenous GABA from rat brain slices in vitro (1988)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 337 (1988), S. 289-295 
    Details
    ISSN: 1432-1912
    Schlagwort(e): Baclofen ; GABA release ; Brain slices ; Muscimol ; Bicuculline
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The effects of the GABAA agonist, muscimol, and of the enantiomers of the GABAB agonist, baclofen, on the release of endogenous GABA from slices of the rat cerebral cortex, striatum and hippocampus were measured by means of a HPLC method with electrochemical detection. Moreover, the effect of the GABAA antagonist, bicuculline, and of the frequency of stimulation were studied in cortical slices. The amount of endogenous GABA released per impulse from cortical slices decreased by about 50% when the frequency was increased from 0.25 Hz to 1 Hz. This might indicate that GABA inhibited its own release. (−)-Baclofen at 1 and 10 μM, but not its (+)-enantiomer, markedly inhibited the release of endogenous GABA, to a similar extent in all 3 areas investigated. The effect of (−)-baclofen was dependent on the frequency of stimulation: at lower frequencies (0.25 and 0.5 Hz) it was more marked than at a higher one (4 Hz). This would be expected from the results showing that the release of endogenous GABA decreases with increasing frequency, which suggests that this amino acid inhibits its own release. Muscimol at 10 μM, on the other hand, was ineffective in all 3 areas at a stimulation frequency of 0.5 Hz. Bicuculline (10 μM) at 4 Hz, at which autosuppression of GABA release is maximal did not enhance the release of endogenous GABA from cortical slices. With cerebellar or nigral slices, no adequate stimulation-induced release of endogenous GABA could be obtained under comparable conditions. These data are compatible with, but do not prove the existence of GABAB-type presynaptic autoreceptors modulating the release of this amino acid. More definite conclusions may possibly be drawn when a GABAB antagonist becomes available, which is expected to enhance GABA release under appropriate conditions.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00168841
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  • 2
    Digitale Medien
    Digitale Medien
    Autoreceptor-mediated regulation of GABA release: role of uptake inhibition and effects of novel GABAB antagonists (1993)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 347 (1993), S. 514-520 
    Details
    ISSN: 1432-1912
    Schlagwort(e): CGP 34348 ; GABAB antagonists ; GABAB autoreceptor ; GABA release ; GABA uptake inhibition ; Frequency dependence
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary While the role of GABAB autoreceptors in the regulation of GABA release in synaptosomes and brain slices is well established, little is known about their role in vivo. Doubts have arisen because there is an apparent discrepancy between the frequencies at which GABA neurons fire and the frequency range within which autoreceptor regulation is observed in vitro. To see whether this apparent mismatch could be due to the use of a GABA uptake inhibitor in the release experiments in slices, we have compared the frequency dependencies of GABA release in the presence and absence of uptake inhibition. Beforehand, the previously incomplete frequency curve in the presence of uptake inhibition was extended at the lower end. To achieve this, stimulation was performed by means of groups of 4 pseudo-one-pulses (POP's) at inter-POP intervals corresponding to frequencies of 0.015625-0.5 Hz. It could be shown that activation of the GABAB autoreceptor by endogenously released GABA begins at a stimulation frequency as low as 0.0625 Hz. Experiments with the antagonist, CGP 35348, at inter-POP intervals of 1 min, at which the preceding POP has no longer an effect on GABA release during the next one, showed that basal release alone already substantially activated the autoreceptor. The frequency dependence in the absence as compared to the presence of uptake inhibition was shifted towards higher frequencies by a factor of 4. We do not consider this enough to remove our doubts about the in vivo operativity of GABAB autoreceptors. Further experiments in the presence of uptake inhibition were made to see whether the expectation was met that autoreceptor-mediated regulation of GABA release could be blocked out by sufficiently high concentrations of potent antagonists. As judged from the frequency dependence in the presence of 1 μmol/l of the potent compound CGP 55845 as well as from the similarity of the maximal increases of GABA release caused at 0.125 and 2 Hz by various other potent, novel GABAB antagonists, this was not the case. Possible explanations are the occurrence of an agonist and an antagonist state of the autoreceptor prevailing at low GABA concentrations or, less likely, the occurrence of two autoreceptor subtypes with different relative sensitivities towards GABA and baclofen on the one hand and towards aminophosphonous acid antagonists on the other. Finally, it was shown that also in the absence of uptake inhibition, regulation of GABA release was mediated entirely by GABAB autoreceptors. Both muscimol and bicuculline at 1 and 10 μmol/1 were without effect.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00166744
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  • 3
    Digitale Medien
    Digitale Medien
    A role for computer simulation in solving the riddles of autoreceptor-mediated regulation of GABA release (1993)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 348 (1993), S. 618-627 
    Details
    ISSN: 1432-1912
    Schlagwort(e): GABA release ; Autoreceptor ; GABA uptake ; computer simulation ; GABAB antagonists ; Baclofen
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The autoreceptor-mediated control of GABA release was simulated on a personal computer using commercially available software (STELLATM/ITHINKTM). The experimental data to be matched were taken from previous publications. A basic model was able to fairly accurately reproduce frequency dependencies of GABA release in the presence and absence of uptake inhibition as well as concentration-response curves for changes in release produced by the agonist, (−)-baclofen, or by relatively low concentrations of the antagonists, phaclofen and CGP 35348. Obvious mismatch was observed at high concentrations of a potent antagonist, at a stimulation frequency of 2 Hz. Whereas the experimental data indicate a 3-fold increase in release as compared to controls, simulation predicts a 7-fold increase. By adaptation of the model, simulation data were obtained indicating that this mismatch was not due to (a) the autoreceptor occurring as two subtypes with different affinities for antagonists, (b) the occurrence of an agonist and antagonist state of the autoreceptor, with the latter prevailing at low synaptic concentrations of endogenous GABA, and (c) overruling of uptake inhibition by markedly elevated synaptic GABA concentrations. On the other hand, a simple restriction of the amount of transmitter able to be released per time unit produced much better matching data. A refined model assuming a restricted replacement capacity for exocytotically emptied synaptic vesicles at their docking sites gave similar results. As a consequence, we shall attempt to address this possibility experimentally. Simulation can never prove a case in the positive sense. It can, however, help to exclude ill-matching solutions of a problem and to prioritize among possible ones, which then must be experimentally addressed. We found simulation with this user-friendly software extraordinarily useful, also and not least because it necessitates and stimulates very intense dealing with a subject.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00167238
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  • 4
    Digitale Medien
    Digitale Medien
    Release of endogenous GABA from the substantia nigra is not controlled by GABA autoreceptors (1989)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 340 (1989), S. 372-378 
    Details
    ISSN: 1432-1912
    Schlagwort(e): GABA release ; Electrical/K+ stimulation ; Substantia nigra slices ; Baclofen ; Muscimol ; Bicuculline
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The characteristics of the release of GABA from slices of the rat substantia nigra, elicited by electrical stimulation at frequencies of 0.5–48 Hz and by elevated K+ concentrations ranging from 15–35 mmol/l, was studied. Comparisons were made with cortical slices where the data were not available from previous studies. No GABA release could be evoked from rat nigral slices by electrical stimulation between 0.5 and 4 Hz, in contrast to cortical slices, in which this pool is sensitive towards inhibition by (−)-baclofen. Also, comparatively less GABA release could be evoked from nigral than from cortical slices by K+ concentrations between 15 and 25 mmol/l. While (−)-baclofen at 10 μmol/l inhibited release caused by 15 μmol/l K+ in cortical, it did not in nigral slices. GABA release caused by higher frequencies (8–48 Hz) or 30 mmol/l K+ concentrations was Ca2+-dependent and in the former case also tetrodotoxin-sensitive. It had similar characteristics as in cortical slices and was insensitive towards (−)-baclofen, muscimol and bicuculline. Even more markedly than in the cortex, 30 mmol/l K+ released greater amounts of GABA than electrical stimulation at 24 Hz of a similar duration, suggesting the existence of one or several additional pool(s) of lesser excitability. Since the majority of gabaergic nerve endings in the nigra belong to striato- and pallidonigral projection neurons and those in the cortex probably exclusively to various types of interneurons, it seems that (a) one or several of the latter release GABA at low frequencies in a baclofen-sensitive manner and are absent or rare in the s. nigra, and (b) the striato- and pallidonigral projection neurons are not controlled by presynaptic autoreceptors of the GABAA or GABAB type, because neither GABA release elicited by electrical stimulation nor by 30 mmol/l K+ was affected by agents interfering with these types of receptors.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00167037
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