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  • 1990-1994  (4)
  • 1980-1984  (1)
  • Baclofen  (3)
  • GABAB antagonists  (2)
  • 3-Methoxytyramine  (1)
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Material
Years
Year
Keywords
  • 1
    Electronic Resource
    Electronic Resource
    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
    Keywords: CGP 34348 ; GABAB antagonists ; GABAB autoreceptor ; GABA release ; GABA uptake inhibition ; Frequency dependence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00166744
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    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
    Keywords: GABA release ; Autoreceptor ; GABA uptake ; computer simulation ; GABAB antagonists ; Baclofen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00167238
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  • 3
    Electronic Resource
    Electronic Resource
    3-methoxytyramine: Its suitability as an indicator of synaptic dopamine release (1981)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 315 (1981), S. 219-225 
    Details
    ISSN: 1432-1912
    Keywords: 3-Methoxytyramine ; Haloperidol ; Dopamine release ; Dopamine agonists ; Gas chromatography ; Mass Spectrometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The value of 3-methoxytyramine (3-MT) as an indicator of impulse-related dopamine (DA) release has been assessed in rat corpus striatum. Moreover, the turnover of 3-MT was estimated by measuring its disappearance rate after COMT inhibition. Quantitation of 3-MT and DA was performed by gas chromatography/mass spectrometry (selected ion monitoring). Haloperidol in doses between 0.05 and 3 mg/kg p.o. did not increase endogenous 3-MT levels at any time up to 24 h after its administration, whereas it dose-dependently increased homovanillic acid and 3,4-dihydroxyphenylacetic acid. However, in doses above 0.1 mg/kg p.o., it enhanced the accumulation of 3-MT in clorgyline-pretreated animals. Conversely, baclofen in doses of 2 mg/kg i.p. and above decreased endogeneous 3-MT levels, but reduced the accumulation of this amine only poorly at 20 mg/kg i.p. in clorgyline-pretreated rats. A number of dopamine agonists, apomorphine (0.5 mg/kg i.v.), dipropyl-ADTN (0.03 mg/kg i.v.), but not bromocriptine (1 mg/kg i.v.) reduced endogenous 3-MT levels 10 min after administration by approximately 50%. The DA releasing agents d-amphetamine and methylphenidate showed different effects: the former increased endogenous 3-MT greatly, whereas the latter was without effect. The difference is likely to be related to the MAO inhibitory properties of amphetamine. 3-MT disappeared rapidly after COMT inhibition with 50 mg/kg i.v. tropolone (half-life of the initial disappearance about 1 min). The curve flattened off after 5–10 min. Turnover was calculated to be about 7 nmol/g/h, which corresponds to about a third of the turnover of DA. Our results suggest that an important part of DA metabolism occurs through 3-MT and that this amine is very effectively deaminated by MAO-A, so effectively indeed that increased formation does not increase its endogeneous levels. It appears, therefore, that 3-MT is not suitable as an indicator of increased DA release. However, it seems to have some value for an assessment of lowered DA release.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00499838
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  • 4
    Electronic Resource
    Electronic Resource
    Investigations on GABAB receptor-mediated autoinhibition of GABA release (1990)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 341 (1990), S. 88-93 
    Details
    ISSN: 1432-1912
    Keywords: GABA release ; Electrical stimulation ; Cortex slices ; GABAB autoreceptor ; Baclofen ; Phaclofen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In this study, we have investigated the effects of phaclofen on the [3H] overflow from [3H]GABA prelabelled rat cortical slices and its interaction with the effects of (−)-baclofen in dependence of the stimulation frequency. (−)-Baclofen strongly depressed the [3H] overflow in the frequency range of 0.125 to 4 Hz to a constant residual level (ICIn50 = 0.37 μmol/l at 0.125 Hz), but became inactive above. The potency of the (+)-enantiomer was considerably weaker by a factor of nearly 1000. The GABAB antagonist, phaclofen, increased [3H] overflow at 300 μmol/l and, moremarkedly, at 3 and 1 mmol/l, respectively. However, the increase was virtually independent of the frequency between 0.125 and 16 Hz. If the compound interacted only with the putative GABAB autoreceptor involved in the regulation of GABA release, the extent of the enhancing effect should increase with increasing frequency because of the concomitant rise in synaptic GABA concentration. In order to further investigate this phenomenon, the IC50 of (−)-baclofen and antagonism of phaclofen against (−)-baclofen were determined at 0.125 Hz and 2 Hz, respectively. Whereas the IC50 of (−)-baclofen was 0.63 ± 0.04 μmol/l at 0.125 Hz, it increased to 4.88 + 0.45 μmol/l at 2 Hz. The pA10-values of phaclofen were about the same at both frequencies, whereas the pA2-values differed by a factor of 2.3. Therefore, the possibility should be considered that (−)-baclofen does not only interact with presynaptic GABA autoreceptors, but also may interact with other - presumably somatodendritic- GABAB-receptors whose pharmacology is not identical with that of the receptors by which (−)-baclofen exerts its effects on GABA release.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00195063
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  • 5
    Electronic Resource
    Electronic Resource
    Systemic administration of baclofen and the GABAB antagonist, CGP 35348, does not affect GABA, glutamate or aspartate in microdialysates of the striatum of conscious rats (1992)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 345 (1992), S. 548-552 
    Details
    ISSN: 1432-1912
    Keywords: Baclofen ; CGP 35348 ; Extracellular GABA ; Extracellular glutamate ; Extracellular aspartate ; Brain dialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Previous in vitro experiments have shown that the GABAB agonist, baclofen, and the antagonist, CGP 35348, respectively, decrease and increase the autoreceptor-mediated release of GABA in brain slices and synaptosomes. Since it is not clear whether these autoreceptors are operative in vivo, an attempt was made to reproduce these results in brain dialysis experiments, knowing that only positive results would permit a conclusion in view of the doubts expressed in the literature with respect to the origin of extracellular GABA. Because of older reports of an inhibitory action of baclofen on the in vitro release of glutamate, which might be ascribed to the action of presynaptic GABAB heteroreceptors, extracellular glutamate and aspartate were also measured. Neither (−)-baclofen, administered systemically at a dose of 20 mg/kg i.p., nor the GABAB antagonist, CGP 35348 (300 mg/kg i.p.) had significant effects on basal overflow of GABA, glutamate, or aspartate nor on that evoked by 100 mmol/l K+ in the striatum of the conscious, freely moving rat. To ascertain this result, (−)-baclofen was also administered between two K+ stimulations, so that the first stimulation could serve as an intraindividual control of the second. The compound did not significantly affect K+ evoked overflow of any of the three transmitter amino acids under these conditions. It must be emphasized that these data do not exclude the operativity of presynaptic GABAB auto- and hetero-receptors in vivo. They only suggest that this question must, in all probability, be addressed by other techniques than brain dialysis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00168947
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