P C Waldmeier

Novartis, Bâle, Basel-City, Switzerland

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Publications (104)297.7 Total impact

  • Peter C. Waldmeier, Klemens Kaupmann, Stephan Urwyler
    Journal of Neural Transmission 04/2009; · 2.87 Impact Factor
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    Peter C. Waldmeier, Klemens Kaupmann, Stephan Urwyler
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    ABSTRACT: Γ-Aminobutyric acid B (GABAB) receptors are heterodimers composed of two subunits GABAB(1) and GABAB(2), the former existing in two isoforms GABAB(1a) and GABAB(1b). The contributions of individual receptor subunits and isoforms to GABAB auto- and heteroreceptor functions were investigated, using release experiments in cortical slice preparations from corresponding knockout mice. Presynaptic GABAB autoreceptors are located on GABAergic terminals and inhibit GABA release, whereas presynaptic GABAB heteroreceptors control the release of other neurotransmitters (e.g. glutamate). Neither baclofen nor the selective antagonist CGP55845 at maximally active concentrations affected [3H]GABA release in slices from GABAB(1)−/− mice. The amount of [3H]GABA released per pulse was unaffected by the stimulation frequency in slices from GABAB(1)−/− and GABAB(2)−/− demonstrating a loss of GABAB autoreceptor function in these knockout animals. The GABAB receptor agonist baclofen was ineffective in modulating glutamate release in cortical slices from GABAB(2)−/− mice, showing that heteroreceptor function was abolished as well. Next we investigated knockout mice for the two predominant GABAB(1) isoforms expressed in brain, GABAB(1a) and GABAB(1b). In cortical, hippocampal and striatal slices from both GABAB(1a)−/− and GABAB(1b)−/− mice, the frequency dependence of [3H]GABA released per pulse was maintained, suggesting that both isoforms participate or can substitute for each other in GABAB autoreceptor function. By contrast, the efficacy of baclofen to inhibit glutamate release was substantially reduced in GABAB(1a)−/−, but essentially unaltered in GABAB(1b)−/− mice. Our data suggest that functional GABAB heteroreceptors regulating glutamate release are predominantly, but not exclusively composed of GABAB(1a) and GABAB(2) subunits.
    Journal of Neural Transmission 10/2008; 115(10):1401-1411. · 2.87 Impact Factor
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    ABSTRACT: Understanding the mechanisms of neuronal death in concert with the identification of drugable molecular targets key to this process has held great promise for the development of novel chemical entities (NCEs) to halt neurodegenerative disease progression. Two key targets involved in the apoptotic process identified over the past decade include the mixed lineage kinase (MLK) family and glyceraldehyde phosphate dehydrogenase (GAPDH). Two NCEs, CEP-1347 and TCH346, directed against these respective targets have progressed to the clinic. For each, robust neuroprotective activity was demonstrated in multiple in vitro and in vivo models of neuronal cell death, but neither NCE proved effective Parkinson's disease (PD) patients. These recent clinical failures require a reassessment of both the relevance of apoptosis to neurodegenerative disease etiology and the available animal models used to prioritize NCEs for advancement to the clinic in this area.
    Biochemical Pharmacology 12/2006; 72(10):1197-206. · 4.65 Impact Factor
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    ABSTRACT: The clinically established positron emission tomography (PET) tracers 6-[(18)F]-fluoro-l-DOPA ([(18)F]FDOPA), 6-[(18)F]-fluoro-l-m-tyrosine ([(18)F]FMT) and 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-[(18)F]-fluoroethyl)-nortropane ([(18)F]FECNT) serve as markers of presynaptic integrity of dopaminergic nerve terminals in humans. This study describes our efforts to adopt the methodology of human Parkinson's disease (PD) PET studies to mice. The PET imaging characteristics of [(18)F]FDOPA, [(18)F]FMT and [(18)F]FECNT were analyzed in healthy C57BL/6 mice using the dedicated small-animal PET tomograph quad-HIDAC. Furthermore, [(18)F]FECNT was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. [(18)F]FDOPA and [(18)F]FMT failed to clearly visualize the mouse striatum, whereas PET experiments using [(18)F]FECNT proved that the employed methodology is capable of delineating the striatum in mice with exquisite resolution. Moreover, [(18)F]FECNT PET imaging of healthy and MPTP-lesioned mice demonstrated that the detection and quantification of striatal degeneration in lesioned mice can be accomplished. This study shows the feasibility of using [(18)F]FECNT PET to analyze noninvasively the striatal degeneration in the MPTP mouse model of PD. This methodology can be therefore considered as a viable complement to established in vivo microdialysis and postmortem techniques.
    Nuclear Medicine and Biology 08/2006; 33(5):607-14. · 2.41 Impact Factor
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    ABSTRACT: GABAB1-/- mice, which are devoid of functional GABAB receptors, consistently exhibit marked hyperlocomotion when exposed to a novel environment. Telemetry recordings now revealed that, in a familiar environment, GABAB1-/- mice display an altered pattern of circadian activity but no hyperlocomotion. This indicates that hyperlocomotion is only triggered when GABAB1-/- mice are aroused by novelty. In microdialysis experiments, GABAB1-/- mice exhibited a 2-fold increased extracellular level of dopamine in the striatum. Following D-amphetamine administration, GABAB1-/- mice released less dopamine than wild-type mice, indicative of a reduced cytoplasmic dopamine pool. The hyperdopaminergic state of GABAB1-/- mice is accompanied by molecular changes, including reduced levels of tyrosine hydroxylase mRNA, D1 receptor binding-sites and Ser40 phosphorylation of tyrosine hydroxylase. Tyrosine hydroxylase activity, tissue dopamine content and dopamine metabolism do not appear to be measurably altered. Pharmacological and electrophysiological experiments support that the hyperdopaminergic state of GABAB1-/- mice is not severe enough to inactivate dopamine D2 receptors and to disrupt D2-mediated feedback inhibition of tyrosine hydroxylase activity. The data support that loss of GABAB activity results in a sustained moderate hyperdopaminergic state, which is phenotypically revealed by contextual hyperlocomotor activity. Importantly, the presence of an inhibitory GABA tone on the dopaminergic system mediated by GABAB receptors provides an opportunity for therapeutic intervention.
    Journal of Neurochemistry 06/2006; 97(4):979-91. · 4.24 Impact Factor
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    ABSTRACT: gamma-Hydroxybutyrate (GHB), a metabolite of gamma-aminobutyric acid (GABA), is proposed to function as a neurotransmitter or neuromodulator. gamma-Hydroxybutyrate and its prodrug, gamma-butyrolactone (GBL), recently received increased public attention as they emerged as popular drugs of abuse. The actions of GHB/GBL are believed to be mediated by GABAB and/or specific GHB receptors, the latter corresponding to high-affinity [3H]GHB-binding sites coupled to G-proteins. To investigate the contribution of GABAB receptors to GHB actions we studied the effects of GHB in GABAB(1)-/- mice, which lack functional GABAB receptors. Autoradiography reveals a similar spatial distribution of [3H]GHB-binding sites in brains of GABAB(1)-/- and wild-type mice. The maximal number of binding sites and the KD values for the putative GHB antagonist [3H]6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene acetic acid (NCS-382) appear unchanged in GABAB(1)-/- compared with wild-type mice, demonstrating that GHB- are distinct from GABAB-binding sites. In the presence of the GABAB receptor positive modulator 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol GHB induced functional GTPgamma[35S] responses in brain membrane preparations from wild-type but not GABAB(1)-/- mice. The GTPgamma[35S] responses in wild-type mice were blocked by the GABAB antagonist [3-[[1-(S)-(3,4dichlorophenyl)ethyl]amino]-2-(S)-hydroxy-propyl]-cyclohexylmethyl phosphinic acid hydrochloride (CGP54626) but not by NCS-382. Altogether, these findings suggest that the GHB-induced GTPgamma[35S] responses are mediated by GABAB receptors. Following GHB or GBL application, GABAB(1)-/- mice showed neither the hypolocomotion, hypothermia, increase in striatal dopamine synthesis nor electroencephalogram delta-wave induction seen in wild-type mice. It, therefore, appears that all studied GHB effects are GABAB receptor dependent. The molecular nature and the signalling properties of the specific [3H]GHB-binding sites remain elusive.
    European Journal of Neuroscience 12/2003; 18(10):2722-30. · 3.67 Impact Factor
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    ABSTRACT: The pharmacological properties of morpholin-2-yl-phosphinic acids were evaluated on GABA(B) receptors. In rat neocortical slices maintained in Mg2+-free Krebs medium, baclofen, a GABA(B) receptor agonist, produced a concentration-dependent depression of the frequency of spontaneous discharges with an EC50 of 14 +/- 5.5 microM, which was antagonised reversibly by the morpholin-2-yl-phosphinic derivatives. The order of potency was 3-[(3S,6R)-6-[(cyclohexylmethyl)hydroxyphosphinoylmethyl- morpholin-3-yl]benzoic acid (CGP 76290A) (pA2 = 7.1 +/- 0.05) > its enantiomer 3-[(3R,6S)-6-[(cyclohexylmethyl)hydroxyphosphinoylmethyl]-++ +morpholin-3-yl]benzoic acid (CGP 76291A) (pA2 = 6.8 +/- 0.1) > cyclohexylmethyl-[(2R',5S')-5-(3-nitrophenyl)-morpholin-2-++ +ylmethyl]phosphinic acid (CGP 71978) (pA2 = 6.5 +/- 0.05) > cyclohexylmethyl-[(2R,5S)-5-phenyl-morpholin-2-ylmethyl++ +]phosphinic acid (CGP 71980) (pA2 = 6.3 +/- 0.15) > its enantiomer cyclohexylmethyl-[(2S,5R)-5-phenyl-morpholin-2-ylmethyl++ +]phosphinic acid (CGP 71979) (pA2 = 5.8 +/- 0.1). An open chain analogue of CGP 76290A, CGP 56999A (3-[1(R)-[(3-cyclohexylmethyl-hydroxyphosphinoyl)-2(S)-hydro xypropyl-amino]-ethyl]benzoic acid lithium salt) gave a pA2 of 6.6 +/- 0.2. In GABA(B) receptor binding assays, CGP 71982 (the racemic mixture of CGP 76290A and CGP 76291A), CGP 76290A, CGP 76291A, CGP 71978, CGP 71980 and CGP 71979 had IC50 values against [3H]CGP 27492 binding of 8, 1.85, 69, 124, 326 and 1460 nM, respectively. In electrically-evoked [3H]GABA release from rat cortical slices, CGP 71982, CGP 71978, CGP 71980 and its enantiomer CGP 71979, antagonised GABA(B) autoreceptors with EC150 values of 2.5, 33, 181 and 474 nM, respectively. These compounds form a novel class of potent GABA(B) receptor antagonists.
    European Journal of Pharmacology 11/1998; 362(1):27-34. · 2.68 Impact Factor
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    ABSTRACT: Lamotrigine, carbamazepine and oxcarbazepine inhibit veratrine-induced neurotransmitter release from rat brain slices in concentrations corresponding to those reached in plasma or brain in experimental animals or humans after anticonvulsant doses, presumably due to their sodium channel blocking properties. Microdialysis measurements of extracellular glutamate and aspartate were carried out in conscious rats in order to investigate whether corresponding effects occur in vivo Veratridine (10 microM) was applied via the perfusion medium to the cortex and the corpus striatum in the presence of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (1 mM in perfusion medium). Maximally effective anticonvulsant doses of carbamazepine (30 mg/kg), oxcarbazepine (60 mg/kg) and lamotrigine (15 mg/kg) were given orally. The uptake inhibitor increased extracellular glutamate and aspartate about 2-fold in striatum and about 7-fold and 3-fold, respectively, in cortex. Veratridine caused a further 2-3-fold increase in extracellular glutamate in striatum and cortex, respectively, but its effect on extracellular aspartate was less marked in both areas. None of the anticonvulsant compounds affected the veratridine-induced increases in extracellular glutamate or aspartate in the striatum which were, however, markedly inhibited by tetrodotoxin (1 microM) and thus are sensitive to sodium channel blockade. In the cortex the same drugs at the same doses did cause about 50% inhibition of the veratridine-induced increase in extracellular glutamate. Carbamazepine and to a lesser extent lamotrigine, but not oxcarbazepine, also inhibited the veratridine-induced increase in extracellular aspartate in the cortex. Although our results might seem to support the view that inhibition of glutamate and aspartate release is responsible for the anticonvulsant effects of lamotrigine, carbamazepine and oxcarbazepine, two complementary findings argue against this interpretation. First, as previously shown, inhibition of electrically induced released of glutamate requires 5 to 7 times higher concentrations of these compounds than release elicited by veratrine. Second, the present study indicates that doses totally suppressing convulsions caused no inhibition in the striatum and at best a 50% inhibition in the brain cortex. From this we conclude that the doses used here, although to some extent effective against veratridine, did not suppress the release of GLU and ASP elicited by the normal ongoing electrical activity of the glutamatergic and aspartatergic neurons and that the mechanism of the suppression of convulsions must be sought elsewhere.
    Archiv für Experimentelle Pathologie und Pharmakologie 08/1996; 354(2):164-72. · 2.36 Impact Factor
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    ABSTRACT: Brofaromine (4-5(-methoxy-7-bromobenzofuranyl)-2-piperidine-HCl) is a potent and selective inhibitor of monoamine oxidase (MAO) A. Two methods for its synthesis and a preliminary positron emission tomography (PET) evaluation in monkey brain are described. The first method, at low carrier concentration of CO2, consisted of direct O-methylation of (4-(5-hydroxy-7-bromobenzofuranyl)-2-piperidine). The total radiochemical yield achieved ranged from 30 to 50% (from end of bombardment [EOB] and decay corrected) with an overall synthesis time of 45 min. The second approach, with high carrier amounts of CO2 arising from inherent target problems, was accomplished in a three-step route involving protection of secondary amino functionality, O-methylation and deprotection. The total radiochemical yield was 10% (from EOB and decay corrected) with a total synthesis time of 70 min. For both methods methylation was achieved using the classical methylating agent [11C]CH3I, and radiochemical purity was higher than 98%. PET evaluation of the radioligand in a Rhesus monkey showed a high uptake of radioactivity in the brain. Using the irreversible MAO-A inhibitor clorgyline and reversible MAO-A inhibitors moclobemide and brofaromine, three blockade experiments were designed to determine the extent of specific binding of [11C]brofaromine to MAO-A. No apparent decrease in accumulation of radioactivity in the monkey brain was observed when compared to a baseline scan.
    Nuclear Medicine and Biology 05/1996; 23(3):229-34. · 2.41 Impact Factor
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    ABSTRACT: An involvement of GABAergic neurons has been suggested in the process of memory consolidation based on anatomical evidence and increasing physiological and biochemical data. With the advent of orally active GABAB antagonists, such as CGP 36742, the question of their therapeutic value, for example in Alzheimer's disease, becomes relevant. Therefore, a new GC/MS method was developed to determine the concentration of CGP 36742 (3-amino-propyl-n-butyl phosphinic acid) in various intra- and extracerebral tissues after different routes of application. The compound was chemically derivatised in a two-step process (acylation of the amino group and esterification of the phosphinic acid). The limit of detection of the method was 0.01 microgram/g tissue and 0.0005 microgram/mL plasma. The time-course after i.p. treatment showed peak levels of CGP 36742 between 30 min and 1 hr after injection. After a dose of 100 mg/kg, the concentration in the brain ranged from 1 to 1.4 microgram/g or 6 to 8 microM, assuming that 1 mg tissue equals 1 microL (i.e., below the IC50 of the interaction with GABAB receptors as measured by [3-3H]-aminopropyl-phosphinic acid binding [35 microM]). These results are discussed in light of the psychopharmacological effects (improvement of cognitive performance of rats) of CGP 36742 observed at very low oral doses.
    Biochemical Pharmacology 04/1996; 51(5):613-9. · 4.65 Impact Factor
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    ABSTRACT: The antidepressant activity of monoamine oxidase inhibitors has been well established for 30 years. Nevertheless, this group of compounds was handled with great care, mainly because of the interaction potential with tyramine-containing foodstuff. With the discovery of reversible and selective inhibitors of monoamine oxidase type A a renaissance of these compounds has begun. In this paper one of these new substances--brofaromine--will be described in detail. Biochemical and pharmacological aspects will be reviewed, showing that brofaromine is a selective and reversible inhibitor of monoamine oxidase type A with additional serotonin reuptake inhibiting properties. Both mechanisms of action may synergize in the antidepressant effect of the compound. The main results of clinical trials in depression and other indication areas will also be covered. Special attention will be put on the side effect profile.
    Journal of Neural Transmission 02/1996; 103(1-2):217-45. · 2.87 Impact Factor
  • Pharmacochemistry Library 01/1996; 24:253-270.
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    ABSTRACT: The alkaloid and medicinal herb constituent, R,R-(-)-daurisoline, was originally reported to be a N-type Ca2+ channel blocker, but newer evidence indicates that it is a blocker of P-type Ca2+ channels. To clarify its specificity with respect to N- and P-channels, we compared its effects on the electrically induced release of endogenous glutamate, 3H-GABA and 3H-noradrenaline, from brain slices with those of omega-agatoxin IVA and omega-conotoxin GVIA. Like omega-agatoxin IVA (but with about 1000-fold lower potency), and unlike omega-conotoxin GVIA, R.R-(-)-daurisoline inhibited the release of 3H-GABA and glutamate, with IC50 values of 8 and 18 microM. However, inhibition particularly of 3H-GABA release was more complete than by omega-agatoxin IVA, indicating interaction with one or more additional voltage-sensitive Ca2+ channels, possibly the Q-type. Its potency to inhibit glutamate release elicited either electrically, by veratrine or by high concentrations of K+ was similar, in contrast to sodium channel blockers. The effects of R,R-(-)-daurisoline on the release of 3H-noradrenaline, 3H-dopamine and 3H-acetylcholine were in agreement with previous knowledge from experiments with omega-agatoxin IVA suggesting an involvement of P-channels. A weak inhibition of 3H-noradrenaline release at 10 microM, similar to that by omega-agatoxin IVA at 0.03 microM, was occluded by alpha 2-antagonistic properties and could be unmasked in presence of rauwolscine. At 10 microM, it also inhibited electrically evoked 3H-dopamine and 3H-5-hydroxytryptamine release and caused a marked spontaneous release of all three monoamines in a reserpine-like manner. Spontaneous and evoked release of 3H-acetylcholine was inhibited by about 25% at 10 microM. In radioligand binding studies, R,R-(-)-daurisoline interacted with alpha 1- and alpha 2-adrenoceptors, 5-HT2 and muscarinic cholinergic receptors with IC50 values close to 1 microM, and with mu opiate receptors even with 0.18 microM. Atropine reduced the weak inhibitory effect of R,R-(-)-daurisoline on 3H-acetylcholine release somewhat, suggesting that it was brought about by both P channel blockade and cholinergic agonist activity. The effect on 3H-GABA release was unaffected by naloxone, indicating that the interaction of R,R-(-)-daurisoline with mu opiate receptors is antagonistic. The pattern of effects on neurotransmitter release observed with R,R-(-)-daurisoline resembles that of omega-agatoxin IVA and supports previous electrophysiological data suggesting that the compound blocks P-type voltage-sensitive Ca2+ channels. However, the more complete blockade of amino acid release by R,R-(-)-daurisoline suggests interaction with additional Ca2+ channel subtypes. Although it does also possess other pharmacological properties, we think that the compound is suitable to test whether blockade of glutamate release via voltage-sensitive Ca2+ channels is a viable concept to obtain novel neuroprotective and/or anticonvulsant compounds.
    Archiv für Experimentelle Pathologie und Pharmakologie 01/1996; 352(6):670-8. · 2.36 Impact Factor
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    ABSTRACT: We compared the effects of the antiepileptic drugs carbamazepine, oxcarbazepine, and lamotrigine on the release from rat brain slices of endogenous glutamate, [3H]-GABA, and [3H]-dopamine, elicited by the Na+ channel opener, veratrine, and of the same transmitters as well as [3H]-noradrenaline, [3H]-5-hydroxytryptamine, and [3H]-acetylcholine, elicited by electrical stimulation. The three antiepileptic drugs inhibited veratrine-induced release of endogenous glutamate, [3H]-GABA, and [3H]-dopamine, with IC50 values between 23 and 150 microM, in or near the concentration range in which they interact with Na+ channels, and there was little difference between the compounds. They were five to seven times less potent in inhibiting electrically as compared with veratrine-stimulated release of [3H]-GABA and [3H]-dopamine; similarly, carbamazepine and tetrodotoxin were more potent in inhibiting veratrine-induced as compared with electrically induced release of endogenous glutamate. Carbamazepine, oxcarbazepine, and lamotrigine also inhibited electrically stimulated release of [3H]-5-hydroxytryptamine (IC50 values, 150 to 250 microM) and [3H]-acetylcholine (IC50 values, 50 to 150 microM); [3H]-noradrenaline release was affected to a lesser degree. The active concentration ranges of these drugs with respect to inhibition of veratrine-stimulated neurotransmitter release matched the therapeutic plasma and brain concentrations. It is uncertain whether these effects are relevant in vivo at anticonvulsant doses, because the drugs are markedly less potent in inhibiting the more physiologic release elicited by electrical stimulation. Therefore, the hypothesis that inhibition of glutamate release is the mechanism of anticonvulsant action of lamotrigine (or carbamazepine and oxcarbazepine) is doubtful. Other consequences of Na+ channel blockade may have an important role.
    Neurology 11/1995; 45(10):1907-13. · 8.30 Impact Factor
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    ABSTRACT: 1. The effects of a series of nine GABAB receptor antagonists of widely varying potencies on electrically stimulated release from cortical slices of [3H]-GABA in the absence or presence of 10 microM of the GABAB agonist, (-)-baclofen and of endogenous glutamate in the presence of (-)-baclofen were compared. 2. The concentrations of the compounds half maximally increasing [3H]-GABA release (EC50's) at a stimulation frequency of 2 Hz correlated well with the IC50 values obtained from the inhibition of the binding of the agonist, [3H]-CGP 27492, to GABAB receptors in rat brain membranes (rank order of potency: CGP 56999 A > or = CGP 55845 A > CGP 52432 > or = CGP 56433 A > CGP 57034 A > CGP 57070 A > or = CGP 57976 > CGP 51176 > CGP 35348). 3. Likewise, the concentrations causing half-maximal increases of [3H]-GABA in the absence or presence of (-)-baclofen, and of endogenous glutamate in the presence of (-)-baclofen, correlated well with each other. Reports in the literature suggesting the CGP 35348 exhibits a 70 fold preference for inhibition of (-)-baclofen's effects on glutamate over [3H]-GABA release, and that CGP 52432 shows a 100 fold preference in the opposite sense, could not be confirmed in our model. 4. Therefore, our results suggest that, if there are pharmacological differences between GABAB autoreceptors and GABAB heteroreceptors on glutamatergic nerve endings in the rat cortex, they are not revealed by this series of compounds of widely different potencies. 5. In particular, our results with CGP 35348 and CGP 52432 do not support the hypothesis that GABAB autoreceptors and GABAB heteroreceptors on glutamatergic nerve endings represent subtypes with different pharmacology.
    British Journal of Pharmacology 12/1994; 113(4):1515-21. · 4.99 Impact Factor
  • P C Waldmeier, P Wicki
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    ABSTRACT: Electrically stimulated release of neurotransmitters in brain slices normally displays frequency dependence because of progressive activation of autoreceptors by endogenously released transmitter, which is abolished by blockade of autoreceptors. In consequence, the maximal increase caused by an autoreceptor antagonist in percent of the corresponding controls should be greater at higher than at lower frequencies. In the case of gamma-aminobutyric acid (GABA), we have previously found a marked deviation from this expectation. Among several explanations envisaged, computer simulation suggested only one to be compatible with the experimental data: the release mechanism may not be able to cope with high demand. This hypothesis was tested by investigating the frequency dependence of the release of 3H-GABA in the presence and absence of a high concentration of the potent GABAB antagonist, CGP 55845, using extremely short stimulation periods. To this end, slices were stimulated with groups of 4 POPs (a POP--pseudo-one-pulse--consists of 4 pulses delivered at 100 Hz). The intervals between the POPs within a group were varied from 60-0.5 s, corresponding to frequencies within the POP group of 0.0167-2 Hz. Under such circumstances, the theoretically expected pattern was indeed observed: the GABAB antagonist abolished the frequency dependence. In a second series of experiments, fractional release per POP was determined when 4-32 POPs were delivered at 2 Hz, with and without CGP 55845. The increase of GABA release elicited by the GABAB antagonist gradually subsided with increasing number of POPs.(ABSTRACT TRUNCATED AT 250 WORDS)
    Archiv für Experimentelle Pathologie und Pharmakologie 07/1994; 349(6):583-7. · 2.36 Impact Factor
  • T Christen, P A Baumann, P C Waldmeier
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    ABSTRACT: The autoreceptor-mediated control of GABA release was simulated on a personal computer using commercially available software (STELLA/ITHINK). 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.
    Archiv für Experimentelle Pathologie und Pharmakologie 01/1994; 348(6):618-27. · 2.36 Impact Factor
  • P C Waldmeier, Peter Wicki, J J Feldtrauer
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    ABSTRACT: The effect of the new glutamate uptake inhibitor, L-trans-pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC), on the electrically evoked release or, rather, overflow of endogenous glutamate in superfusates from rat cortical slices was compared with that of dihydrokainate. In the absence of these presumed uptake inhibitors, electrical stimulation for 4 min at 1 Hz did not elicit a measurable glutamate overflow over baseline at all. Basal overflow increased concentration-dependently in the presence of 10-100 microM L-trans-PDC, about 5-fold at 100 microM. Also, electrical stimulation caused increases of glutamate overflow over basal levels progressive with increasing concentrations of trans-PDC; a stimulated overflow corresponding to about 50% of basal overflow was obtained at 100 microM. Basal as well as evoked release in the presence of dihydrokainate did not exceed ca. 60% of that obtained with 100 microM L-trans-PDC. In synaptosomes, L-trans-PDC much more than dihydrokainate caused a transient increase of spontaneous glutamate release which was diminished in the absence of Na+, indicating that it is transported into the cytoplasm by the glutamate carrier and induces some efflux of the amino acid from this compartment. Moreover, trans-PDC caused a weak to moderate inhibition of K(+)-evoked glutamate release from synaptosomes at 10-300 microM, without obvious concentration-dependence. Glutamate overflow elicited from rat cortical slices by electrical field stimulation at 1 Hz was Ca(2+)-dependent to about 80%. Tetrodotoxin (0.3 microM) reduced it by about 90%.(ABSTRACT TRUNCATED AT 250 WORDS)
    Archiv für Experimentelle Pathologie und Pharmakologie 12/1993; 348(5):478-85. · 2.36 Impact Factor
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    ABSTRACT: CGP 28,014 is a specific inhibitor of catechol-O-methyltransferase (COMT) in vivo. In humans, the inhibition was assessed by measuring urinary excretion of isoquinolines and with the levodopa test. Following administration of CGP 28,014, urinary excretion of isoquinolines was significantly increased. In rats, CGP 28,014 reduced plasma and striatal concentrations of 3-O-methyldopa (30MD) in a dose-dependent manner. Acute and subchronic administration of CGP 28,014 alone or in combination with the peripherally acting decarboxylase inhibitor benserazide decreased plasma 30MD as an index of COMT inhibition by about 50%. There seems to be a close relationship between the time-course of plasma concentrations of CGP 28,014 and the extent of COMT inhibition assessed by the 30MD/DOPA ratio in plasma.
    Neurochemical Research 12/1993; 18(11):1163-7. · 2.55 Impact Factor
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    ABSTRACT: 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. Before-hand, 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.(ABSTRACT TRUNCATED AT 250 WORDS)
    Archiv für Experimentelle Pathologie und Pharmakologie 06/1993; 347(5):514-20. · 2.36 Impact Factor

Publication Stats

2k Citations
297.70 Total Impact Points


  • 2006–2009
    • Novartis
      Bâle, Basel-City, Switzerland
  • 1983–1985
    • Trinity College
      Hartford, Connecticut, United States
    • Central Institute of Mental Health
      Mannheim, Baden-Württemberg, Germany
  • 1982
    • AVACO AG, Switzerland
      Basel-Landschaft, Switzerland