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H Bittiger

Publications and source records attributed to H Bittiger.

At least 37 records · Page 2Linked to original sources
PubMed1992

Experimental absence seizures: potential role of gamma-hydroxybutyric acid and GABAB receptors.

We have investigated whether the pathogenesis of spontaneous generalized non-convulsive seizures in rats with genetic absence epilepsy is due to an increase in the brain levels of gamma-hydroxybutyric acid (GHB) or in the rate of its synthesis. Concentrations of GHB or of its precursor gamma-butyrolactone (GBL) were measured with a new GC/MS technique which allows the simultaneous assessment of GHB and GBL. The rate of GHB synthesis was estimated from the increase in GHB levels after inhibition of its catabolism with valproate. The results of this study do not indicate significant differences in GHB or GBL levels, or in their rates of synthesis in rats showing spike-and-wave discharges (SWD) as compared to rats without SWD. Binding data indicate that GHB, but not GBL, has a selective, although weak affinity for GABAB receptors (IC50 = 150 microM). Similar IC50 values were observed in membranes prepared from rats showing SWD and from control rats. The average GHB brain levels of 2.12 +/- 0.23 nmol/g measured in the cortex and of 4.28 +/- 0.90 nmol/g in the thalamus are much lower than the concentrations necessary to occupy a major part of the GABAB receptors. It is unlikely that local accumulations of GHB reach concentrations 30-70-fold higher than the average brain levels. After injection of 3.5 mmol/kg GBL, a dose sufficient to induce SWD, brain concentrations reach 240 +/- 31 nmol/g (Snead, 1991) and GHB could thus stimulate the GABAB receptor. Like the selective and potent GABAB receptor agonist R(-)-baclofen, GHB causes a dose-related decrease in cerebellar cGMP. This decrease and the increase in SWD caused by R(-)-baclofen were completely blocked by the selective and potent GABAB receptor antagonist CGP 35348, whereas only the increase in the duration of SWD induced by GHB was totally antagonized by CGP 35348. The decrease in cerebellar cGMP levels elicited by GHB was only partially antagonized by CGP 35348. These findings suggest that all effects of R(-)-baclofen are mediated by the GABAB receptor, whereas only the induction of SWD by GHB is dependent on GABAB receptor mediation, the decrease in cGMP being only partially so. Taken together with the observations of Marescaux et al. (1992), these results indicate that GABAB receptors are of primary importance in experimental absence epilepsy and that GABAB receptor antagonists may represent a new class of anti-absence drugs.

4-Butyrolactone↗
PubMed1990

CGP 35348: a centrally active blocker of GABAB receptors.

The biochemical, electrophysiological and pharmacological properties of the new GABAB receptor blocker CGP 35348 are described. In a variety of receptor binding assays CGP 35348 showed affinity for the GABAB receptor only. CGP 35348 had an IC50 of 34 microM at the GABAB receptor. The compound antagonized (100, 300, 1000 microM) the potentiating effect of L-baclofen on noradrenaline-induced stimulation of adenylate cyclase in rat cortex slices. In electrophysiological studies CGP 35348 (10, 100 microM) antagonized the effect of L-baclofen in the isolated rat spinal cord. In the hippocampal slice preparation CGP 35348 (10, 30, 100 microM) blocked the membrane hyperpolarization induced by D/L-baclofen (10 microM) and the late inhibitory postsynaptic potential. CGP 35348 appeared to be 10-30 times more potent than the GABAB receptor blocker phaclofen. Ionophoretic and behavioural experiments showed that GABAB receptors in the brain were blocked after i.p. administration of CGP 35348. This compound may be of considerable value in elucidating the roles of brain GABAB receptors.

Adenylyl Cyclase Inhibitors↗
PubMed1990

CGP 28014, a new inhibitor of cerebral catechol-O-methylation with a non-catechol structure.

CGP 28014 (N-(2-pyridone-6-yl)-N',N'-di-n-propylformamidine) or its methanesulfonate salt CGP 28014 A was suspected to be a catechol-O-methyl-transferase (COMT) inhibitor because it was found to reduce the levels of homovanillic acid (HVA) and to increase those of 3,4-dihydroxyphenylacetic acid (DOPAC) in the rat striatum, after oral or intraperitoneal administration. These effects were maintained after repeated administration. The compound was only weakly active as a COMT inhibitor in vitro. However, its effect on striatal HVA and DOPAC was not prevented by pretreatment with the inhibitor of microsomal drug metabolizing enzymes in the liver, proadifen, indicating that, if CGP 28014 acts as a prodrug, its conversion to the active compound is not by oxidative metabolism in the liver. Also, there was no evidence that conversion to 2-amino-6-hydroxypyridine could explain its effects. The in vivo effect of CGP 28014 was substantiated in two additional in vivo test systems. Thus, it inhibited the accumulation of 3-methoxytyramine in the rat striatum after MAO inhibition by clorgyline, and the formation of O-methyl-DOPA from exogenously administered DOPA. It proved to be equipotent or nearly so with tropolone, and also showed a similar duration of action. Similar to tropolone, it increased S-adenosylmethionine levels in the striatum. Pyrogallol, on the other hand, decreased them, because being a substrate of COMT, it consumes methyl groups. This suggests that CGP 28014 does not inhibit COMT because it is a substrate of the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

CGP 37849 and CGP 39551: novel and potent competitive N-methyl-D-aspartate receptor antagonists with oral activity.

1. The pharmacological properties of CGP 37849 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid; 4-methyl-APPA) and its carboxyethylester, CGP 39551, novel unsaturated analogues of the N-methyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonopentanoate (AP5), were evaluated in rodent brain in vitro and in vivo. 2. Radioligand binding experiments demonstrated that CGP 37849 potently (Ki 220 nM) and competitively inhibited NMDA-sensitive L-[3H]-glutamate binding to postsynaptic density (PSD) fractions from rat brain. It inhibited the binding of the selective NMDA receptor antagonist, [3H]-((+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), with a Ki of 35 nM, and was 4, 5 and 7 fold more potent than the antagonists [+/-)-cis-4-phosphonomethylpiperidine-2-carboxylic acid) (CGS 19755), CPP and D-AP5, respectively. Inhibitory activity was associated exclusively with the trans configuration of the APPA molecule and with the D-stereoisomer. CGP 39551 showed weaker activity at NMDA receptor recognition sites and both compounds were weak or inactive at 18 other receptor binding sites. 3. CGP 37849 and CGP 39551 were inactive as inhibitors of L-[3H]-glutamate uptake into rat brain synaptosomes and had no effect on the release of endogenous glutamate from rat hippocampal slices evoked by electrical field stimulation. 4. In the hippocampal slice in vitro, CGP 37849 selectively and reversibly antagonized NMDA-evoked increases in CA1 pyramidal cell firing rate. In slices bathed in medium containing low Mg2+ levels, concentrations of CGP 37849 up to 10 microM suppressed burst firing evoked in CAl neurones by stimulation of Schaffer collateral-commissural fibres without affecting the magnitude of the initial population spike; CGP 39551 exerted the same effect but was weaker. In vivo, oral administration to rats of either CGP 37849 or CGP 39551 selectively blocked firing in hippocampal neurones induced by ionophoreticallyapplied NMDA, without affecting the responses to quisqualate or kainate. 5. CGP 37849 and CGP 39551 suppressed maximal electroshock-induced seizures in mice with ED50 s of 21 and 4 mg kg'- p.o., respectively. 6. CGP 37849 and CGP 39551 are potent and competitive NMDA receptor antagonists which show significant central effects following oral administration to animals. As such, they may find value as tools to elucidate the roles of NMDA receptors in brain function, and potentially as therapeutic agents for the treatment of neurological disorders such as epilepsy and ischaemic brain damage in man.

2-Amino-5-phosphonovalerate↗
PubMed1989

CGP 31358 binds to a site on the NMDA receptor that is coupled to both the transmitter recognition site and the channel domain.

CGP 31358, a novel triazole, inhibited the binding of L-[3H]glutamate and [3H]MK-801 to the N-methyl-D-aspartate (NMDA) receptor complex in rat brain synaptic membrane fractions, and showed anticonvulsant activity in mice. It had no effect on the strychnine-insensitive binding of [3H]glycine. Saturation and Hill analyses indicated that CGP 31358 binds to a site on the NMDA receptor which is separate from, but coupled to, both the transmitter recognition site and the channel domain. Available data indicate that this site is distinct from those with which tricyclic antidepressants and ifenprodil interact. CGP 31358 is a new chemical entity with a novel mechanism of action at the NMDA receptor, and as such may form a tool for understanding the molecular pharmacology of this receptor-channel complex.

Animals↗
PubMed1987

Substance P depresses neuronal activity in the rat olfactory bulb in vitro and in vivo: possible mediation via gamma-aminobutyric acid release.

The rat olfactory bulb is an area displaying a particularly high density of substance P receptors in the glomerular cell layer whose functions are unknown. In pilot in vivo experiments we discovered that iontophoretically administered substance P potently depressed the spontaneous firing rate of most unidentified neurons of the rat olfactory bulb. To further elucidate the mechanism of this unexpected depressant effect, we studied the peptide's action in vitro on coronal sections of this brain region. Bath applied and microiontophoretically administered substance P depressed the spontaneous discharge of unidentified glomerular neurons in a dose-dependent fashion. This inhibiting effect is mediated indirectly via the release of another transmitter because it was abolished completely if the standard perfusion medium was replaced by a medium containing zero calcium and high magnesium. It appears that substance P acts by means of releasing GABA which in turn evokes the observed cell depression because the depressant effects were completely abolished by bath-applied bicuculline (10 microM) and picrotoxin (100 microM). In conclusion we propose that substance P indirectly depresses neuronal activity in the glomerular cell layer of the rat olfactory bulb by releasing gamma-aminobutyric acid.

Action Potentials↗
PubMed1987

Binding studies with [3H]cis-methyldioxolane in different tissues. Under certain conditions [3H]cis-methyldioxolane labels preferentially but not exclusively agonist high affinity states of muscarinic M2 receptors.

Special conditions--tricine buffer containing Ca2+ and Mg2+, 22 degrees C (TCM)--allow to label a much higher proportion of muscarinic receptors by [3H]cis-methyldioxolane (CD) than hitherto described (Vickroy et al. 1984a). Taking the maximum number of binding sites, Bmax, of [3H]QNB as 100%, Bmax of [3H]CD amounts to 83% in the rat heart instead of the reported 17%, 33% in the cerebral cortex instead of 6%, 20% in hippocampus and 55% in pons/medulla. In the salivary glands specific binding was negligible. The affinities of a number of muscarinic agonists and antagonists to [3H]CD and [3H]QNB binding sites in different tissues of the rat are compared. Apparent affinities of agonists are much higher in the [3H]CD system, affinities of antagonists are slightly higher in the [3H]QNB system. In both assay systems receptors of heart and pons/medulla membranes seem to have similar drug specificity. They differ somewhat from those in the cortex. Receptors in the salivary glands, however, seem to be completely different from those in the other three tissues. In the heart [3H]CD binding can be abolished almost completely by GppNHp. In the cortex about half of the [3H]CD binding is susceptible to GppNHp. The reduction of binding in the cortex is due to a change in Bmax and not in the dissociation constant KD. Competition of unlabelled pirenzepine with [3H]CD: In heart and pons/medulla only low affinity sites for pirenzepine (M2-receptors) are labelled by [3H]CD.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Quantitative assessment of central beta 1- and beta 2-adrenoceptor regulation using CGP 20712 A.

The use of 100 nM CGP 20712 A (1-[2-((3-carbamoyl-4-hydroxy)phenoxy)ethylamino]-3-[4-(1-methyl-4- trifluoromethyl-2-imidazolyl)phenoxy]-2-propanol methanesulfonate), a specific beta 1-adrenoceptor antagonist, in an in vitro [3H]dihydroalprenolol binding assay simplified the detection of drug-induced alterations in central beta 1- and beta 2-adrenoceptor density. Injection of rats with DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride), a selective noradrenergic neurotoxin, caused an increase in neocortical and hippocampal beta 1-adrenoceptor density. Subchronic infusion of desipramine, a noradrenaline uptake inhibitor, effected a decrease in neocortical and hippocampal beta 1-adrenoceptor density. Subchronic infusion of clenbuterol, a centrally acting beta-adrenoceptor agonist, appeared to decrease striatal beta 2-adrenoceptor density. The results are discussed in terms of the quantitation and regulation of central beta-adrenoceptors.

Adrenergic beta-Antagonists↗
PubMed1986

Ifoxetine, a compound with atypical effects on serotonin uptake.

Ifoxetine (CGP 15210 G; (+/-)-bis-[cis-3-hydroxy-4-(2,3-dimethyl-phenoxy)]-piperidine sulfate) prevented the depletion of serotonin (5-HT) induced by H 75/12 and p-chloromethamphetamine in the rat brain, and that caused by endogenously released dopamine after the combined administration of haloperidol and amfonelic acid in the rat striatum. These effects are typically caused by compounds that inhibit 5-HT reuptake. Unexpectedly, ifoxetine only weakly inhibited the uptake of radiolabelled 5-HT into rat brain synaptosomes in vitro or ex vivo, the human thrombocytes in vitro or into rat thrombocytes after pretreatment. The following, among the possible explanations for this apparent discrepancy, were considered and regarded as unlikely: the involvement of an active metabolite; the possibility that ifoxetine accumulates in the brain to an extent sufficient to cause in vivo uptake inhibition; a pharmacokinetic interaction with the depleting agents. The possibility that the depletor tests give false positives was also considered. However, ifoxetine lowered brain 5-hydroxyindoleacetic acid and reduced the accumulation of 5-hydroxytryptophan after central decarboxylase inhibition. This suggests that it also interferes with 5-HT metabolism in the absence of depleting agents, which means that it interacts in some way with serotonergic transmission. Ifoxetine displayed weak or no interactions with 5-HT1, 5-HT2, alpha 1-, alpha 2- and beta-noradrenoceptors, histamine H1, muscarinic acetylcholine, opiate, GABA A, and benzodiazepine receptors in vitro, and with dopamine and 5-HT2 receptors in vivo. It did not antagonize the noradrenaline (NA) depletion induced by H 77/77 in rat brain and only weakly interfered with the uptake of i.v. injected radiolabelled NA into the rat heart. This suggests that its interaction with the 5-HT system is specific. Due to its atypical properties, among which the rather weak potentiation of the neurological effects of 5-hydroxytryptophan is also important, ifoxetine may exhibit a therapeutic and/or side-effect profile which differs from that of classical 5-HT uptake inhibitors.

Animals↗
PubMed1986

CGP 20712 A: a useful tool for quantitating beta 1- and beta 2-adrenoceptors.

CGP 20712 A (1-[2-((3-carbamoyl-4-hydroxy)phenoxy)ethylamino]-3- [4-(1-methyl-4-trifluoromethyl-2-imidazolyl) phenoxy]-2-propanol methanesulfonate), a specific beta 1-adrenoceptor antagonist, was tested for resolution of beta 1- and beta 2-adrenoceptors in an in vitro [3H]dihydroalprenolol ([3H]DHA) binding assay. Competition experiments, using rat neocortical and cerebellar membranes, yielded two dissimilar concentration-effect curves. A distinct biphasic curve was evident for neocortex, with a plateau at 100 nM CGP 20712 A (60% [3H]DHA displacement). This plateau indicated a differentiation between beta 1- and beta 2-adrenoceptors; the ratio of IC50-beta 2 to IC50-beta 1 was approximately 10,000. In contrast, only a monophasic curve was obtained for cerebellum. CGP 20712 A is a useful tool for estimating percentages of beta 1- and beta 2-adrenoceptors in a given tissue.

Adrenergic beta-Agonists↗
PubMed1986

Dose pipecolic acid interact with the central GABA-ergic system?

Several previous studies have suggested a strong GABA-mimetic action of the endogenous brain imino acid, L-pipecolic acid (L-PA). In the present study, these observations were evaluated using electrophysiological and neurochemical methods. In contrast to published data our electrophysiological studies on rat cortical neurones in situ showed only a weak, but bicuculline-sensitive depressant action of L-PA on cortical neurones. Furthermore, L-PA proved to have no affinity for any of the three components of the GABA-benzodiazepine-chloride channel receptor complex. However, using a modification of published methods a weak affinity for the GABA-B receptor site was demonstrated (IC50 = 1.8 X 10(-3) M). L-PA showed no anticonvulsive activity in several tests; in particular, it did not protect mice from seizures induced by inhibition of L-glutamate-1-decarboxylase (EC 4.1.1.15: GAD). L-PA had a very weak action on brain GABA levels of mice, and did not modify the rate of GABA synthesis. In conclusion, these results are not compatible with a strong in vivo interaction between L-PA and GABA-mediated inhibitory transmission.

Animals↗
PubMed1986

Benzodiazepine interactions with central thyroid-releasing hormone binding sites: characterization and physiological significance.

Thyrotropin-releasing hormone (TRH) and several TRH analogs were examined in the [3H]-3-Me-His2-TRH ([3H]MeTRH) receptor-binding assay in rat amygdala, striatal and cortical membranes. The benzodiazepine, chlordiazepoxide, as reported in the literature was found to displace [3H]MeTRH with an IC50 value of 3.6 X 10(-7) M in amygdala membranes. Midazolam was, however, identified as being 6-fold more active than chlordiazepoxide with an IC50 value of 6.3 X 10(-8) M. The effect of these benzodiazepines on [3H]MeTRH binding did not appear to be related to their anxiolytic activity because the novel pyrazoloquinoline nonsedating anxiolytic, CGS 9896 was without effect on [3H]MeTRH binding at concentrations up to 1 X 10(-5) M. Chlordiazepoxide had similar activity in cortical membranes whereas midazolam was some 5 times less active in this preparation than in amygdala. Both compounds were weak displacers of [3H]MeTRH binding in striatal membranes, being at least two orders of magnitude less potent than in amygdala. In contrast TRH and its analogs, RX 77368 and DN-1417, were approximately 2 to 8 times more active in striatum than amygdala membranes. TRH and DN-1417 were less active in cortical membranes whereas RX 77368 was some three times more active than in striatum and amygdala. In three test procedures indicative of TRH agonist activity; thyroid-stimulating hormone release, reversal of pentobarbital sleeping time in mice and elevation of cerebellar cyclic GMP levels, the benzodiazepines were found to be devoid of activity, whereas TRH and related compounds produced their expected responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Amygdala↗
PubMed1985

Pharmacological and neurochemical aspects of kindling.

Rats implanted with amygdaloid stimulating and cortical recording electrodes were kindled by daily low-intensity electrical stimulation. In one experiment amino acid concentrations were measured in amygdala, cortex and hippocampus at behavioural stages 1, 2 and 4 (Racine). Control groups consisted of unstimulated rats. Only alanine showed a significant enhancement of concentration in the kindled rats (stage 4 of Racine). In a second experiment, a group of rats was treated daily with 10mg/kg p.o. of diazepam. Diazepam significantly inhibited kindling and no changes in amino acid concentrations were observed in this group. Increased alanine levels are seen after various seizure types; since pentetrazole, isoniazid and beta-vinyllactic acid seizures were associated with alanine level increases only after and never before seizure occurrence, it is suggested that the alanine increases are a consequence rather than a cause of convulsions. In 3H-flunitrazepam binding studies, no change in affinity or receptor number could be demonstrated during kindling.

Alanine↗
PubMed1984

Affinity changes of rat striatal dopamine receptors in vivo after acute bupropion treatment.

The effect of bupropion (Wellbutrin) was studied on in vivo [3H]spiperone binding in rat striatum and cerebellum. The compound increased binding dose dependently in striatum whereas no effect was observed in cerebellum. Saturation analyses of in vivo binding in the striatum revealed an increased affinity of the receptors rather than changes in the number of binding sites. These results are the first demonstration of an increased sensitivity of central dopamine receptors after acute bupropion treatment.

Animals↗
PubMed1984

Simple radioligand binding assay for the determination of urinary scopolamine.

A sensitive radioligand binding assay is described for the determination of scopolamine in human urine. As a measure for the drug concentration, the quantitative displacement of scopolamine of tritiated quinuclidinyl benzylate from rat brain receptors was used. The assay is sensitive to concentrations as low as 1.2 ng/mL, surpassed only by GC-MS techniques. It can be performed easily and quickly and does not include extraction procedures. Scopoline and scopine , possible metabolites of scopolamine, do not interfere with the assay. After transdermal administration of scopolamine, 34% of the drug is found in the urine. Of the total scopolamine excreted, 79% is conjugated to glucuronic and/or sulfuric acid and 21% is excreted in the unbound form.

Administration, Topical↗
PubMed1983

Alteration of central alpha 2- and beta-adrenergic receptors in the rat after DSP-4, a selective noradrenergic neurotoxin.

A peripheral injection of DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] produced a marked, selective, and lasting depletion of norepinephrine in certain regions of the rat central nervous system. This depletion at 10 days after injection was associated with regional alterations in some, but not all, adrenergic binding sites (receptors) as determined by in vitro [3H]prazosin (alpha 1), [3H]p-aminoclonidine (alpha 2), and [3H]dihydroalprenolol (beta) binding. The neocortical alpha 1-receptor was not changed. The alpha 2-receptor in several regions was altered as indicated by an increase in ligand affinity; additionally, the density of this receptor was slightly decreased in some regions. Depending on the region, the beta-receptor either increased in density or was unchanged. The increased density of this receptor in neocortex corresponded to an increased activity of isoproterenol-sensitive adenylate cyclase. These two changes were not affected by subchronic treatment with desipramine, a norepinephrine uptake inhibitor. The changes were, however, partially or completely reversed by subchronic administration of clenbuterol, a centrally-acting beta-receptor agonist. The dopaminergic receptor in various regions was unaltered as assessed by in vivo and/or in vitro binding of [3H]spiperone. The in vivo binding of this ligand also indicated that the serotoninergic receptor in frontal neocortex was unchanged. Assessment of adrenergic receptors in neocortex at 50 days after injection indicated only the above affinity change of the (presumably postsynaptic) alpha 2-receptor. The alpha 1-receptor remained unaltered. The density of the beta-receptor had normalized, as had the activity of isoproterenol-sensitive adenylate cyclase. Implicit in these findings is the following rank order of receptor sensitivity to chronic norepinephrine depletion: alpha 2 greater than beta greater than alpha 1. The use of DSP-4 has clear advantages over other methods of depleting central norepinephrine. This neurotoxin can be administered by intraperitoneal injection, the depletion of norepinephrine can be readily checked by absence of the post-decapitation reflex, and the changes in other neurotransmitter concentrations are relatively minor or nonexistent. The alteration of alpha 2- and beta-receptors, as a consequence of DSP-4 treatment, may form the basis of a new animal model of adrenergic receptor supersensitivity. Such a model may clarify the importance of these central receptors to physiological and behavioral processes.

Adenylyl Cyclases↗
PubMed1982

Septo-hippocampal system: target for substituted benzamides.

Effects of the substituted benzamide, and of oxiperomide on DA receptors and on Da-related behaviors were the object of the study. The benzamides were practically inactive on DA-sensitive adenylate cyclase and on in vitro [3H] spiperone binding (in the absence of sodium ions). However, all of them inhibited in vivo [3H] spiperone binding in various rat brain regions; this in vivo effect was especially apparent in hippocampus and septum. In frontal cortex, the benzamides (with the exception of metoclopramide) produced only a partial inhibition of [3H] spiperone binding. Such inhibition also occurred in the striatum with sulpiride and tiapride. The results suggest that substituted benzamides are DA antagonists due to their ability to inhibit in vivo [3H] spiperone binding. The lack of agreement between in vivo and in vitro tests is also discussed.

Adenylyl Cyclases↗