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Biomedical subjects

M G Corda

Publications and source records attributed to M G Corda.

At least 55 records · Page 3Linked to original sources
PubMed1988

Decreased sensitivity to diazepam induced by chronic administration of FG 7142.

Chronic treatment with the beta-carboline inverse agonist FG 7142 (25 mg/kg i.p. twice a day for 15 consecutive days) enhances in rats the effects of proconvulsant and convulsant beta-carbolines and of the inverse agonist Ro 15-4513 whilst leaving unchanged the response to the benzodiazepine receptor antagonists. Moreover, the same treatment reduces the sedative and the anticonvulsant effects of diazepam. These results are consistent with the view that chronic treatment with FG 7142 may produce a decrease in the pharmacological effects of benzodiazepines, whilst inducing sensitization to the convulsant effect of inverse agonists.

Animals↗
PubMed1988

The benzodiazepine recognition site inverse agonists Ro 15-4513 and FG 7142 both antagonize the EEG effects of ethanol in the rat.

The aim of the present study was to compare the ability of Ro 15-4513 and FG 7142, two inverse agonists for benzodiazepine recognition sites, to antagonize the EEG effects of ethanol in freely moving rats. Ethanol (2.5 g/kg, p.o.) induced sedation and ataxia associated with a progressive suppression of the fast cortical activities and an enhancement of low frequencies in both cortical and hippocampal tracings. In contrast, Ro 15-4513 (2 mg/kg, i.p.) and FG 7142 (10 mg/kg, i.p.) both caused a state of alertness associated with desynchronized cortical activity and theta hippocampal rhythm as well as spiking activity which was predominantly observed in the cortical tracings. When rats were treated with FG 7142 or RO 15-4513 either before or after ethanol, a reciprocal antagonism of the behavioral and EEG effects of ethanol and of the partial inverse agonists was observed. These data support the view that the anti-ethanol effects of Ro 15-4513 may be related to its partial inverse agonist properties.

Animals↗
PubMed1988

Preferential affinity of 3H-2-oxo-quazepam for type I benzodiazepine recognition sites in the human brain.

The hypnotic drug quazepam and its active metabolite 2-oxo-quazepam (2-oxo-quaz) are two benzodiazepines (BZ) containing a trifluoroethyl moiety on the ring nitrogen at position 1, characterized by their preferential affinity for Type I BZ recognition sites. In the present study we characterized the binding of 3H-2-oxo-quaz in discrete areas of the human brain. Saturation analysis demonstrated specific and saturable binding of 3H-2-oxo-quaz to membrane preparations from human cerebellum. Hill plot analysis of displacement curves of 3H-flunitrazepam (3H-FNT) binding by 2-oxo-quaz yielded Hill coefficients of approximately 1 in the cerebellum and significantly less than 1 in the cerebral cortex, hippocampus, caudate nucleus, thalamus and pons. Self and cross displacement curves for 3H-FNT and 3H-2-oxo-quaz binding in these brain areas indicated that 2-oxo-quaz binds with different affinities to two populations of binding sites. High affinity binding sites were more abundant in the cerebellum (95% of total sites), cerebral cortex, hippocampus and thalamus, whereas low affinity sites were predominant in the caudate nucleus and pons. Competition studies of 3H-2-oxo-quaz (2 nM) and 3H-FNT (0.5 nM) using unlabelled ligands indicated that compounds which preferentially bind to Type I sites are more potent at displacing 3H-2-oxo-quaz than 3H-FNT from cerebral cortex membrane preparations. The results suggest that 3H-2-oxo-quaz may be used for selectively studying Type I BZ recognition sites in the human brain.

Adult↗
PubMed1988

Characterization of 3H-2-oxo-quazepam binding in the human brain.

1. 2-oxo-quazepam (2oxoquaz) is a novel benzodiazepine (BZD) hypnotic containing a trifluoethyl substituent on the ring nitrogen at position 1, which, unlike other BZDs, distinguishes two populations of BZD binding sites. In the present study we characterized the binding of 3H-2oxoquaz to human brain membrane preparations. 2. Self and cross displacement curves for 3H-FNT and 3H-2oxoquaz binding in different brain areas indicate that 2oxoquaz binds with different affinities to two populations of binding sites in the human brain. 3. Competition studies of 3H-2oxoquaz (2 nM) and 3H-FNT (0.5 nM) binding with a series of unlabelled ligands indicate that compounds which preferentially bind to Type I sites are more potent at displacing 3H-2oxoquaz than 3H-FNT from cerebral cortex membrane preparations. 4. The binding of 3H-2oxoquaz is stimulated by gamma-aminobutyric acid (GABA) and pentobarbital in a concentration-dependent manner. 5. The results suggest that in the human brain 3H-2oxoquaz binds with high affinity to a subpopulation of BZD recognition sites (Type I sites) which are functionally linked to the GABA receptor and the chloride ionophore.

Adult↗
PubMed1988

gamma-Aminobutyric acid and pentobarbital enhance 2-[3H]oxoquazepam binding to type I benzodiazepine recognition sites in rat and human brain.

2-Oxoquazepam (2oxoquaz) is a novel benzodiazepine which shows preferential affinity for type I benzodiazepine recognition sites. In the present study, we analyzed the effect of gamma-aminobutyric acid (GABA), pentobarbital, and chloride ions on [3H]2oxoquaz and [3H]flunitrazepam ( [3H]FNT) binding to membrane preparations from rat and human brain. GABA stimulated [3H]-2oxoquaz and [3H]FNT binding in a concentration-dependent manner. The maximal enhancement produced by GABA on [3H]2oxoquaz binding was higher than that produced on [3H]FNT binding in both rat and human tissues. In the rat brain, the effect of GABA on [3H]2oxoquaz was similar throughout different brain areas, whereas the effect on [3H]FNT binding was lower in the cerebral cortex and hippocampus than in the cerebellum. Moreover, both [3H]2oxoquaz and [3H]FNT binding were stimulated by chloride ions and pentobarbital. The results are consistent with the hypothesis that type I benzodiazepine recognition sites are linked functionally to the GABA recognition site and the chloride ionophore.

Adult↗
PubMed1987

The beta-carboline ZK 93423 inhibits reticulata neurons: an effect reversed by benzodiazepine antagonists.

A novel beta-carboline with benzodiazepine-like properties has recently been synthesized. We compared the effect of the i.v. administration of this drug, ZK 93423, with diazepam on the activity of nigral pars reticulata neurons which are known to be very sensitive to the inhibitory effect produced by GABA-mimetics and benzodiazepines. ZK 93423 (0.05-1.0 mg/kg) inhibited reticulata cells in a dose-related manner up to the cessation of their activity. Since the maximal rate-inhibition elicited by diazepam (1.0 mg/kg) was some 55% of baseline, ZK 93423 showed a much greater potency. Moreover, the firing depression by ZK 93423 was prevented and reversed by two benzodiazepine receptor antagonists: Ro15-1788 and ZK 93426. However, the dosage of Ro15-1788 required for these actions was at least five times higher than that for the blockade of the diazepam effect. The results indicate that the beta-carboline agonist ZK 93423 decreases the activity of reticulata neurons more effectively than diazepam.

Action Potentials↗
PubMed1987

The anxiolytic beta-carboline ZK 93423 prevents the stress-induced increase in dopamine turnover in the prefrontal cortex.

The effects of electric foot-shock on the activity of the mesocortical dopaminergic (DAergic) neurons were estimated by measuring the changes in dihydrophenylacetic acid (DOPAC) and DA content in the prefrontal cortex of the rat. A marked rise in DOPAC content (+80%) and a significant decrease in DA levels (-23%) were observed after a 20 min foot-shock session. These effects were completely prevented by pretreatment with diazepam (5 mg/kg i.p.). ZK 93423, a recently synthesized beta-carboline with benzodiazepine-like properties, prevented the decrease in DA content induced by foot-shock at the dose of 20 mg/kg. Moreover, the stress-induced increase in DOPAC levels was partly or completely blocked by pretreatment with 20 or 40 mg/kg of ZK 93423, respectively. These results provide further support for the view that the mesocortical DAergic system can be modulated by drugs that selectively interact with the benzodiazepine recognition site.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Changes in GABAergic transmission induced by stress, anxiogenic and anxiolytic beta-carbolines.

The cerebral cortex of unstressed (handling-habituated) rats has a higher number of low affinity GABA receptors than stressed (naive) rats. Foot shock stress delivered to unstressed rats decreases the density of cortical low affinity GABA receptors to the level found in the naive animals. The effect of stress on GABA receptors is mimicked by anxiogenic beta-carbolines, both after in vitro addition (10(-6) M) to cortical membrane preparations or after the in vivo administration (20 mg/kg IP) to unstressed rats. Vice versa, benzodiazepines or anxiolytic beta-carbolines (ZK 93423, 10(-5) M) added to membranes from naive rats increase GABA binding to the level of unstressed rats and remove the decrease in the density of GABA receptors elicited by anxiogenic beta-carbolines. Rats chronically treated with the anxiogenic beta-carboline, FG 7142 (15 mg/kg IP twice a day for 10 consecutive days) have an enhanced sensitivity to punishment at 5 and 15 days after the last treatment. The behavioural effect is paralleled by a marked decrease in the total number of cortical low affinity GABA receptors. Both biochemical and behavioural effects elicited by chronic FG 7142 are prevented by the concurrent administration of the benzodiazepine antagonist Ro15-1788. These results suggest that (a) anxiolytic beta-carbolines, like benzodiazepines, increase the GABAergic transmission, (b) acute and chronic anxiogenic beta-carboline administration, like stress, decreases GABAergic transmission. Since all these effects are antagonized by the benzodiazepine receptor blocker Ro15-1788, it is tempting to speculate that stress releases an endogenous ligand for benzodiazepine recognition sites.

Animals↗
PubMed1987

Enhanced sensitivity to beta-carboline inverse agonists in rats chronically treated with FG 7142.

The biochemical and behavioural effects of the chronic administration of the beta-carboline inverse agonist FG 7142 were studied in the rat. Repeated administration of FG 7142 (15 mg/kg IP, twice daily for 10 consecutive days) induced sensitization to the effects of this drug, which from proconvulsant became a full convulsant. Thus, myoclonic seizures were observed in 30% and 80% of the animals by the third and the eighth day of treatment, respectively. The sensitization to the convulsant effect of FG 7142 persisted for up to 50 days after withdrawal and was completely prevented by the concurrent administration of the benzodiazepine receptor antagonist Ro15-1788 (15 mg/kg IP, twice a day for 10 days). Moreover, four to twelve days after withdrawal from chronic treatment with FG 7142, an increased sensitivity to the proconvulsant beta CCE and to the convulsant DMCM was observed. In addition, convulsions induced by isoniazid (350 mg/kg, SC) were potentiated in rats chronically treated with FG 7142 at 5 and 20 days after withdrawal. These pharmacological effects were paralleled by a decrease in the density of low affinity GABA receptors in the cerebral cortex and cerebellum. These results are consistent with the view that repeated administration of FG 7142 induces a long-lasting down-regulation of the GABAergic function which results in an increased sensitivity to beta-carboline inverse agonists and isoniazid. The possibility that a concomitant decrease in the responsiveness to benzodiazepines and Ro15-1788 takes place after chronic treatment with FG 7142 is also discussed.

Animals↗
PubMed1987

Enhancement of gamma-aminobutyric acid binding by the anxiolytic beta-carbolines ZK 93423 and ZK 91296.

The effects of two anxiolytic beta-carboline derivatives, ZK 93423 and ZK 91296, on the binding of gamma-[3H]aminobutyric acid ([3H]GABA) to brain membrane preparations from rat cerebral cortex were examined. ZK 93423 concentration-dependently enhanced the specific binding of [3H]GABA, with a maximal increase of 45% above control at a 50 microM concentration. A less pronounced increase was induced by diazepam and by the partial agonist ZK 91296. Scatchard plot analysis revealed that the effect of ZK 93423 was due to an increase in the total number of high- and low-affinity GABA binding sites. The action of ZK 93423 was mediated by benzodiazepine recognition sites since it was blocked by the benzodiazepine antagonists Ro 15-1788 and ZK 93426 at concentrations that failed to modify [3H]GABA binding on their own. Moreover the stimulatory effect of ZK 93423 on [3H]GABA binding was also blocked by the beta-carboline inverse agonist ethyl beta-carboline-3-carboxylate. These results are consistent with the view that ZK 93423 and ZK 91296, similarly to benzodiazepines, exert their pharmacological effects by enhancing the GABAergic transmission at the level of the GABA/benzodiazepine receptor complex.

Animals↗
PubMed1986

Behavioural and biochemical evidence for a long-lasting decrease in GABAergic function elicited by chronic administration of FG 7142.

Chronic treatment with the beta-carboline derivative FG 7142 (15 mg/kg i.p. twice a day for 10 consecutive days) produced a long-lasting enhancement of shock-induced suppression of drinking in rats, without affecting unpunished behaviour. This proconflict effect was observed up to 15 days after withdrawal from FG 7142. A significant sensitization to seizures induced by isoniazid, a drug known to inhibit GABAergic transmission, was also found to occur after long-term (25 days) withdrawal. Moreover, the density of low-affinity GABA receptors was decreased by 30% in the cerebral cortex of rats repeatedly injected with FG 7142 at 5 and 15 days after withdrawal. The capacity of high-affinity GABA receptors, as well as the apparent dissociation constants for both high- and low-affinity GABA receptors were unchanged. Similar modifications in [3H]GABA binding were also observed in the cerebellum. The enhancement of punishment suppressed behaviour, the sensitization to isoniazid-induced convulsions and the decrease in the density of low-affinity GABA receptors suggest that chronic administration of FG 7142 induces a persistent down-regulation of GABAergic transmission in the central nervous system.

Animals↗
PubMed1986

Striato-nigral denervation increases type II benzodiazepine receptors in the substantia nigra of the rat.

The degeneration of the striato-nigral projection induced by the injection of kainic acid into the striatum produced a 30% increase in the density of type II benzodiazepine binding sites (measured as the proportion of [3H]flunitrazepam which remained after the addition of 2 X 10(-7) M CL 218872). The lesion did not change the number of type I benzodiazepine binding sites (measured using [3H]ethyl-beta-carboline-3-carboxylate). The increase of type II benzodiazepine binding sites persisted and was markedly enhanced in the substantia nigra, previously lesioned with kainic acid. In fact, the injection of kainic acid into the nigra caused, 3 weeks after the treatment, a 80% decrease in the total number of type I benzodiazepine binding sites, and no change in the number of type II benzodiazepine binding sites. The density of type II sites increased by 70% following a subsequent injection of kainic acid into the striatum, homolateral to the lesioned substantia nigra. The results suggest that type I benzodiazepine binding sites in the nigra are located on kainic acid-sensitive elements (probably intrinsic neurones), while type II benzodiazepine binding sites, the number of which increased after degeneration of the striato-nigral pathway, are localized on kainic acid-resistant structures (probably axons or terminals) that receive an input from striatal afferents and from interneurones in the nigra.

Animals↗
PubMed1986

Proconflict effect of GABA receptor complex antagonists. Reversal by diazepam.

The effect of drugs which down-regulate the function of GABA at the level of the GABA/benzodiazepine receptor complex was studied on the conflict test in the rat. The GABA receptor antagonist, bicuculline, and the blockers of the GABA-receptor-coupled chloride channel, picrotoxin and pentylenetetrazol, produced a dose-dependent proconflict effect. This effect occurred at dose levels which failed to affect unpunished behaviour. The most effective compounds were bicuculline and picrotoxin. The proconflict effect of these drugs was prevented by diazepam but not by the specific benzodiazepine antagonist, Ro15-1788. The data indicate that a diminished GABAergic activity at different subunits of the GABA receptor complex resulted in an enhancement of punishment-suppressed behaviour in rats.

Animals↗
PubMed1986

Enhancement of gamma-aminobutyric acid binding by quazepam, a benzodiazepine derivative with preferential affinity for type I benzodiazepine receptors.

We evaluated the effect of the two N-trifluoroethyl benzodiazepines, quazepam and its 2-oxo metabolite SCH 15725, which possess preferential affinity for type I benzodiazepine recognition sites, on the binding of [3H] gamma-aminobutyric acid ([3H]GABA) to rat brain membrane preparations. The study also included compounds such as diazepam and N-desalkyl-2-oxoquazepam (SCH 17514), which have equal affinity for the type I and type II receptor subtypes. Binding of [3H]GABA was studied in frozen-thawed and repeatedly washed cortical membranes incubated in 20 mM KH2PO4 plus 50 mM KCl, pH 7.4, at 4 degrees C in the absence and presence of quazepam or its metabolites. Addition of 10(-6) M quazepam increased by 30% specific [3H]GABA binding; as revealed by Scatchard plot analysis, the effect was due to an increase in the total number of GABA receptors. The effect of quazepam was concentration dependent, and it was shared by its active metabolite SCH 15725. The potency of quazepam and SCH 15725 in enhancing [3H]GABA binding was similar to that of diazepam, whereas CL 218872 and SCH 17514 were less active. Moreover, the [3H]GABA binding-enhancing effect of quazepam was mediated by an occupancy of benzodiazepine receptors, because it was specifically antagonized by 5 X 10(-6) M Ro15-1788.

Animals↗