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M G Corda

Publications and source records attributed to M G Corda.

At least 73 records · Page 4Linked to original sources
PubMed1985

Long-lasting proconflict effect induced by chronic administration of the beta-carboline derivative FG 7142.

In this study, the effect of the chronic administration of the benzodiazepine (BZD) receptor ligand FG 7142 on the rat conflict test was examined. Rats chronically treated with FG 7142 (15 mg/kg, i.p. twice a day for 10 days) had an enhanced sensitivity to punishment at 4 and 15 days after the last treatment. This 'proconflict' effect was prevented by the concurrent administration of the BZD antagonist Ro 15-1788. The hypothesis that the long-lasting proconflict effect of chronic FG 7142 administration is the consequence of a persistent down-regulation of the GABAergic transmission is discussed.

Animals↗
PubMed1985

Involvement of benzodiazepine recognition sites in the foot shock-induced decrease of low affinity GABA receptors in the rat cerebral cortex.

The cerebral cortices of rats habituated to the handling manipulation that precedes sacrifice by guillotine (unstressed rats) have a higher number of low affinity GABA receptors than naive rats (stressed rats). Foot shock stress delivered to handling-habituated rats 5 min before sacrifice decreased the number of low affinity GABA receptors to the level found in naive animals, while leaving almost unchanged the [3H]GABA binding in the latter group. Since benzodiazepine (BZ) recognition sites are the target through which benzodiazepines modulate the emotional states of the animals, we investigated whether these receptors were involved in the action of foot shock stress on GABA binding. The in vitro addition of diazepam (5 X 10(-6) M) to cortical membranes from foot-shocked handling-habituated rats brought back the number of low affinity GABA receptors to the level found in cortical membranes from handling habituated rats. Moreover, the effect of foot shock on low affinity GABA receptors was completely antagonized in vivo by pretreatment with the specific benzodiazepine antagonist Ro15-1788 (30 mg/kg per os). Since the effect of foot shock on [3H]GABA binding is mimicked by the in vitro addition of beta-carbolines to cortical membranes from handling habituated rats, our working hypothesis is that an endogenous ligand for BZ recognition sites, possessing beta-carboline-like properties, is released during foot shock stress.

Animals↗
PubMed1985

Increase in nigral type II benzodiazepine recognition sites following striatonigral denervation.

In the rat substantia nigra Type II benzodiazepine recognition sites (measured as the portion of [3H]flunitrazepam binding which remain after the addition of 2 X 10(-7) M Cl 218872) represent 50% of the total benzodiazepine recognition sites. The density of Type II sites was increased by 35% following the degeneration of the striatonigral afferents induced by the intrastriatal injection of kainic acid. On the other hand the same lesion failed to change the density of the remaining nigral Type I sites. The results indicate that denervation induces supersensitivity to nigral Type II benzodiazepine recognition sites.

Animals↗
PubMed1985

Selective blockade of benzodiazepine receptors by Ro 15-1788 prevents foot shock-induced decrease of low affinity gamma-aminobutyric acid receptors.

The cerebral cortex of unstressed rats has a higher density of low affinity gamma-aminobutyric acid (GABA) receptors than that of stressed animals. Stress (handling or foot shock) produces a sudden decrease in the total number of low-affinity GABA receptors in the cerebral cortex of unstressed rats but leaves unchanged the density of GABA receptors in the cortex of stressed animals. The in vivo administration of Ro 15-1788 (30 mg/kg per os), a specific benzodiazepine receptor antagonist, completely prevents the effect of footshock on the low-affinity GABA receptors. The results suggest that (a) benzodiazepine recognition sites are involved in the action of stress on GABA receptors, and (b) stress may release an endogenous ligand for the benzodiazepine recognition site.

Animals↗
PubMed1985

Changes in the characteristics of low affinity GABA binding sites elicited by Ro15-1788.

3H-GABA binding was studied in cortical membranes from cerebral cortex of handling-habituated and naive rats after the in vitro addition of Ro15-1788. At low concentrations (10(-8), 10(-9) M) Ro15-1788 increased the total number of low affinity 3H-GABA binding sites in brain tissue from naive rats but failed to modify 3H-GABA binding in tissue from handling-habituated ones. On the contrary, Ro15-1788 at higher concentrations (10(-5), 10(-6)M) decreased the total number of low affinity 3H-GABA binding sites in tissue from handling-habituated rats but failed to modify 3H-GABA binding in tissue from naive animals. Ro15-1788 (10(-7)M) failed to modify significantly low affinity 3H-GABA binding in membranes from both naive and handling-habituated rats. However, this concentration abolished the effect of beta-carbolines and diazepam on 3H-GABA binding in membranes from naive and handling-habituated rats, respectively. The changes in the affinity of 3H-GABA binding were inversely related to the changes in the number. The results suggest that: a) the action "in vitro" of Ro15-1788 on low affinity 3H-GABA binding depends from its concentration at the benzodiazepine recognition sites; b) the benzodiazepine recognition site has a modulatory role in the control of the function of GABA-ergic receptor. Our data might explain the conflicting results obtained with this compound "in vivo".

Animals↗
PubMed1984

Evidence for the presence of benzodiazepine receptor subclasses in different areas of the human brain.

The kinetic characteristics of [3H]flunitrazepam ([3H]FNT) and [3H]ethyl-beta-carboline-3-carboxylate ([3H]beta-CCE) were compared in three different areas of the human brain. As revealed by the Scatchard plot analysis the total number of binding sites labelled by [3H]beta-CCE was markedly lower than that labelled by [3H]FNT. In fact, only 50% of the binding sites for [3H]FNT were also available for [3H]beta-CCE. This finding indicates that in the cerebral cortex, hippocampus and cerebellum of the human brain at least 50% of the benzodiazepine recognition sites are that of Type II. This conclusion is further supported by the evidence that CL-218872 (5 X 10(-6) M), a specific ligand for Type I benzodiazepine recognition site, inhibited [3H]FNT binding by 50% in membranes from the above brain areas. The results suggest that two distinct types of benzodiazepines recognition sites are present in different areas of the human brain.

Adult↗
PubMed1984

Stress and beta-carbolines decrease the density of low affinity GABA binding sites; an effect reversed by diazepam.

Cerebral cortex membranes from rats habituated to manipulations preceding decapitation (habituated rats) had 40% higher GABA binding than membranes from naive animals. Diazepam (5 X 10(-6) M), added to membranes from naive rats, increased GABA binding to the level of habituated rats, but failed to induce any further increase in membranes from the latter animals. Vice versa, beta-carbolines (FG 7142, beta-CCE, DMCM) added to membranes from habituated rats lowered GABA binding to the level of naive animals, but caused no further decrease in the membranes from this last group. Diazepam removed the effect of beta-carbolines in membranes from habituated rats. It is suggested that handling represents a stressful stimulus for naive animals and that stress lowers GABA binding by releasing an endogenous ligand for benzodiazepine receptors possessing similar properties to beta-carbolines. Finally, the results indicate that the emotional status of animals from which brain tissue is obtained should be considered when connections between GABA and benzodiazepine receptors are studied.

Animals↗
PubMed1984

Isolation, purification and partial sequence of a neuropeptide (diazepam-binding inhibitor) precursor of an anxiogenic putative ligand for benzodiazepine recognition site.

Diazepam binding inhibitor (DBI), a brain neuropeptide putative ligand for benzodiazepine binding sites, has been isolated and purified to homogeneity. This compound, like the anxiogenic beta-carbolines, injected intracerebroventricularly facilitates shock-induced suppression of drinking in thirsty rats. Cyanogen bromide (CNBr) cleavage of DBI produces three peptide fragments: the carboxy terminal fragment (F3 approximately equal to 1800 mol.wt.) and an intermediate fragment (F2 approximately equal to 3200 mol.wt.) are inactive, whereas the fragment that contains the amino terminus (F1 approximately equal to 6500 mol. wt.) facilitates punishment inhibition of operant behavior in rat. These data suggest that the F1 peptide contains the active sequence. The latter might be the natural effector of benzodiazepine recognition sites while DBI could be a polyprotein functioning as the precursor of the putative endogenous ligand of the benzodiazepine recognition site.

Amino Acid Sequence↗
PubMed1983

GABAergic synapses. Supramolecular organization and biochemical regulation.

Extraneurally released gamma-aminobutyric acid (GABA) interacts with specific recognition sites associated with proteins located in postsynaptic neuronal membranes that function as chloride (Cl-)ionophores. As a result of the interaction between GABA and the recognition sites, Cl- ionophores are opened causing an influx or an efflux of Cl-, depending on the values of the Cl- equilibrium potential and of the membrane potential. Hyperpolarization or depolarization will result from inward or outward Cl- fluxes, respectively. Independently of the change in conductivity elicited by GABA, this amino acid transmitter will reduce the effectiveness of the sodium ion (Na+) excitatory potential. In attempts to elucidate the molecular mechanism, whereby benzodiazepines facilitate the action of GABA on membrane conductance without changing the activity of Cl- or other ionophore, a basic protein (GABA-modulin, GM) has been isolated from rat brain which is similar in structure to the small molecular weight myelin basic protein, found in rodent brain. While GABA-modulin is located in synaptosomes, the small molecular weight myelin basic protein is located in the myelin fraction: more important, GABA-modulin inhibited the high affinity binding of GABA to crude synaptic membranes while the basic myelin protein did not. Also, amino acid composition and molecular weight differentiate the two proteins. The GABA-modulin can be phosphorylated with different stoichiometry by cyclic AMP-dependent protein kinase (4 mol PO4(-3)) or Ca2+-dependent protein kinase (1 mol PO4(-3)). Only cyclic AMP-dependent phosphorylation inhibited the action of GABA-modulin on GABA binding.

Animals↗
PubMed1983

On a brain polypeptide functioning as a putative effector for the recognition sites of benzodiazepine and beta-carboline derivatives.

Stimulation of benzodiazepine recognition sites by various ligands can elicit opposite types of responses such as proconvulsant and anticonvulsant or proconflict and anticonflict actions. The study of the pharmacological profile of various ligands makes it possible to distinguish three classes of compounds: (1) those that elicit anticonflict responses in the Vogel test, inhibit the convulsions due to an impairment of GABAergic transmission and increase the Bmax of the high affinity recognition site for GABA; (2) those that displace benzodiazepines from specific binding sites, facilitate convulsions due to impairment of GABAergic mechanisms, elicit proconflict responses in Vogel's test and inhibit the facilitation by benzodiazepines of GABA binding and (3) those that displace benzodiazepines and beta-carboline-derivatives from specific binding sites, antagonize the anticonflict, the proconflict, the anticonvulsant and the proconvulsant actions of the two preceding groups of substances and in very large doses elicit a small proconvulsant action. Examples of the latter are an imidazobenzodiazepine (RO 15-1788) and a pyrazolquinolinone derivative (CGS 8216). The nomenclature for these three classes of drugs should be kept flexible until the action of the endogenous ligand that functions as the physiological effector of the benzodiazepine/beta-carboline recognition site is known. A putative ligand for this site (DBI = diazepam binding inhibitor) has been isolated and purified to homogeneity. It includes 104 amino acid residues, the sequence of the last 45 amino acids has been determined. This compound elicits a proconflict action, displaces beta-carboline derivatives more than anxiolytic benzodiazepines, but its high molecular weight and relative low affinity for the binding sites in brain might suggest that it is a precursor, rather than the putative effector for benzodiazepine and/or beta-carboline recognition sites.

Animals↗
PubMed1983

Biochemical changes in the rat cerebellar cortex elicited by chronic treatment with methyl mercury.

Long-term (20 days) treatment with methyl mercury (MeHg) increases the total number of benzodiazepine binding sites and decreases essentially the content of cyclic GMP in the cerebellar cortex. In contrast, this treatment fails to modify the content of GABA and cyclic AMP, GAD activity and GABA binding sites in the same brain area. The changes in cyclic GMP and benzodiazepine binding sites in the cerebellar cortex are discussed in relation to the motor disturbances associated with MeHg intoxication.

Animals↗
PubMed1983

Isolation, characterization, and purification to homogeneity of an endogenous polypeptide with agonistic action on benzodiazepine receptors.

A brain polypeptide termed diazepam-binding inhibitor (DBI) and thought to be chemically and functionally related to the endogenous effector of the benzodiazepine recognition site was purified to homogeneity. This peptide gives a single band of protein on NaDodSO4 and acidic urea gel electrophoresis. A single UV-absorbing peak was obtained by HPLC using three different columns and solvent systems. DBI has a molecular mass of approximately equal to 11,000 daltons. Carboxyl-terminus analysis shows that tyrosine is the only residue while the amino-terminus was blocked. Cyanogen bromide treatment of DBI yields three polypeptide fragments, and the sequences of two of them have been determined for a total of 45 amino acids. DBI is a competitive inhibitor for the binding of [3H]diazepam, [3H]flunitrazepam, beta-[3H]carboline propyl esters, and 3H-labeled Ro 15-1788. The Ki for [3H]-diazepam and beta-[3H]carboline binding were 4 and 1 microM, respectively. Doses of DBI that inhibited [3H]diazepam binding by greater than 50% fail to change [3H]etorphine, gamma-amino[3H]butyric acid, [3H]-quinuclidinyl benzilate, [3H]dihydroalprenolol, [3H]adenosine, and [3H]imipramine binding tested at their respective Kd values. DBI injected intraventricularly at doses of 5-10 nmol completely reversed the anticonflict action of diazepam on unpunished drinking and, similar to the anxiety-inducing beta-carboline derivative FG 7142 (beta-carboline-3-carboxylic acid methyl ester), facilitated the shock-induced suppression of drinking by lowering the threshold for this response.

Amino Acids↗
PubMed1983

beta-Carbolines enhance shock-induced suppression of drinking in rats.

By using Vogel's method to test the anxiolytic action of benzodiazepines and reducing the intensity of the current delivered to the drinking tube, it is possible to distinguish the pharmacological activity of three types of ligands for the benzodiazepine recognition site. An anticonflict action typical of anxiolytic benzodiazepines, a proconflict action typical of many beta-carbolines, including FG 7142 (beta-carboline-3-carboxylic acid ethyl ester methyl amide), and an antagonistic action of the proconflict and anticonflict actions typical of RO 15-1788 (ethyl-8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5-alpha]-[1, 4]-benzodiazepine-3-carboxylate) and CGS 8216 (2-phenylpyrazolo[4,3-c]quinolin-3-(5H)-one). Pentylenetetrazole, which causes convulsions by interacting with a subunit of the gamma-aminobutyric acid receptor that is different from the benzodiazepine recognition site, also induces a proconflict action that is antagonized by anxiolytic benzodiazepines but not by RO 15-1788.

Animals↗
PubMed1983

Modulation of GABA receptor binding by Ca2+.

In frozen-thawed repeatedly washed rat cortical synaptic membranes, Ca2+ (1-5 mM) decreased the binding of [3H]muscimol whereas it increased the binding of [3H]gamma-aminobutyric acid (GABA). However, the binding of [3H]GABA was decreased by the same extent as the binding of [3H]muscimol when the membranes were incubated with baclofen (a selective ligand for the GABAB binding site) and Ca2+. Scatchard analysis of [3H]muscimol binding revealed that Ca2+ reduced the density of GABA binding sites without affecting the dissociation constant. Ca2+ was more potent than Ba2+, Mg2+ was ineffective, and the Ca2+ antagonist La3+ stimulated [3H]muscimol binding. The inhibition of [3H]muscimol binding by Ca2+ was not influenced by calmodulin (50 micrograms/ml), trifluoperazine (10(-5) M), verapamil (10(-6) M), quinacrine (10(-4) M), cordycepin (0.1 mM), leupeptin (20 microM), or soybean trypsin inhibitor (0.1 mg/ml). Moreover, the effect of Ca2+ was additive to that of GABA-modulin. These results indicate that Ca2+ decreases the number of GABAA binding sites while unveiling GABAB binding sites.

Animals↗