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Biomedical subjects

A Concas

Publications and source records attributed to A Concas.

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

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↗
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

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↗
PubMed1985

Partial protection by CDP-choline against kainic acid-induced lesion in the rat caudate nucleus.

The acute intraperitoneal administration of CDP-choline to rats caused an increase in striatal dopamine (DA) synthesis, measured by DOPA accumulation after decarboxylase inhibition. Moreover, the chronic treatment with CDP-choline induced a decrease in the total number of 3H-spiroperidol binding sites, while partially antagonizing the disappearance of DA-sensitive adenylate cyclase activity elicited by intrastriatal kainic acid. These results suggest that CDP-choline may have a trophic and/or stimulant action on the function of nigrostriatal dopaminergic neurons.

3,4-Dihydroxyphenylacetic Acid↗
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

Evidence for an involvement of GABA receptors in the mediation of the proconvulsant action of ethyl-beta-carboline-3-carboxylate.

The kinetic characteristics of binding of [3H]-GABA and the pattern of isoniazid-induced convulsions were studied in rats treated with repeated intraventricular injections of ethyl-beta-carboline-3-carboxylate (beta-CCE) (10 micrograms/rat, twice daily for 8 days). Thirty-six hours after the last injection, the total number of binding sites for [3H]-GABA was decreased (25%) in the cerebral cortex and hippocampus. On the other hand, there was no significant difference in the dissociation constant (KD) between beta-CCE and solvent-treated rats. The decrease in binding sites for [3H]-GABA was paralleled by a strong potentiation of the convulsant pattern elicited by isoniazid. The results suggest that the proconvulsant effect elicited by beta-CCE is mediated by the decrease in the total number of binding sites for GABA, secondary to the interaction between beta-CCE and the benzodiazepine receptor coupled to the GABA receptor.

Animals↗
PubMed1983

beta-Carbolines activate neurons in the substantia nigra pars reticulata: an effect reversed by diazepam and Ro15-1788.

Diazepam (0.5 mg/kg i.v.) was found to inhibit the firing rate of substantia nigra pars reticulata (SN-PR) cells by 50%. In contrast, beta-CCM, at the doses of 125 and 250 micrograms/kg i.v. increased the firing rate by 90 and 150%, respectively, while DMCM produced similar increases at doses of 250 and 500 micrograms/kg i.v. Both beta-carboline-induced excitation and diazepam-induced inhibition were reversed to baseline values by the specific antagonist of benzodiazepine recognition sites, Ro15-1788 (2.0 mg/kg i.v.). Moreover, the stimulant effect of beta-carbolines was also reversed by diazepam (1.0 mg/kg) to about 50% of baseline. The results indicate that beta-carbolines specifically influence the activity of SN-PR cells through a mechanism opposite to that of benzodiazepines themselves, acting on benzodiazepine recognition sites.

Animals↗
PubMed1983

Increase of cyclic GMP in cerebellum by methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM).

The intraperitoneal administration of DMCM (0.5-3 mg/kg) produced a dose-related increase in the content of cyclic GMP in the rat cerebellar cortex. The effect of DMCM on cyclic GMP was abolished by pretreatment with benzodiazepine receptor ligands, diazepam and Ro15-1788 and by the GABA agonist muscimol. The results suggest that DMCM increases cerebellar cyclic GMP content through a direct action on benzodiazepine receptors located in the cerebellar cortex. The interaction between DMCM and the GABAergic system associated with benzodiazepine receptors is discussed. Cerebellar cyclic GMP content can be used as a biochemical index to differentiate agonists and antagonists for benzodiazepine receptors.

Animals↗
PubMed1983

Effect of a vitamin A-free diet on [3H]diazepam and [3H]GABA binding in the rat retina.

Benzodiazepine and GABA binding sites in the rat retina are influenced by a vitamin A-free diet. In rats fed a vitamin A-free diet, the total number of [3H]GABA and [3H]diazepam binding sites was markedly higher than in rats given a balanced diet. No differences were found in the apparent affinities of [3H]GABA and [3H]diazepam for their specific binding sites. The results suggest that GABA and benzodiazepine binding sites have a role in the function of the retina.

Animals↗
PubMed1983

Brain benzodiazepine receptors increase after chronic ethyl-beta-carboline-3-carboxylate.

Rats were treated with repeated intraventricular injections of ethyl-beta-carboline-3-carboxylate (beta-CCE) (10 micrograms/rat, twice daily for 8 days), 36 h after the last injection, the total number of 3H-diazepam binding sites was increased in the cerebral cortex, cerebellum and hippocampus by 63, 51 and 38%, respectively. On the other hand, there were no significant differences in the dissociation constants (KD) between beta-CCE and solvent treated rats. In contrast, chronic beta-CCE administration failed to change the number of the apparent affinity of 3H-beta-CCE binding sites in all the brain areas examined. The results suggest that beta-CCE is an antagonist at the 3H-diazepam binding 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↗