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Biomedical subjects

G Biggio

Publications and source records attributed to G Biggio.

At least 163 records · Page 9Linked 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↗
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

3H-SCH 23390 binding sites in the rat substantia nigra: evidence for a presynaptic localization and innervation by dopamine.

Chronic treatment with SCH 23390, a selective D-1 dopamine receptor antagonist, elicited a 32% increase in the density of 3H-SCH 23390 binding sites in nigral membrane preparations but failed to change the apparent KD of the ligand for its binding sites. Haloperidol, a D-2 dopamine receptor antagonist which blocks the dopamine-sensitive adenylate cyclase and (-) sulpiride, a selective D-2 dopamine receptor blocker, which does not block the dopamine-sensitive adenylate cyclase, failed to change both the Bmax and KD of 3H-SCH 23390 binding. Finally, the intrastriatal injection of kainic acid produced a marked decrease of both GAD activity and GABA content and 3H-SCH 23390 binding sites (65%) in the homolateral substantia nigra. The results show that in the rat substantia nigra most of the 3H-SCH 23390 binding sites have a presynaptic localization on the striato-nigral GABAergic afferent terminals and suggest that dopamine released from nigral dendrites exerts a tonic influence on these presynaptic D-1 dopamine receptors.

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↗
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

[3H]SCH 23390 binding sites increase after chronic blockade of D-1 dopamine receptors.

Chronic treatment with SCH 23390, a selective D-1 dopamine receptor antagonist, increased (40%) the density of [3H]SCH 23390 binding sites in striatal membrane preparations but failed to change the apparent KD of the ligand for its binding sites. Haloperidol, which preferentially blocks D-2 receptors, induced only a slight, not significant increase in the total number of [3H]SCH 23390 binding sites. (-)Sulpiride, a selective D-2 receptor blocker, also failed to change either Bmax or KD of [3H]SCH 23390 binding. Thus, chronic blockade of D-1 receptor sites by SCH 23390 can lead to an increase in their total number.

Adenylyl Cyclases↗
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

SCH 23390, a selective dopamine D1 antagonist, activates dopamine neurons but fails to prevent their inhibition by apomorphine.

SCH 23390, a rather selective D1 receptor blocker, activates the firing rate of dopamine (DA) neurons in the substantia nigra (SN-DA neurons) in rats, similarly to haloperidol (a D1-D2 receptor antagonist) and sulpiride (a selective D2 receptor blocker). These neuroleptics produce no additional increase over the maximal activation produced by SCH 23390. Unlike haloperidol or sulpiride, SCH 23390 fails to prevent the inhibition by apomorphine of SN-DA neurons, a DA autoreceptor-mediated effect. It is suggested that the doses of SCH 23390 that stimulate DA neurons block D2 in addition to D1 receptors, or that D1 blockade results in the functional inactivation of a specific population of D2 receptors as well. The failure of SCH 23390 to block the apomorphine effect indicates that DA autoreceptors can be pharmacologically differentiated form postsynaptic DA receptors.

Action Potentials↗
PubMed1985

Sedation and sleep induced by high doses of apomorphine after blockade of D-1 receptors by SCH 23390.

The effect of SCH 23390, a selective blocker of D-1 receptors, on apomorphine-induced behavioural and EEG changes was studied in rats. In control rats, a low dose of apomorphine (50 micrograms/kg s.c.) produced sedation associated with EEG synchronization. A high dose of apomorphine (1 mg/kg s.c.) produced stereotypy associated with EEG desynchronization. At the dose of 1 mg/kg i.p., SCH 23390 decreased motor activity but failed to alter the EEG pattern. The administration of either the low or high dose of apomorphine to SCH 23390-treated rats elicited a marked sedative response associated with EEG synchronization. The EEG synchronization produced by apomorphine (50 micrograms/kg) in SCH 23390-treated rats was prevented by (-)-sulpiride (25 mg/kg i.p.), a D-2 receptor blocker. It is concluded that by preventing the excitatory response to apomorphine SCH 23390 discloses the existence of a population of D-2 receptors mediating sedation and sleep.

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↗