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Biomedical subjects

O Giorgi

Publications and source records attributed to O Giorgi.

65 records · Page 4Linked to original sources
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

Sulfation of peptides and simple phenols by rat brain phenolsulfotransferase. Inhibition by dichloronitrophenol.

Brain phenolsulfotransferase (PST) is involved in the sulfation of simple phenols like dopamine and of precursors of biologically active peptides like cholecystokinin octapeptide (CCK-8). Therefore, inhibition of brain PST would provide a new approach to studying the sulfation of CCK-8 and other sulfated compounds. Since 2,6-dichloro-4-nitrophenol (DCNP) produces a prolonged and selective inhibition of the sulfoconjugation of exogenous phenols by the liver, we decided to examine the applicability of DCNP to studies of sulfation of CCK-8 and other compounds by brain. DCNP was capable of completely inhibiting PST activity in rat brain homogenates incubated with p-nitrophenol, phenol or dopamine as substrates. The IC50 values for p-nitrophenol and dopamine were 12 and 14 microM respectively. The concentrations of DCNP in brain cortex and plasma were measured by high pressure liquid chromatography (HPLC) after a dose of 100 mumoles/kg, i.p. Peak concentrations of 380 microM in plasma and 25 mumoles/kg in brain were achieved 30 min after injection. Subsequently, DCNP concentrations decreased with half-lives of 8 and 6 hr in plasma and brain cortex, respectively. To establish if DCNP can inhibit CCK sulfation in vivo, rats were injected with 100 micromoles/kg, i.p., of the drug 30 min before injection of 35SO4(2-) into the cerebral cortex and were killed 4.5 hr later. DCNP caused a 55% inhibition of [35S]CCK-8-SO4 formation as measured by HPLC. No change in the content of endogenous CCK-8-SO4 was detectable, however, in the brain cortex of rats treated with DCNP for up to 4 days, indicating that the PST which remained active was capable of maintaining CCK-8 content at steady state.

Animals↗
PubMed1984

A reduction of the tone of 5-hydroxytryptamine neurons decreases utilization rates of striatal and hypothalamic enkephalins.

The administration of drugs such as fenfluramine, p-chlorophenylalanine or 5,7-dihydroxytryptamine, which lower brain 5-hydroxytryptamine content, increases the enkephalin content of hypothalamus and striatum. None of these treatments changes proenkephalin mRNA content. On the basis of these results, we propose that 5-hydroxytryptamine does not increase the biosynthesis of enkephalin, but might increase the content of the neuropeptide by reducing peptide utilization.

5,7-Dihydroxytryptamine↗
PubMed1984

Dorsal root ganglia and nerve growth factor: a model for understanding the mechanism of GM1 effects on neuronal repair.

The experimental strategy of adding monosialoganglioside GM1 to a culture medium of fetal chick dorsal root ganglia (DRG) was utilized as a model system in which to examine the potential role of GM1 in modulation of neuronal cell responsiveness to nerve growth factor (NGF). Data indicate that the addition of GM1 to DRG explants or to DRG dissociated neuronal cells in culture enhances NGF-induced neurite outgrowth, neurite complexity, and neuronal cell survival following NGF withdrawal. The GM1 molecule apparently facilitates the acquisition or maintenance of the NGF-induced specific neuronal properties. Results are consistent with the hypothesis that the presence of GM1 molecules on the neuronal cell surface, either endogenous or following stable insertion of exogenous molecules, plays a prominent role in the modulation of functional neuronal cell behavior in response to varying neuronotrophic signals. This may prove to be relevant for the comprehension of GM1 effects on the facilitation of central nervous system repair processes.

Animals↗
PubMed1984

Gamma-aminobutyric acid turnover in rat striatum: effects of glutamate and kainic acid.

The turnover rate of gamma-aminobutyric acid (GABA) in the rat striatum was estimated by measuring its accumulation after inhibition of GABA-transaminase (GABA-T) with gabaculine. Intrastriatal injections of 100 micrograms gabaculine induced a rapid and complete inhibition of GABA-T. GABA accumulation was linear with time for at least 60 min (estimated turnover rate = 25 nmol/mg protein/h). The accumulation of GABA after gabaculine administration in animals that had been treated with kainic acid (5 nmol intrastriatally, 7 days) was only 40% of the control value, indicating that a major fraction of the net increase in GABA content induced by gabaculine originates in kainic acid-sensitive neurons. Intrastriatal injection of a mixture of kainic acid (5 nmol) and gabaculine caused a net increase in striatal GABA content significantly greater than that observed in controls, suggesting that neuronal death induced by kainic acid is preceded by a period of increased neuronal activity. Glutamic acid, the putative neurotransmitter for the excitatory corticostriatal pathway, also produced a significant increase in striatal GABA accumulation when injected together with gabaculine. This effect was blocked by the administration of the glutamate receptor antagonist glutamic acid diethyl ester. The interactions between GABAergic neurons and other neurotransmitters present in the striatum were also analyzed.

Animals↗
PubMed1983

Cholecystokinin turnover in brain.

Cholecystokinin octapeptide (CCK-8) occurs in relatively large amounts in some neurons of the cerebral cortex. Unlike most other mammalian neuropeptides, this compound contains a sulfate ester. We injected radiolabelled inorganic sulfate [( 35S]sulfate) into rat cerebral cortex and measured the formation and elimination of radiolabelled CCK-8 using HPLC. The data allow the first calculation of the turnover rate of a putative transmitter neuropeptide in brain. The turnover of CCK-8 (half-life = 16 h) is considerably slower than that of the biogenic amines and amino acid neurotransmitters (half-lives less than 4 h).

Animals↗
PubMed1981

Decreased 3H-L-quinuclidinyl benzilate binding and muscarine receptor subsensitivity after chronic gamma-butyrolactone treatment.

A significant decrease in the number of 3H-quinuclidinyl benzilate (3H-QNB) binding sites in striatal membranes was observed in rats exposed to gamma-butyrolactone (GBL) during 3 weeks. This decrease in 3H-QNB binding was not due to a direct effect of GBL on muscarine receptors since no alterations of binding were produced by high concentrations of GBL or of its active metabolite gammahydroxybutyric acid (GHB) when added in vitro. Challenge doses of pilocarpine were less effective in producing catalepsy and tremors in rats chronically treated with GBL. It is proposed that the partial inhibition of the nigro-striatal dopaminergic pathway produced by chronic GBL treatment leads to a persistent activation of the intrastriatal cholinergic interneurons, which are tonically inhibited by dopaminergic nigrostriatal neurons. The activation of striatal cholinergic interneurons results in a decreased number of muscarine receptors and in a lower sensitivity to cholinomimetic agents. Moreover, tolerance to the anesthetic effect of GBL was found to occur after chronic treatment with this drug. The brain levels of GHB at the time of regaining of the righting reflex were 50% higher in GBL pretreated animals then in controls. Indicating the tolerance to GBL-induced "sleep" is due to a decrease sensitivity of the effector to GHB rather than to a faster inactivation of elimination of the drug.

4-Butyrolactone↗
PubMedDate not supplied

D-1 dopamine receptors labelled with 3H-SCH 23390: decrease in the striatum of aged rats.

The effects of age on the binding parameters of 3H-SCH 23390, the most selective D-1 dopamine receptor ligand available at present, were studied in membrane preparations from rat striatum. When compared with 3 month old animals, there was a significant decrease in the density of 3H-SCH 23390 binding sites in 20 month old (-37%) and in 26 month old (-44%) rats, without alterations in the apparent dissociation constant values. No significant changes in the density or affinity of D-1 DA receptors were observed in 14 month old rats. In view of the behavioural effects mediated by D-1 DA receptors recently described (i.e., grooming, stereotypies and EEG desynchronization), the decrease in the density of these receptors in senescent rats may underlie some of the age-related alterations in dopaminergic functions in the rat brain.

Aging↗