Search PubMed⌕ Search

Biomedical subjects

G Biggio

Publications and source records attributed to G Biggio.

At least 19 recordsLinked to original sources
PubMed1992

Carbon dioxide inhalation reduces the function of GABAA receptors in the rat brain.

The effect of CO2 inhalation on the function of the GABA(A)-coupled chloride channel was evaluated in rat brain. This treatment decreased the capability of GABA to stimulate 36Cl- uptake and produced a significant increase of [35S]-TBPS ([35S]t-butylbicyclophosphorothionate) binding in the cerebral cortex, cerebellum and hippocampus. These results demonstrate that a brief exposure of rats to CO2 inhalation reduces the function of the GABA(A)-ionophore receptor complex in rat brain.

Administration, Inhalation↗
PubMed1992

Differential turnover rates of D1 dopamine receptors in the brain and retina of adult and senescent rats.

The present study was designed to investigate the turnover rates of D1 dopamine receptors in the brain and retina of adult and aged rats. To this aim, we monitored the increase in the density of 3H-SCH 23390 binding sites after the administration of the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2 dihydroquinoline (EEDQ). The results indicate that, in aged rats, the production rate of D1 receptors decreases by 41% to 61% in the striatum, nucleus accumbens and substantia nigra, whereas a smaller reduction in the degradation rate of these receptors is observed (-21% to -40%). In contrast, the production rate of D1 receptors in the retina of aged rats remains unchanged, whilst the degradation rate decreases by 25%. These alterations in the rates of receptor production and degradation may account for the age-related decrease in the density of D1 dopamine receptors in the striatum, nucleus accumbens and substantia nigra as well as for the increase in the density of these receptors in the retina of aged rats.

Aging↗
PubMed1992

Pharmacology of gamma-aminobutyric acidA receptor complex after the in vivo administration of the anxioselective and anticonvulsant beta-carboline derivative abecarnil.

In rodents, the effect of the beta-carboline derivative isopropyl-6- benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate (abecarrnil), a new ligand for benzodiazepine receptors possessing anxiolytic and anticonvulsant properties, was evaluated on the function of central gamma-aminobutyric acid (GABA)A receptor complex, both in vitro and in vivo. Added in vitro to rat cortical membrane preparation, abecarnil increased [3H]GABA binding, enhanced muscimol-stimulated 36Cl- uptake and reduced the binding of t-[35S]butylbicyclophosphorothionate ([35S]TBPS). These effects were similar to those induced by diazepam, whereas the partial agonist Ro 16-6028 (tert-butyl-(S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H- imidazo[1,5-a]-pyrrolo-[2,1-c][1,4]benzodiazepine-1-carboxylate) showed very weak efficacy in these biochemical tests. After i.p. injection to rats, abecarnil and diazepam decreased in a time-dependent and dose-related (0.25-20 mg/kg i.p.) manner [35S]TBPS binding measured ex vivo in the cerebral cortex. Moreover, both drugs at the dose of 0.5 mg/kg antagonized completely the convulsant activity and the increase of [35S]TBPS binding induced by isoniazide (350 mg/kg s.c.) as well as the increase of [35S]TBPS binding induced by foot-shock stress. To better correlate the biochemical and the pharmacological effects, we studied the action of abecarnil on [35S]TBPS binding, exploratory motility and on isoniazid-induced biochemical and pharmacological effects in mice. In these animals, abecarnil produced a paralleled dose-dependent (0.05-1 mg/kg i.p.) reduction of both motor behavior and cortical [35S]TBPS binding. Moreover, 0.05 mg/kg of this beta-carboline reduced markedly the increase of [35S]TBPS binding and the convulsions induced by isoniazid (200 mg/kg s.c.).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

The neutral endopeptidase-24.11 (enkephalinase) inhibitor, SCH 32615, increases dopamine metabolism in the nucleus accumbens of the rat.

SCH 32615 is a novel inhibitor of the enzyme, neutral endopeptidase (NEP, E.C. 3.4.24.11), the so called 'enkephalinase', which plays a functional role in the degradation of [Met5]- and [Leu5]enkephalin. The present study was designed to assess whether SCH 32615 is able to modify the activity of dopaminergic neurons as reflected by changes in the content of the major dopamine metabolite, dihydroxyphenylacetic acid (DOPAC), in three different areas of the rat brain: the nucleus accumbens, the striatum, and the prefrontal cortex. When administered at analgesically active doses (1-100 mg/kg s.c., 60 min before killing), SCH 32615 induced a dose-dependent increase in dopamine metabolism in the nucleus accumbens but was ineffective in the striatum and in the prefrontal cortex. This effect appears to be mediated via opioid receptors, since it was completely prevented by naloxone (5 mg/kg s.c.). The increase in DOPAC content in the prefrontal cortex elicited by foot-shock was unaffected by pretreatment with SCH 32615. In the nucleus accumbens, dopamine metabolism was increased to the same extent by foot-shock and SCH 32615 administered separately, but these effects were not additive, suggesting that SCH 32615 and foot-shock act via a common mechanism. Taken together, these results support the hypothesis that inhibition of the in vivo degradation of enkephalins induced by the systemic administration of SCH 32615 increases the enkephalinergic tone in the central nervous system and thereby activates the mesolimbic dopaminergic neurons.

Animals↗
PubMed1991

Neurochemical action of the general anaesthetic propofol on the chloride ion channel coupled with GABAA receptors.

The effect of propofol, a novel short acting anaesthetic, on the function of the GABAA/ionophore receptor complex was studied in vitro in cortical membrane preparations from rat cerebral cortex and was compared with the action of pentobarbital and alphaxalone, two general anaesthetics known to enhance GABAergic transmission. Propofol, mimicking the action of pentobarbital and alphaxalone, increased [3H]GABA binding, reduced [35S]TBPS binding and enhanced muscimol-stimulated 36Cl- uptake in a concentration-dependent manner. While the efficacy of the drugs in affecting these biochemical parameters was similar, they differed markedly in potency being alphaxalone greater than propofol greater than pentobarbital. However, separate sites of action or different mechanisms for these drugs can be suggested by the result that the concomitant addition of propofol either with alphaxalone or pentobarbital or diazepam produced a simple additive inhibition of [35S]TBPS binding as well as an additive enhancement of [3H]GABA binding and muscimol-stimulated 36Cl- uptake. The effect of propofol at the level of the GABA/ionophore receptor complex seems to be strictly dependent on the interaction of GABA with its recognition site. In fact, the specific GABAA receptor antagonist bicuculline antagonized the decrease of [35S]TBPS binding as well as the enhancement of [3H]GABA binding and muscimol-stimulated 36Cl- uptake induced by propofol. On the other hand, propofol was able to enhance [3H]GABA binding in membranes previously incubated with the specific chloride channel blocker picrotoxin. Finally, the finding that propofol fails to affect [3H]flunitrazepam binding together with the failure of Ro 15-1788 and PK 11195 to antagonize its effect on [35S]TBPS binding excludes a direct interaction at the level of benzodiazepine recognition sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics↗
PubMed1991

"In vivo" administration of valproate decreases t-[35S]butylbicyclophosphorothionate binding in the rat brain.

The effect of the "in vivo" administration of sodium valproate on t-[35S]butylbicyclophosphorothionate (35S-TBPS) binding measured "ex vivo" in the rat cerebral cortex was investigated. Sodium valproate produced a decrease of 35S-TBPS binding. The maximal effect (-32%) was reached with the dose of 400 mg/kg i.p., 60 min after the administration of the drug. Saturation experiments revealed that the effect of sodium valproate was due to a decrease in the total number of binding sites with no changes in the affinity constant. A small dose of diazepam (0.5 mg/kg, i.p.), which per se does not modify 35S-TBPS binding, markedly potentiated the inhibitory effect of sodium valproate on 35S-TBPS binding. Moreover, the "in vitro" addition of sodium valproate to cortical membranes failed to modify 35S-TBPS binding, indicating that the effect of the "in vivo" administration of this drug is not due to its direct interaction with the chloride associated binding sites. These results strongly suggest that this drug enhances the function of GABAergic synapses at the level of the GABA-coupled chloride channel. This conclusion supports the hypothesis that an enhancement of GABAergic transmission plays a role in the molecular mechanism involved in the antiepileptic action of sodium valproate.

Animals↗
PubMed1991

Foot-shock stress enhances the increase of [35S]TBPS binding in the rat cerebral cortex and the convulsions induced by isoniazid.

We report earlier that isoniazid and foot-shock stress individually increase the maximal number of [35S]TBPS binding sites (Bmax) measured "ex vivo" in unwashed membranes from rat cerebral cortex and that the increase due to both treatments are prevented by pretreatment "in vivo" with diazepam which alone induced a significant decrease in the total number of [35S]TBPS binding sites. In the present paper, the effect of stress was studied on both the increase in [35S]TBPS binding and the convulsant activity induced by isoniazid in unstressed rats. Isoniazid induced a time dependent increase in [35S]TBPS binding. The isoniazid-induced increase in [35S]TBPS binding was markedly potentiated by foot-shock stress. Moreover, foot-shock stress markedly reduced the latency to the appearance of generalized seizures induced by isoniazid (300 mg/kg s.c.). The results provide evidence that the "in vivo" inhibition of GABAergic transmission elicited by isoniazid results in an increase of [35S]TBPS binding in the rats cerebral cortex. The finding that stress, like isoniazid, enhances [35S]TBPS binding suggests that this treatment also inhibits the function of GABAergic synapses.

Animals↗
PubMed1991

Failure of gamma-hydroxybutyrate to alter the function of the GABAA receptor complex in the rat cerebral cortex.

The present study was designed to evaluate the possible interaction of gamma-hydroxybutyrate (GHB) with the GABAA receptor complex in the rat cerebral cortex. To this purpose we studied the effect of in vitro addition and in vivo administration of GHB on the biochemical parameters currently used to evaluate the function of the GABAergic system. In vitro addition of increasing concentrations of GHB failed to modify [3H]flunitrazepam ([3H]FNZ) binding and the modulatory action of GABA on this binding. Moreover, unlike diazepam, GHB did not modify in vitro both muscimol-stimulated 36Cl- uptake and t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to rat cerebral cortex. In vivo administration of sedative and hypnotic doses of GHB (300-750 mg/kg IP) failed to induce in 60 min any significant change in the [35S]TBPS binding to unwashed cortical membranes. Moreover, GHB also failed to antagonize the increase in [35S]TBPS binding (+55%) induced by isoniazid (350 mg/kg SC). In contrast, at the highest doses used, this drug completely antagonized the seizure activity induced by isoniazid. In conclusion, our data show that GHB fails to alter the function of the GABAA/benzodiazepine/ionophore receptor complex in the rat cerebral cortex.

Animals↗
PubMed1991

Biochemical and electrophysiologic evidence that propofol enhances GABAergic transmission in the rat brain.

The influence of propofol, a new intravenous anesthetic agent, on brain gamma-aminobutyric acid (GABA)-ergic transmission has been investigated both in vitro and in vivo. In vitro, propofol, like benzodiazepines, 1) markedly enhanced 3H-GABA binding in cortical membrane preparations; 2) potentiated muscimol-induced stimulation of 36Cl- uptake in membrane vesicle preparations (the propofol potentiating effect was antagonized by bicuculline); and 3) inhibited 35S-TBPS binding to unwashed membrane preparations from rat cerebral cortex. Finally, propofol failed to displace 3H-flunitrazepam from its binding site, indicating that its site of action in brain is different from that of benzodiazepines. In vivo, the effect of propofol was studied using single-unit recording of the electrical activity of both nondopaminergic neurons in the pars reticulata of the substantia nigra (PR neurons) and of dopaminergic neurons in the pars compacta of the substantia nigra (DA neurons). PR neurons are known to be inhibited by GABA-mimetic drugs and benzodiazepines, whereas DA neurons are tonically inhibited by PR neurons. The intravenous administration of propofol, in a fat emulsion formulation, produced a brief dose-dependent inhibition of the firing rate of PR neurons. The dose producing 50% inhibition of the firing rate was calculated to be 1.2 +/- 0.1 mg/kg. The inhibitory effect lasted less than 5 min. Repeated injections of propofol reproduced the same inhibitory response, whereas continuous infusion (0.5 mg.kg-1.min-1) produced a persistent inhibition of neuronal firing. The inhibitory effect of propofol on PR neurons was potentiated by diazepam and reversed by picrotoxin and bicuculline but was not influenced by the benzodiazepine antagonist Ro 15-1788. These findings suggest that propofol exerts a GABA-mimetic action on PR neurons by acting on a site distinct from the benzodiazepine recognition site. Unlike benzodiazepines, propofol inhibited the firing rate of DA neurons with a potency proportional to its inhibitory effect on PR neurons. The inhibition of DA neurons was reversed by bicuculline and picrotoxin. The results suggest that propofol enhances the inhibitory control over DA neurons by strionigral GABAergic neurons.

Animals↗
PubMed1991

Differential turnover rates of D1 dopamine receptors in the retina and in distinct areas of the rat brain.

The present study was designed to examine the steady-state density and the turnover rates of D1 dopamine (DA) receptors in the striatum, nucleus accumbens, substantia nigra, and retina of the rat. The turnover rates were measured by monitoring the repopulation kinetics of D1 DA receptors labelled with [3H]SCH 23390 after the irreversible inactivation induced by a single dose of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (10 mg/kg s.c.). The repopulation of D1 DA receptors could be described adequately in all the neural tissues investigated by a theoretical model that assumes a constant rate of receptor production (i.e., zero order) and a rate of degradation that is dependent on the receptor density at any time (i.e., first order). The quantitative analysis of the experimental data using this theoretical model revealed significant regional differences in the rates of receptor production and degradation. Thus, the receptor production rates determined in the nucleus accumbens and striatum (8.03 and 9.96 fmol/mg of protein/h, respectively) were four- to sixfold larger than those measured in the substantia nigra (1.80 fmol/mg of protein/h) and retina (1.50 fmol/mg of protein/h). On the other hand, the receptor degradation rates in the striatum, nucleus accumbens, and retina (0.0093 h-1, 0.0110 h-1, and 0.0123 h-1, respectively) were 2.6-3.5-fold larger than the receptor degradation rate in the substantia nigra (0.0035 h-1).

Adrenergic alpha-Antagonists↗
PubMed1991

Ex vivo binding of t-[35S )butylbicyclophosphorothionate: a biochemical tool to study the pharmacology of ethanol at the gamma-aminobutyric acid-coupled chloride channel.

The effects of acute administration of ethanol on t-[35S]Butylbiclophosphorothionate (35S-TBPS) binding measured ex vivo in unwashed membrane preparations of rat cerebral cortex were investigated. Ethanol, given i.g., decreased in a dose-related (0.5-4 g/kg) and time-dependent manner the binding of 35S-TBPS. This effect was similar to that induced by the administration of diazepam (0.5-4 mg/kg i.p.). Scatchard plot analysis of this radioligand binding revealed that ethanol, differently from diazepam, decreased the apparent affinity of 35S-TBPS recognition sites whereas it failed to change the density of these binding sites. The effect of ethanol on 35S-TBPS binding could not be reversed by the previous administration to rats of the benzodiazepine receptor antagonist, Ro 15-1788 (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H- imidazo[1,5a][1,4]benzodiazepine-3-carboxylate). Vice versa, the benzodiazepine receptor partial inverse agonist, Ro 15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H- imidazo[1,5a][4,4]benzodiazepine-3-carboxylate) (8 mg/kg i.p.), prevented completely ethanol-induced decrease of 35S-TBPS binding. The ability of Ro 15-4513 to prevent the action of ethanol was shared by the anxiogenic and proconvulsant beta-carboline derivatives, FG 7142 (N-methyl-beta-carboline-3-carboxamide) (12.5 mg/kg i.p.) and ethyl-beta-carboline-3-carboxylate (0.6 mg/kg i.v.), which, per se, enhanced this parameter. Moreover, ethanol (0.5-4 g/kg) was able to reverse the increase of 35S-TBPS binding elicited by the s.c. injection of isoniazid (350 mg/kg) and to clearly attenuate the severity of tonic-clonic seizures produced by this inhibitor of the GABAergic transmission.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Selective unilateral inactivation of striatal D1 and D2 dopamine receptor subtypes by EEDQ: turning behavior elicited by D2 dopamine receptor agonists.

The unilateral intrastriatal injection of the irreversible dopamine (DA) receptor blocker N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) induces a marked decrease in the density of D1 (-48%) and D2 (-51%) DA receptors available for binding to [3H]SCH 23390 and [3H]raclopride, respectively. A challenge dose of the D2 agonist LY 171555 (1 mg/kg, i.p., 24 h after EEDQ) causes intensive ipsiversive circling behavior, whereas the selective D1 agonist SKF 38393 (20 mg/kg, i.p., 24 h after EEDQ) is unable to induce rotations. The density of D1 and D2 DA receptors returns to basal levels by 7 days after the intrastriatal infusion of EEDQ. This biochemical recovery is associated with a progressive decrease in the number of rotations elicited by a challenge dose of LY 171555, suggesting that EEDQ does not cause any relevant neuronal damage. A selective inactivation of striatal D1 or D2 DA receptors can be obtained by injecting EEDQ 30 min after the administration of the D2 antagonist raclopride (20 mg/kg, i.p.) or of the D1 antagonist SCH 23390 (2 mg/kg, s.c.), respectively. The intensity of the circling behavior induced by LY 171555 24 h after EEDQ in animals with a selective inactivation of D2 DA receptors is similar to that found in rats in which both D1 and D2 DA receptors have been inactivated. In contrast, LY 171555 does not cause rotations when the density of D1 DA receptors is selectively decreased by EEDQ in rats pretreated with raclopride.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗