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O Giorgi

Publications and source records attributed to O Giorgi.

At least 19 recordsLinked to original sources
PubMed1992

Age-related changes in the turnover rates of D1-dopamine receptors in the retina and in distinct areas of the rat brain.

The steady-state density and the turnover rates of D1-dopamine receptors were investigated in the striatum, nucleus accumbens, substantia nigra, and retina of adult (3-month-old) and aged (23-month-old) rats. The turnover rates were measured by monitoring the repopulation kinetics of D1-dopamine receptors labeled with [3H]-SCH 23390 after the irreversible inactivation induced by a single dose of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 10 mg/kg, s.c.). In all the neural tissues examined, the repopulation of D1 dopamine receptors could be adequately described 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 results obtained indicate that the reduction in the density of D1-dopamine receptors in the striatum, nucleus accumbens and substantia nigra of aged rats is the result of a larger decrease in the receptor production rate (-44 to -60%) than in the receptor degradation rate (-21 to -46%). By contrast, the production rate of D1-dopamine receptors in the retina of aged rats remains unchanged, whilst the degradation rate is reduced by 25%. This results in an age-related increase in the density of D1-dopamine receptors in the rat retina.

Adrenergic alpha-Antagonists↗
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

Decrease in GABAergic function induced by pentylenetetrazol kindling in rats: antagonism by MK-801.

The role of tau-aminobutyric acid (GABA)A receptors and of the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors was studied in the pentylenetetrazol (PTZ) kindling model. The repeated administration of subconvulsant doses of PTZ (30 mg/kg i.p., 3 times a week for up to 10 weeks) produced chemical kindling in 80% of rats under treatment. PTZ kindling was associated with a decrease in GABA-mediated inhibition in the central nervous system. Thus, the binding of [3H]GABA, the binding of 35S-t-butylbicyclophosphorothionate and the GABA-stimulated uptake of 36Cl- were significantly decreased in the cerebral cortex of PTZ-kindled rats as compared with control rats chronically treated with saline. Moreover, PTZ-kindled rats showed a persistent increase in the sensitivity to the convulsant action of different GABA function inhibitors, such as isonicotinic acid hydrazide (120 mg/kg s.c.), picrotoxin (1.5 mg/kg i.p.), bicuculline (1.3 mg/kg s.c.), FG 7142 (N-methyl-beta-carboline-3-carboxamide; 20 mg/kg i.p.) and Ro 15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H- imidazo-(1,5-a) (1,4)-benzodiaze pine-3-carboxylate; 20 mg/kg i.p.). The pretreatment with the noncompetitive NMDA receptor antagonist, MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate; 0.1-1.0 mg/kg i.p., 40 min before each injection of PTZ], prevented in a concentration-dependent manner the development of kindling and the increase in the responsiveness to the convulsant effects of GABA function inhibitors observed in PTZ-kindled rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Age-related decrease in the density of benzodiazepine recognition sites in the brain of the fresh water eel (Anguilla anguilla).

The binding parameters of benzodiazepine receptors labeled with [3H]flunitrazepam were investigated in the brain of male adult eels at the trophic phase (4 years old) and of male silver eels (6 year old ocean migrants). The density of [3H]flunitrazepam binding sites was significantly decreased (-26%) in the brain of silver eels compared with younger counterparts. In contrast, the apparent dissociation constant (Kd) was not significantly different in the two experimental groups. These results are discussed in terms of the possible involvement of stress, behavioral and environmental factors and age-related degenerative processes.

Aging↗
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

MK-801 prevents chemical kindling induced by pentylenetetrazol in rats.

The repeated administration of pentylenetetrazol (PTZ) at a subconvulsant dose (30 mg/kg i.p., three times a week for nine weeks) produced kindling in 90% of rats under treatment. Pretreatment with the N-methyl-D-aspartate receptor antagonist, MK-801 (1 mg/kg i.p., 40 min before PTZ), prevented the behavioral manifestation (i.e. motor seizures) as well as the development of kindling. In fact, convulsions were not observed in rats pretreated with MK-801 either during the chronic PTZ administration or when challenged with PTZ three and 10 days after completion of the chronic treatment. The results suggest an involvement of excitatory amino acid neurotransmission in PTZ kindling.

Amino Acids↗
PubMed1991

Pentylenetetrazol-induced kindling in rats: effect of GABA function inhibitors.

The repeated administration of subconvulsant doses of pentylenetetrazol (PTZ) produced a progressive sensitization to the effects of this compound (i.e., chemical kindling) in the rat. A very similar time-course for PTZ-induced kindling was observed using two different treatment schedules: 1) one injection every day (30 mg/kg, IP), and 2) one injection (30 mg/kg, IP) every second day. When these treatment schedules were used for eight consecutive weeks, more than 80% of the rats displayed convulsions by the end of treatment. In contrast, only 20% of the rats were sensitized if PTZ was administered twice daily at the dose of 15 mg/kg, IP. The increased sensitivity to the convulsant effect of PTZ was still present one year after completion of the chronic treatment. Moreover, rats kindled with PTZ showed an enhanced susceptibility to convulsions induced by different inhibitors of central GABAergic function, such as the chloride channel blocker picrotoxin, the benzodiazepine receptor ligands FG 7142 and Ro 15-4513, and the inhibitor of GABA synthesis isoniazid. In contrast, the sensitivity to the convulsant action of the glycine receptor antagonist strychnine was unchanged by repeated PTZ administration. It is suggested that kindling produced by PTZ may be associated with a persistent reduction in the inhibitory function of the GABAergic system in the brain.

Animals↗
PubMed1991

MK-801 prevents the decrease in 35S-TBPS binding in the rat cerebral cortex induced by pentylenetetrazol kindling.

Chemical kindling was induced in the rat by chronic treatment with pentylenetetrazol (PTZ, 30 mg/kg, IP, three times a week for eight weeks). PTZ kindling was associated with a reduction in central GABAergic function, as reflected by a significant decrease in the density of 35S-t-butylbicyclophosphorothionate (35S-TBPS) binding sites in the cerebral cortex. The pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (1 mg/kg, IP, 40 min before each PTZ injection) prevented the development of kindling as well as the reduction in 35S-TBPS binding. The results suggest that NMDA receptors may play a role in the alterations of GABAergic function observed in PTZ-kindled rats.

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↗
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↗
PubMed1990

Differential effect of aging on 3H-SCH 23390 binding sites in the retina and in distinct areas of the rat brain.

The effects of age on the binding parameters of the selective D-1 dopamine (DA) receptor antagonist 3H-SCH 23390 were studied in membrane preparations from rat striatum, substantia nigra, olfactory tubercle, prefrontal cortex and retina. When compared with 3-month-old animals, there was a significant decrease in the density of 3H-SCH 23390 binding sites in the striatum (-25%), substantia nigra (-24%), and olfactory tubercle (-23%), but not in the prefrontal cortex of senescent (23-month-old) rats. The affinity of 3H-SCH 23390 for D-1 DA receptors did not change with age in any of the brain areas analyzed. In contrast, the density of 3H-SCH 23390 binding sites was higher (+53%) in the retina of aged rats that in 3-month-old controls. Confirming previous studies, we observed that light deprivation induced a significant increment in the density of 3H-SCH 23390 binding sites in the retina of adult rats (+31%) but not in the retina of aged animals. The ability of light exposure to activate DAergic neurons in the rat retina was not altered by normal aging. In fact, a similar increase in the concentration of DOPAC was observed in the retina of light-adapted adult and senescent rats when compared to their respective dark-adapted controls (+94% and +95%, respectively). The results indicate that aging has a differential effect on D-1 DA receptors in the retina and different areas of the rat brain. Finally, the age-related increment in the density of retinal D-1 DA receptors does not appear to depend on presynaptic mechanisms, since DA metabolism is increased by light to the same extent in young and aged rats.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Unilateral inactivation of dopamine receptors after intrastriatal injection of N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ): a novel rotational model to investigate dopamine receptor interactions.

The interaction between D1 and D2 dopamine (DA) receptors was investigated in a novel rotational model. Rats were unilaterally injected into the striatum with the irreversible DA receptor blocker N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). This treatment induced a marked decrease in the density of D1 (-48%) and D2 (-45%) DA receptors available for binding to 3H-SCH 23390 and 3H-spiperone, respectively. Under these experimental conditions, the effect of DA receptor agonists were predominant on the intact side and resulted in rotations ipsilateral to the injected side. The effects of different agonists and antagonists for D1 and D2 DA receptors were evaluated 24 hr after EEDQ administration. The D2 agonist LY 171555 induced ipsilateral rotations in a dose-dependent manner (0.1-10.0 mg/kg, IP) in rats treated intrastriatally with EEDQ. In contrast, the D1 agonist SKF 38393 (1-20 mg/kg, IP) was unable to elicit circling behavior per se. However, SKF 38393 increased the number of rotations caused by LY 171555. The circling behavior induced by LY 171555 was blocked by the D2 antagonists (-)sulpiride and raclopride and by the D1 antagonist SCH 23390. Moreover, the inhibition of circling behavior induced by SCH 23390 was reversed by SKF 38393 in a dose-dependent manner. LY 171555 (1 mg/kg, IP) was unable to induce rotations in EEDQ-treated rats following DA depletion by alpha-methyl-p-tyrosine, whilst the combined administration of LY 171555 (1 mg/kg, IP) and SKF 38393 (10 mg/kg, IP) elicited intense circling behavior in DA depleted rats.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

GABAergic and dopaminergic transmission in the rat cerebral cortex: effect of stress, anxiolytic and anxiogenic drugs.

Benzodiazepines produce their pharmacological effects by regulating the interaction of GABA with its recognition site on the GABAA receptor complex. In fact, the anxiolytic effect of benzodiazepines may be considered the consequence of the activation of the GABAA receptors induced by these drugs. On the contrary, beta-carboline derivatives which bind with high affinity to benzodiazepine recognition sites modulate the GABAergic transmission in a manner opposite to that of benzodiazepines. Thus, these compounds reduce the function of the GABA-coupled chloride channel and produce pharmacological effects (anxiogenic, proconvulsant and convulsant) opposite to those of benzodiazepines. Taken together, these data strongly indicate that the GABAA receptor complex plays a major role in the pharmacology, neurochemistry and physiopathology of stress and anxiety. This conclusion is further supported by the finding that the function of the GABAA/benzodiazepine receptor complex may be modified by the emotional state of the animals before sacrifice. Accordingly, using an unstressed animal model, the 'handling-habituated' rats, it has been demonstrated that stress, like anxiogenic drugs, decreases the function of GABAA receptor complex, an effect mimicked by the in vivo administration of different inhibitors of GABAergic transmission and antagonized by anxiolytic benzodiazepines. Moreover, a long-lasting down regulation of GABAergic synapses can be obtained after repeated administration of anxiogenic, proconvulsant and convulsant negative modulators of GABAergic transmission. The latter finding further suggests that GABAergic synapses undergo rapid and persistent plastic changes when the GABAergic transmission is persistently inhibited. Finally, the evidence that the activity of mesocortical dopaminergic pathways is altered in opposite manner by drugs that either inhibit or enhance the GABAergic transmission indicates that GABA has a functional role in regulation of dopaminergic neurons in the rat cerebral cortex. Altogether these results suggest that cortical GABAergic and dopaminergic transmission play a major role in the pharmacology, neurochemistry and pathology of the emotional states and fear.

Animals↗
PubMed1990

Decrease in the function of the gamma-aminobutyric acid-coupled chloride channel produced by the repeated administration of pentylenetetrazol to rats.

The acute administration of pentylenetetrazol (PTZ; 25-75 mg/kg i.p.) failed to modify the specific binding of t-[35S]butylbicyclophosphorothionate ([35S]TBPS) to membrane preparations from the cerebral cortex of the rat. In contrast, the repeated administration of PTZ (30 mg/kg i.p., three times a week for 12 weeks) reduced by 26% the density of [35S]TBPS binding sites without modifying the dissociation constant. This effect was observed 3 days after the last PTZ administration. A parallel reduction of gamma-aminobutyric acid (GABA)-stimulated 36Cl- uptake was measured in the cerebral cortex of PTZ-treated rats 3 days after the last injection. The repeated administration of PTZ produced sensitization to the drug, or chemical kindling. In fact, no convulsions were observed in the first week of treatment, but all the animals became sensitized to PTZ by the 12th week. The results are consistent with the hypothesis that chronic treatment with PTZ at a subconvulsant dose causes a decrease in GABA-coupled chloride channel activity that may be related to the chemical kindling produced by this compound.

Animals↗
PubMed1989

Functional coupling of GABAA receptors and benzodiazepine recognition site subtypes in the spinal cord of the rat.

The interaction between GABAA receptors and benzodiazepine (BZD) recognition site subtypes in the spinal cord of the rat was investigated. Computer analysis of displacement curves for [3H]flunitrazepam [( 3H]FNT) binding by 2-oxo-quazepam (2OXOQ) indicated the presence of two subtypes of BZD recognition sites in this region. Type I sites accounted for approximately 25% of the total number of BZD recognition sites, the remainder being Type II sites. A similar proportion of Type I and Type II sites was obtained by Scatchard analysis of the saturation curves for [3H]FNT, [3H]2OXOQ and [3H]ethyl-beta-carboline-3-carboxylate [( 3H]beta CCE) binding. The in vitro addition of GABA (10(-8)-10(-4) M) to spinal cord membrane preparations produced an increase in the binding of [3H]FNT and [3H]2OXOQ. The maximal enhancement produced by GABA was 50 and 82% above control values for [3H]FNT and [3H]2OXOQ, respectively. In contrast, GABA stimulated both [3H]FNT and [3H]2OXOQ binding in the cerebellum to a similar extent. We also evaluated the effects of different ligands for BZD recognition sites on the binding of [3H]GABA to spinal cord membranes, as compared with brain areas containing a higher proportion ( greater than 30%) of Type I sites. Diazepam, quazepam and the beta-carboline, ZK 93423, enhanced the specific binding of [3H]GABA in a concentration-dependent manner (10(-7)-10(-5) M) in the cerebral cortex and hippocampus but not in the spinal cord and cerebellum. These results indicate that there is a regional variation in the interaction between GABA and BZD recognition sites in the central nervous system.

Animals↗
PubMed1989

Ro 15-4513, a partial inverse agonist for benzodiazepine recognition sites, has proconflict and proconvulsant effects in the rat.

The present report describes the effects of Ro 15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-(1,5-a) (1,4)-benzodiazepine-3-carboxylate) in the conflict test, on convulsions induced by isoniazid and DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) and on the binding of [3H]gamma-aminobutyric acid ([3H]GABA) to rat brain membrane preparations. Ro 15-4513 produced a dose-dependent proconflict effect that was prevented by the administration of the benzodiazepine antagonist, Ro 15-1788. In addition, Ro 15-4513 was not convulsant per se but enhanced the convulsions produced by isoniazid and completely blocked the convulsions induced by the full inverse agonist, DMCM. In vitro, Ro 15-4513, like ethyl-beta-carboline-3-carboxylate (beta CCE), antagonized the increase in [3H]GABA binding induced by diazepam. The results indicate that Ro 15-4513 is anxiogenic and interacts with benzodiazepine recognition sites as a partial inverse agonist.

Animals↗