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A Concas

Publications and source records attributed to A Concas.

At least 37 records · Page 2Linked to original sources
PubMed1996

Time-dependent changes in rat brain neuroactive steroid concentrations and GABAA receptor function after acute stress.

The time courses of changes in rat brain neuroactive steroid concentrations and gamma-aminobutyric acid type A (GABAA) receptor function elicited by acute stress were investigated in animals exposed to CO2 for 1 min, a treatment known to induce stress in rats and panic attacks in humans. Inhalation of CO2 induced increases in cerebral cortical steroid concentrations, the time dependence of which varied with the steroid examined. Thus, progesterone and deoxycorticosterone showed maximal increases (10- and 4-fold, respectively) 10 min after CO2 inhalation and had returned to basal values by 30 and 60 min, respectively. In contrast, pregnenolone and 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) concentrations showed maximal increases (+174 and + 200%, respectively) at 30 min, were still higher than control at 60 min and returned to control values 120 min after stress. Inhalation of CO2 also resulted in increases in plasma steroid concentrations, most of which peaked at 30 min and had returned to control values by 60 min. A parallel analysis of the stress-induced changes in GABAA receptor function, assessed either biochemically by t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to cerebral cortical membranes or behaviorally by the punished responding score in Vogel's test, showed that the effects of CO2 inhalation on both parameters were maximal (+51 and -40%, respectively) after 10 min; the behavioral reaction returned to normal after 60 min, whereas [35S]TBPS binding had returned to control values 120 min after stress. The results show that: (a) the maximal increase in the brain concentrations of allopregnanolone, a potent and efficacious positive modulator of GABAA receptors, occurred at a time (30 min) when both conflict behavior and [35S]TBPS binding begun to decrease, and (b) both allopregnanolone concentrations and [35S]TBPS binding had returned to control values 120 min after CO2 inhalation. The data are thus consistent with a physiological role of neuroactive steroids in restoring GABAergic tone after stress.

Animals↗
PubMed1995

Biochemical and functional identification of GABA receptors in Hydra vulgaris.

GABA binding sites labelled in vitro with [3H]GABA are present in crude membrane preparations from Hydra vulgaris. [3H]GABA binding is specific (70%), saturable and it is completely displaced by the GABA mimetic muscimol but not by bicuculline or baclofen. Scatchard analysis of saturation data indicates the presence of only one population of binding sites with a Bmax of 4, 75 pmol/mg of protein and a KD of 76 nM. In the living animal GABA and benzodiazepines increase the duration of mouth opening during the glutathione-induced feeding response. Bicuculline prevents the GABA-induced increase of the feeding response. Diazepam activity is enhanced by simultaneous GABA administration and it is suppressed by the specific antagonist flumazenil. In contrast, no [3H]-flunitrazepam binding is detected in membrane preparations. We conclude that a population of GABA receptors is present in Hydra tissues, where they are involved in the modulation of response to chemical stimulation.

Animals↗
PubMed1994

Neurosteroids in the brain of handling-habituated and naive rats: effect of CO2 inhalation.

In rats habituated to the manipulation that precedes killing (handling-habituated) the cerebral cortical concentrations of pregnenolone and progesterone were significantly lower (-57% and -69%, respectively) than in naive animals. An acute stress, induced by CO2 inhalation, elicited a marked increase in the concentrations of pregnenolone, progesterone and deoxycorticosterone in the brain cortex and hippocampus of handling-habituated rats. An accepted stress, such as foot shock, also enhanced the brain cortical levels of pregnenolone, progesterone and deoxycorticosterone in handling-habituated rats. These data show that the rat brain cortical and hippocampal steroid content is related to the 'emotional state' of the animal.

Administration, Inhalation↗
PubMed1994

Effects of propofol, pentobarbital and alphaxalone on t-[35S]butylbicyclophosphorothionate binding in rat cerebral cortex.

The effects of propofol, pentobarbital, alphaxalone, etomidate and diazepam on t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to membrane preparations from rat cerebral cortex were studied in the absence of gamma-aminobutyric acid (GABA). Addition of low concentrations (3-10 microM) of propofol to washed membrane preparations (devoid of GABA) markedly enhanced [35S]TBPS binding (maximal enhancement, 85%), whereas higher concentrations (50-100 microM) inhibited this parameter. Diazepam also enhanced [35S]TBPS binding in this preparation (maximal enhancement, 38%). In contrast, pentobarbital, alphaxalone and etomidate decreased [35S]TBPS binding in a concentration-dependent manner. The propofol-induced increase in [35S]TBPS binding in washed membranes was completely reversed by the addition of GABA at a concentration (0.3 microM) that alone did not modify [35S]TBPS binding (78% increase with 10 microM propofol alone, 33% decrease in the additional presence of GABA). The ability of GABA to reverse the effect of propofol on [35S]TBPS binding in washed membranes was shared by pentobarbital (200 microM) and alphaxalone (3 microM); etomidate (20 microM) only partially antagonized the effect of propofol. Diazepam at a concentration (30 microM) that alone had no effect on [35S]TBPS binding failed to modify the propofol-induced increase in [35S]TBPS binding, whereas at a concentration (3 microM) that alone increased [35S]TBPS binding the effect of diazepam was additive with that of propofol. The addition of bicuculline to washed membranes failed to abolish the increase in [35S]TBPS binding induced by propofol or diazepam, but completely antagonized the effects of pentobarbital, alphaxalone and etomidate.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics↗
PubMed1994

The effect of cyclopyrrolones on GABAA receptor function is different from that of benzodiazepines.

The effects of the cyclopyrrolones zopiclone and suriclone on the function of the central gamma-amino-butyric acid type A (GABAA) receptor complex in mouse brain were evaluated both in vitro and in vivo. Added in vitro to mouse cerebral cortical membranes, these compounds potently inhibited [3H]flumazenil binding with IC50 (50% inhibitory concentration) values of 35.8 nM (zopiclone) and 1.1 nM (suriclone). Similar results were obtained with cerebellar membranes, indicating that these drugs do not discriminate between putative type I and type II benzodiazepine receptors. The interaction of cyclopyrrolones with recognition sites present at the level of the GABA receptor complex appears to be competitive, because zopiclone decreased the affinity of the receptors for [3H]flumazenil without affecting the maximal number of binding sites. Moreover, zopiclone and suriclone did not affect the rate of dissociation of [3H]flumazenil from benzodiazepine receptors. The in vitro efficacy of zopiclone appeared different from that of suriclone and the benzodiazepines diazepam and flunitrazepam. Thus, zopiclone failed to affect muscimol-stimulated 36Cl- uptake and only slightly inhibited t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding. In contrast, like diazepam and flunitrazepam, suriclone increased muscimol-stimulated 36Cl- uptake and markedly inhibited [35S]TBPS binding. In contrast, like diazepam and flunitrazepam, suriclone increased muscimol-stimulated 36Cl- uptake and markedly inhibited [35S]TBPS binding. On the other hand, suriclone, like zopiclone, did not modify [3H]muscimol binding to mouse cerebral cortical membranes. Moreover, zopiclone antagonized the reduction in [35S]TBPS binding elicited by the benzodiazepine receptor full of agonist diazepam. Consistent with its low efficacy in vitro, oral administration of zopiclone (2.5 to 100 mg/kg, p.o.) in mice failed to modify [35S]TBPS binding subsequently measured in cerebral cortical membranes "ex vitro".(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

2-Chloro-N6-cyclopentyladenosine (CCPA), an adenosine A1 receptor agonist, suppresses ethanol withdrawal syndrome in rats.

The ability of 2-chloro-N6-cyclopentyladenosine (CCPA) to suppress ethanol withdrawal syndrome was tested in male rats rendered physically dependent on ethanol by intragastric administrations of ethanol (12-18 g/kg daily for 6 days). CCPA administered 24 hr after the last ethanol dose produced a dose-dependent inhibition of withdrawal signs such as tremors and audiogenically induced seizures, an effect prevented by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX).

Adenosine↗
PubMed1993

Carbon dioxide inhalation, stress and anxiogenic drugs reduce the function of GABAA receptor complex in the rat brain.

1. The effect of different stressful stimuli on the function of the GABAA-ionophore receptor complex was evaluated by measuring the binding of 35S-TBPS to the chloride channel associated recognition sites. 2. Foot-shock stress enhanced 35S-TBPS binding in membrane preparation from rat cerebral cortex. The effect of foot-shock on 35S-TBPS binding was mimicked by the anxiogenic and proconvulsant beta-carboline FG 7142 and antagonized by anxiolytic benzodiazepines and by the novel anxiolytic and anticonvulsant beta-carboline, abecarnil. 3. A brief exposure of rats to CO2 inhalation produced, like foot-shock and FG 7142, a marked increase of 35S-TBPS binding in the cerebral cortex, cerebellum and hippocampus. The effect of CO2 inhalation was maximal 10 min after treatment and return to control value in 2 hours. Previous administration of anxiolytic drugs (alprazolam and abecarnil) completely prevented the CO2 inhalation-induced increase of 35S-TBPS binding. 4. All together these data strongly suggest that carbon dioxide inhalation, like stress and anxiogenic drugs, decreases the function of the GABAA receptor complex.

Administration, Inhalation↗
PubMed1993

Chronic ethanol intoxication induces differential effects on GABAA and NMDA receptor function in the rat brain.

The effect of long-term treatment with ethanol was investigated on the function of gamma-aminobutyric acid A (GABAA) and N-methyl-d-aspartic acid (NMDA) receptors. Rats were rendered ethanol-dependent by repeated forced administration of a 20% ethanol solution (12 to 18 g/kg/day po) for 6 days and tested while still intoxicated or at different time intervals after withdrawal. t-[35S]Butylbicyclophosphorothionate (35S-TBPS) binding was increased by 30% in cortical homogenates of rats killed 1 to 3 hr after last ethanol administration, when compared with saline-treated animals. However, GABA-stimulated 36Cl- uptake and its enhancement by flunitrazepam was decreased in the ethanol-treated animals. 35S-TBPS binding and 36Cl- influx measured 9 to 24 hr following the last ethanol injection, when withdrawal signs were present, were unmodified with respect to saline-treated rats. Moreover, the effects of both isoniazid and FG 7142 on 35S-TBPS binding were unchanged in ethanol-dependent rats tested at 1 to 3 and 9 to 24 hr, compared with controls. In contrast, ethanol-withdrawn rats tested at 9 to 24 hr showed a dramatic enhancement in their sensitivity to the convulsant action of isoniazid (50 to 250 mg/kg, sc). The same animals were also more susceptible to the convulsant action of NMDA (0.5 to 5 micrograms/5 microliters/rat intracerebroventricularly) and kainic acid (12 mg/kg, ip), and this effect was paralleled by an enhancement (+25%) in the density of 3H-MK 801 recognition sites in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Withdrawal Delirium↗
PubMed1993

Anticonvulsant doses of 2-chloro-N6-cyclopentyladenosine, an adenosine A1 receptor agonist, reduce GABAergic transmission in different areas of the mouse brain.

The possible relationship between A1 adenosine receptors and the gamma-aminobutyric acid (GABAA) receptor complex was evaluated in the mouse brain. We studied the effect of in vitro addition and in vivo administration of 2-chloro-N6-cyclopentyladenosine (CCPA), the most selective ligand for A1 receptors, on the biochemical parameters used currently to evaluate GABAergic function. In vitro, CCPA (0.01-100 microM) failed to modify [3H] GABA binding, [3H]flunitrazepam binding, t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding and muscimol-stimulated 36Cl- uptake. On the contrary, in vivo, CCPA (1.4-27.6 mumol/kg i.p.) increased [35S]TBPS binding in membranes from the cerebral cortex, hippocampus, striatum and substantia nigra, but not from the cerebellum, thalamus, hypothalamus and olfactory tubercle. The specific A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxantine (9.8 mumol/kg i.p.) abolished the effect of CCPA on [35S]TBPS binding, indicating that the action of this compound is mediated by its interaction with A1 receptors. Diazepam (1.7 mumol/kg i.p.), a positive modulator of GABAergic transmission, antagonized the increase of [35S]TBPS binding induced by CCPA. CCPA (2.8-8.3 mumol/kg i.p.) antagonized convulsions induced by isoniazid, an inhibitor of GABA synthesis, but neither antagonized nor potentiated isoniazid-induced increase of [35S]TBPS binding. CCPA (2.8-8.3 mumol/kg i.p.) antagonized the convulsions induced by pentylenetetrazol (398 mumol/kg i.p.), methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (50 mumol/kg i.p.) and bicuculline methiodide (9.8 mumol/kg i.p.). The results show that, in spite of its anticonvulsant activity, CCPA reduces the function of the GABA-coupled chloride channel function. This finding suggests that the anticonvulsant target sites are different from those involved in the action of CCPA on GABAA receptors.

Adenosine↗
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

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

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↗