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Pharmacological evidence for full agonist activity of abecarnil at certain GABAA receptors
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Felbamate antagonizes isoniazid-and FG 7142-induced reduction of GABA-A receptor function in mouse brain
No full textInjection of the antiepileptic drug, felbamate (2-phenyl-1,3-propanediol dicarbamate), into mice reduced in a dose-dependent manner (150-300 mg/kg i.p.) the isoniazid (200 mg/kg s.c.)-induced increase in ex vivo binding of t-[S-35]butylbicyclo-phosphorothionate ([S-35]TBPS) to cerebral cortical and hippocampal membranes. The same doses of felbamate reduced significantly the number of mice exhibiting isoniazid-induced seizures. A dose of felbamate (50 mg/kg) ineffective in isoniazid-treated mice completely antagonized the increase of [S-35]TBPS binding elicited by FG 7142 (N-methyl-beta-carboline-3-carboxamide), a benzodiazepine receptor inverse agonist. The above effects of felbamate resembled those of diazepam. Accordingly, the combination of ineffective doses of felbamate (50 mg/kg) and diazepam (0.2 mg/kg) elicited a marked decrease of [S-35]TBPS binding. The results indicate that facilitation of gamma-aminobutyric acid type A (GABA(A)) receptor function may play a role in the anticonvulsant action of felbamate
NMDA RECEPTOR FUNCTION IS ENHANCED IN THE HIPPOCAMPUS OF AGED RATS
No full textThe density and functional activity of the N-methyl-D-aspartate (NMDA)-sensitive glutamate receptor was examined in various brain areas of 3-, 18- and 24-month-old rats. The total numbers of binding sites for the NMDA receptor antagonists [H-3]CGP 39653 and [H-3]MK 801 binding sites were decreased in the hippocampus, cerebral cortex and striatum of 18- and 24-month-old rats, relative to 3-month-old animals. In the hippocampus of 18-month-old rats, the reduced number of NMDA receptors was associated with an increased sensitivity of [H-3]MK 801 binding to the stimulatory action of glycine and glutamate. Thus, 10 mu M glycine and 10 mu M glutamate increased [H-3]MK 801 binding in the hippocampus of Is-month-old rats by 75 and 160%, respectively; in 3-month-old animals, the same concentration of these amino acids increased binding by 37 and 95%, respectively. The sensitivity of [H-3]MK 801 binding to glycine and glutamate was not increased in the cerebral cortex and striatum of aged rats. Moreover, an increased efficacy of glycine and glutamate in stimulating the binding of [H-3]MK 801 in the hippocampus was no longer apparent in the 24-month-old rats. The increased sensitivity of [H-3]MK 801 binding to glycine and glutamate in the hippocampus of 18-month-old rats may reflect an increase in NMDA receptor activity to compensate for the decrease in receptor number
Antagonism by abecarnil of enhanced acetylcholine release in the rat brain during anticipation but not consumption of food
No full textBiochemical evaluations of the effects of loreclezole and propofol on the GABA(A) receptor in rat brain
No full textThe effects of loreclezole on the function of the gamma-aminobutyric acid type A. (GABA(A)) receptor complex in rat cerebral cortical membrane preparations were compared with those of propofol and diazepam. Loreclezole and propofol modulated [H-3]muscimol binding and t-[S-35]butylbicyclophosphorothionate ([S-35]TBPS) binding to washed and unwashed membranes with potencies and efficacies greater than those of diazepam. Loreclezole and propofol enhanced [H-3]flunitrazepam binding to washed membranes with efficacies lower than those of GABA and muscimol. Both loreclezole and propofol showed biphasic effects on [S-35]TBPS binding to washed membranes: at low concentrations (5 to 10 mu M), both drugs, with different efficacies, enhanced [S-35]TBPS binding whereas, at higher concentrations (30 to 100 mu M), they inhibited this biochemical parameter. In contrast, diazepam enhanced [S-35]TBPS binding to washed membranes at all concentrations tested. The combination of loreclezole with GABA, at a concentration (0.3 mu M) that only slightly increased [S-35]TBPS binding to washed membranes, reversed the increase in binding elicited by loreclezole (5 to 10 mu M) and significantly potentiated the inhibitory effect exerted by higher concentrations (30 to 100 mu M) of this drug. Similar effects were observed with the combination of GABA and propofol. However, GABA had no effect on the enhancement of [S-35]TBPS binding induced by diazepam. The ability of GABA to reverse and potentiate the effects of loreclezole and propofol on [S-35]TBPS binding to washed membranes was shared by pentobarbital (200 mu M) and alphaxalone (3 mu M). These anesthetics showed greater efficacies in combination with propofol than with loreclezole. These results suggest that, unlike diazepam, loreclezole and propofol may activate the receptor-associated Cl- channel in the absence of GABA. Furthermore, the difference in the pharmacological profiles of loreclezole and propofol may result from their different effectiveness in activating the receptor Cl- channel directly
Antagonism of convulsions but failure to enhance GABA(A) receptor function by felbamate in mice tolerant to diazepam
No full textThe transfer of tolerance between drugs may indicate a common mode of action. The development of cross-tolerance to the anticonvulsant effect of felbamate after long-term treatment of mice with diazepam, a positive modulator of gamma-aminobutyric acid (GABA)-mediated transmission, was therefore studied in order to clarify the mechanism of this action of felbamate. A challenge injection of felbamate, administered 36 h after the last dose of chronic diazepam treatment, antagonized convulsions elicited by administration of isoniazid. In contrast, felbamate had no effect on the isoniazid-induced increase in t-[S-35]butylbicyclophosphorothionate binding to cerebral cortical membranes of diazepam-tolerant mice. These results suggest that the action of felbamate on GABAergic transmission is not required for the anticonvulsant effect of this drug. This conclusion is consistent with studies that have indicated that the antiepileptic activity of felbamate depends on its modulatory activity at excitatory amino acid receptors
Chronic administration of an anticonvulsant dose of imidazenil fails to induce tolerance of GABAA receptor function in mice.
No full textThe ability of an anticonvulsant dose (0.1 mg/kg i.p.) of imidazenil, a new partial agonist of benzodiazepine receptors, to antagonize the convulsions and the increase in t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to the gamma-aminobutyric acid type A (GABAA) receptor elicited by isoniazid, an inhibitor of central GABAergic function, was evaluated in mice chronically treated (3 times daily for 30 days) with the same dose of imidazenil. The challenge dose of imidazenil, administered 36 h after the last injection of the chronic treatment protocol, reduced both isoniazid-induced convulsions and the isoniazid-induced increase in [35S]TBPS binding to the same marked extent as in control mice. These results indicate that long-term treatment with a pharmacologically effective dose of imidazenil failed to induce tolerance to both the anticonvulsant effect and the positive modulatory action on GABAA receptor function of this drug in mouse brain
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