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

Article date: 1992/12/1

PubMed ID: 1361574

Journal name: The Journal of pharmacology and experimental therapeutics (ISSN: 0022-3565)


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)

Author List: Serra M, Foddi M C, Ghiani C A, Melis M A, Motzo C, Concas A, Sanna E, Biggio G

Publication Types: Journal Article; Research Support, Non-U.S. Gov't

Substances mentioned in the article: Anti-Anxiety Agents; Anticonvulsants; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Carbolines; Chlorides; Receptors, GABA-A; gamma-Aminobutyric Acid; tert-butylbicyclophosphorothionate; abecarnil; Isoniazid;

Mesh terms: Animals; Anti-Anxiety Agents/pharmacology; Anticonvulsants/pharmacology; Bridged Bicyclo Compounds/metabolism; Bridged Bicyclo Compounds, Heterocyclic; Carbolines/pharmacology; Chlorides/metabolism; Exploratory Behavior/drug effects; In Vitro Techniques; Isoniazid/pharmacology; Male; Rats; Rats, Sprague-Dawley; Receptors, GABA-A/drug effects; Stress, Physiological/metabolism; gamma-Aminobutyric Acid/metabolism;

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