Pharmacology of gamma-aminobutyric acidA receptor complex after the in vivo administration of the anxioselective and anticonvulsant beta-carboline derivative abecarnil
Serra, M.; Foddi, M.C.; Ghiani, C.A.; Melis, M.A.; Motzo, C.; Concas, A.; Sanna, E.; Biggio, G.
Journal of Pharmacology and Experimental Therapeutics 263(3): 1360-1368
1992
ISSN/ISBN: 0022-3565 PMID: 1361574 Document Number: 401890
In rodents, the effect of the beta-carboline derivative isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate (abecarnil), 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 isoniazid (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.). These results demonstrate that abecarnil enhances GABAergic transmission with an efficacy similar to or even greater than diazepam, a full agonist of the benzodiazepine receptor. In contrast, the partial agonist Ro 16-6028 has much lower efficacy both in vivo and in vitro experiments.