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

Abstract

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)