Beta-carboline interactions at the BZ-GABA receptor chloride-ionophore complex in the rat cerebral cortex.

beta-Carboline congeners can act at the benzodiazepine (BZ) recognition site of the BZ-GABA receptor complex to increase GABA-stimulated chloride conductance (agonist effect), inhibit this conductance (inverse agonist effect) or block the actions of agonists and inverse agonists (antagonist effect). In this communication we describe the effects of several beta-carbolines (ZK 93423, ZK 91296, ZK 93426, and DMCM) on GABA-stimulated chloride influx into vesicles prepared from rat cerebral cortex. ZK 93423 produces an approximate 2-fold left-shift of the GABA dose-response curve at a concentration of 1.0 microM consistent with its full agonist activity (positive intrinsic efficacy), while the same concentration of ZK 91296 produces over a 1-fold left-shift consistent with its partial agonist activity. At higher concentrations (0.1 mM), ZK 91296 inhibits GABA-stimulated chloride influx which appears to be mediated through a non-BZ receptor mechanism since this effect is not reversed by the BZ antagonist ZK 93426. The augmenting effect of both ZK 93423 and ZK 91296 on GABA-stimulated chloride flux was reduced by the antagonist ZK 93426 in a dose-dependent manner and reached GABA-stimulated control levels at a ZK 93426 concentration of 1.0 microM. Interestingly, there was a further inhibition of the GABA-stimulated chloride influx at higher concentrations of ZK 93426 which is not seen when ZK 93426 is used in the absence of BZ agonists. The inverse agonist activity of DMCM was incompletely blocked by the antagonist ZK 93426. These data show that ZK 93426 can antagonize the effects of the full agonist ZK 93423 and partial agonist ZK 91296 at the BZ receptor. Furthermore, the interaction of the agonists with ZK 93426 results in the appearance of inverse agonist-like activity.(ABSTRACT TRUNCATED AT 250 WORDS)