THE BETA-CARBOLINE DERIVATIVE DMCM DECREASES GAMMA-AMINOBUTYRIC-ACID RESPONSES AND CA2+-MEDIATED K+-CONDUCTANCE IN RAT NEOCORTICAL NEURONS IN-VITRO

Electrophysiological recordings from neurons of rat frontal neocortical slices have been used to investigate the action of the beta-carboline methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), on responses to beta-aminobutyric acid (GABA) and on the excitability of the neurons. Iontrophoretic application of GABA close to the intracellularly recorded cells (resting membrane potential - 74 +/- 0.9 mV) elicited a depolarization associated with a decrease of input resistance, mediated by GABA(A) receptors. Bath application of DMCM (0.1-1 mu M) reduced these GABA responses decreasing the affinity of the receptors for GABA. This effect was blocked by the benzodiazepine receptor (BZR) antagonist ZK 93426 (1 mu M). DMCM (0.1 mu M) also decreased the hyperpolarization that followed a train of action potentials (AHP), mediated by Ca2+-dependent K+ conductance, and increased the duration of Ca2+-dependent action potentials recorded after blockade of Na+ and K+ conductances. Neither effect was blocked by BZR antagonists. These results indicate that DMCM increases the excitability of neurons not only by reducing the gain of the GABA(A)/BZR complex, but also by modulating intrinsic membrane mechanisms.