The beta-carboline derivative DMCM decreases gamma-aminobutyric acid responses and Ca(2+)-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 gamma-aminobutyric acid (GABA) and on the excitability of the neurons. Iontophoretic 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 GABAA receptors. Bath application of DMCM (0.1-1 microM) 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 microM). DMCM (0.1 microM) also decreased the hyperpolarization that followed a train of action potentials (AHP), mediated by Ca(2+)-dependent K+ conductance, and increased the duration of Ca(2+)-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 GABAA/BZR complex, but also by modulating intrinsic membrane mechanisms.
Department of Physiology and Biochemistry G. Moruzzi, University of Pisa, Italy.
M
M
Capogna
N
N
Berretta
F
F
Berton
R
R
Bianchi
M
M
Brunelli
W
W
Francesconi
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002243:Carbolines / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D003292:Convulsants / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D007478:Iontophoresis; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D002243:Carbolines; D003292:Convulsants; D058787:GABA-A Receptor Antagonists; D015221:Potassium Channels; D011963:Receptors, GABA-A; D013757:Tetraethylammonium Compounds; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; C042568:ZK 93426; D002118:Calcium