Modulation of the responses to the GABA-mimetics, THIP and piperidine-4-sulphonic acid, by agents which interact with benzodiazepine receptors. An electrophysiological study on cultured mouse neurones.
Electrophysiological recordings from mouse neurones in tissue culture have been used to investigate how agents which interact with the benzodiazepine receptor modulate neuronal responses to gamma-aminobutyric acid (GABA) and its mimetics, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) and piperidine-4-sulphonic acid (P4S). Experiments were performed in a physiological medium, pH 7.35 at 34-36 degrees C. gamma-Aminobutyric acid, THIP and P4S were applied by iontophoresis to neuronal somata. Responses were assessed by current-clamp or voltage-clamp recordings. Midazolam (an agonist at the benzodiazepine receptor) and the beta-carboline, methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM; an inverse agonist at the BZ receptor), were applied by pressure ejection from blunt pipettes. The potency order of the agonists was GABA greater than P4S greater than THIP. Midazolam (10(-7)-10(-5) M) potentiated responses to all three agonists to a similar extent with a shift to the left of the dose-response curve. The drug DMCM (10(-6)-10(-5) M) decreased the responses to all three agonists to a similar extent. The DMCM-induced depression was of a non-competitive nature. It has previously been proposed that THIP is a partial agonist and P4S an antagonist at the GABA receptor coupled to the benzodiazepine receptor, or that the benzodiazepine-receptor-coupled and electrophysiological GABA receptors are distinct. In the present study, responses to the three agonists were modulated to a comparable extent following manipulation of the benzodiazepine receptor. It is therefore unnecessary to invoke the above explanations to account for these results.
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D002478:Cells, Cultured; D003292:Convulsants / Q000494:pharmacology; D004594:Electrophysiology; D005260:Female; D007478:Iontophoresis; D007555:Isoxazoles / Q000494:pharmacology*; D051379:Mice; D008874:Midazolam; D009474:Neurons / Q000187:drug effects; D010080:Oxazoles / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D002243:Carbolines; D003292:Convulsants; D007555:Isoxazoles; D010080:Oxazoles; D010880:Piperidines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D005680:gamma-Aminobutyric Acid; C023402:piperidine-4-sulfonic acid; C015542:gaboxadol; D008874:Midazolam