title: 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.
abstract: 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.
mesh_terms: 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*
chemical_list: 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