title: Antipsychotic clozapine inhibits the function of alpha7-nicotinic acetylcholine receptors.
abstract: The effects of the antipsychotic clozapine on the function of the cloned alpha(7) subunit of the nicotinic acetylcholine (nACh) receptor expressed in Xenopus oocytes was investigated by using the two-electrode voltage-clamp technique. Clozapine reversibly inhibited nicotine (10 microM)-induced currents in a concentration-dependent manner (300 nM to 90 microM), with an IC(50) value of 3.2+/-0.4 microM. The effect of clozapine was not dependent on the membrane potential. Clozapine did not affect the activity of endogenous Ca(2+)-dependent Cl(-) channels since the inhibition by clozapine was unaltered by the intracellularly injected Ca(2+) chelator BAPTA and perfusion with Ca(2+)-free bathing solution containing 2mM Ba(2+). Clozapine decreased the maximal nicotine-induced responses without significantly affecting its potency, indicating that it acts as a noncompetitive antagonist on alpha(7)-nACh receptors. In hippocampal slices, the whole-cell recordings from CA1 pyramidal neurons indicated that the increases in the frequency and amplitudes of the GABA-mediated spontaneous inhibitory postsynaptic currents induced by bath application of 2 mM choline, a specific agonist for alpha(7)-nACh receptors, were abolished after 10 min application of 5 microM clozapine. In conclusion, these results demonstrate that clozapine inhibits the function of alpha(7)-nACh receptors expressed in Xenopus oocytes and in hippocampal neurons.
authors.affiliation: Laboratory of Molecular & Cellular Neurobiology, National Institute on Alcohol Abuse & Alcoholism, NIH/DHHS, 12501 Washington Avenue, Bethesda, MD 20892-8205, USA.
authors.forename: Sachin K
authors.initials: SK
authors.lastname: Singhal
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Marisela
authors.initials: M
authors.lastname: Morales
authors.forename: Murat
authors.initials: M
authors.lastname: Oz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002794:Choline / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D005260:Female; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D008845:Microinjections / Q000379:methods; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D017966:Pyramidal Cells / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011978:Receptors, Nicotinic / Q000502:physiology*; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D014150:Antipsychotic Agents; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D018697:Nootropic Agents; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D003024:Clozapine; D002794:Choline