Antipsychotic clozapine inhibits the function of alpha7-nicotinic acetylcholine receptors.
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.
Singhal
Sachin K
SK
Laboratory of Molecular & Cellular Neurobiology, National Institute on Alcohol Abuse & Alcoholism, NIH/DHHS, 12501 Washington Avenue, Bethesda, MD 20892-8205, USA.
Zhang
Li
L
Morales
Marisela
M
Oz
Murat
M
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
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