Antipsychotic clozapine inhibits the function of α7-nicotinic acetylcholine receptors

The effects of the antipsychotic clozapine on the function of the cloned α7 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 μM)-induced currents in a concentration-dependent manner (300 nM to 90 μM), with an IC50 value of 3.2 ± 0.4 μM. The effect of clozapine was not dependent on the membrane potential. Clozapine did not affect the activity of endogenous Ca2+-dependent Cl− channels since the inhibition by clozapine was unaltered by the intracellularly injected Ca2+ chelator BAPTA and perfusion with Ca2+-free bathing solution containing 2 mM Ba2+. Clozapine decreased the maximal nicotine-induced responses without significantly affecting its potency, indicating that it acts as a noncompetitive antagonist on α7-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 α7-nACh receptors, were abolished after 10 min application of 5 μM clozapine. In conclusion, these results demonstrate that clozapine inhibits the function of α7-nACh receptors expressed in Xenopus oocytes and in hippocampal neurons.