title: Effects of clozapine and N-desmethylclozapine on synaptic transmission at hippocampal inhibitory and excitatory synapses.
abstract: Clozapine is the first atypical antipsychotic, and improves positive and negative symptoms of many patients with schizophrenia resistant to treatment with other antipsychotic agents. Clozapine induces minimal extrapyramidal side effects, but is more often associated with seizures. A large number of studies have been conducted to elucidate pharmacological profiles of clozapine and its major active metabolite, N-desmethylclozapine (NDMC). However, there are only a limited number of electrophysiological studies examining their effects on synaptic transmission. In this study, we examined effects of clozapine and NDMC on synaptic transmission by measuring inhibitory and excitatory postsynaptic currents in rat cultured hippocampal neurons. We found that clozapine and NDMC have qualitatively similar actions. They depressed the inhibitory transmission at 1-30 μM, and the excitatory transmission at 30 μM, the former being much more sensitive. The depression of IPSCs by 30 μM of these drugs was associated with an increase in the paired-pulse ratio. The GABA-induced currents were suppressed by these drugs, but less sensitive than IPSCs. The AMPA-induced currents were slightly potentiated by these drugs at 30 μM. At 30 μM, clozapine and NDMC slightly suppressed Ca(2+) and Na(+) channels. These results strongly suggest that clozapine and NMDC depress the inhibitory synaptic transmission mainly by antagonizing postsynaptic GABA(A) receptors, but at higher concentrations additionally by acting on presynaptic site, possibly in part through inhibition of presynaptic Ca(2+) and Na(+) channels. Preferential depression of inhibitory synaptic transmission by clozapine and NDMC might contribute to therapeutic actions and/or side-effects of clozapine.
authors.affiliation: Faculty of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-0942, Japan. shosaku@med.kanazawa-u.ac.jp
authors.forename: Takako
authors.initials: T
authors.lastname: Ohno-Shosaku
authors.forename: Yuto
authors.initials: Y
authors.lastname: Sugawara
authors.forename: Chiho
authors.initials: C
authors.lastname: Muranishi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nagasawa
authors.forename: Kozue
authors.initials: K
authors.lastname: Kubono
authors.forename: Nami
authors.initials: N
authors.lastname: Aoki
authors.forename: Mitsuki
authors.initials: M
authors.lastname: Taguchi
authors.forename: Ryousuke
authors.initials: R
authors.lastname: Echigo
authors.forename: Naotoshi
authors.initials: N
authors.lastname: Sugimoto
authors.forename: Yui
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: Ryoko
authors.initials: R
authors.lastname: Watanabe
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Yoneda
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D014150:Antipsychotic Agents; C058272:norclozapine; D003024:Clozapine