Effects of clozapine and N-desmethylclozapine on synaptic transmission at hippocampal inhibitory and excitatory synapses
| Autor: | Nami Aoki, Mitsugu Yoneda, Chiho Muranishi, Yuto Sugawara, Keisuke Nagasawa, Takako Ohno-Shosaku, Mitsuki Taguchi, Naotoshi Sugimoto, Ryoko Watanabe, Ryousuke Echigo, Kozue Kubono, Yui Kikuchi |
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| Rok vydání: | 2011 |
| Předmět: |
Patch-Clamp Techniques
medicine.drug_class Postsynaptic Current medicine.medical_treatment Atypical antipsychotic Pharmacology Neurotransmission Inhibitory postsynaptic potential Hippocampus Synaptic Transmission Rats Sprague-Dawley Postsynaptic potential medicine Animals Antipsychotic Molecular Biology Clozapine N-desmethylclozapine Chemistry General Neuroscience Rats IPSC EPSC Synapses Excitatory postsynaptic potential Neurology (clinical) Developmental Biology medicine.drug Antipsychotic Agents |
| Zdroj: | Brain research. 1421 |
| ISSN: | 1872-6240 |
| Popis: | 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 Ca2+ and Na+ channels. These results strongly suggest that clozapine and NMDC depress the inhibitory synaptic transmission mainly by antagonizing postsynaptic GABAA receptors, but at higher concentrations additionally by acting on presynaptic site, possibly in part through inhibition of presynaptic Ca2+ and Na+ channels. Preferential depression of inhibitory synaptic transmission by clozapine and NDMC might contribute to therapeutic actions and/or side-effects of clozapine. © 2011 Elsevier B.V. All rights reserved. |
| Databáze: | OpenAIRE |
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