title: Characterization of clozapine-induced changes in synaptic plasticity in the hippocampal-mPFC pathway of anesthetized rats.
abstract: Synaptic plasticity expressed as long-term potentiation (LTP) in the hippocampal-medial prefrontal cortex (mPFC) pathway is considered to be involved in cognitive function and learning and memory processes, but its synaptic mechanism remains unknown. The present study characterized LTP in the mPFC using the atypical antipsychotic clozapine, with a focus on dopaminergic modulation. The magnitude of LTP was facilitated by pretreatment with clozapine (20 mg/kg, i.p.), but not by the typical antipsychotic haloperidol (1 mg/kg, i.p.). Clozapine-induced LTP augmentation was blocked by the dopamine D(1) receptor antagonist SCH-23390 (10 microg/rat, i.c.v.), but not by the D(2) receptor antagonist remoxipride (10 microg/rat, i.c.v.) or the 5-HT(1A) receptor antagonist WAY-100635 (20 microg/rat, i.c.v.). SCH-23390 (10 microg/rat, i.c.v.) by itself did not affect LTP induction. The D(1) receptor agonist SKF-38393 (10 microg/kg, i.c.v.) facilitated LTP, mimicking the clozapine-induced response. Furthermore, in vivo microdialysis showed that transient increases in mPFC dopamine levels induced by tetanic stimulation sustained facilitation following clozapine administration (20 mg/kg, i.p.). These results demonstrate the importance of the D(1) receptor as a mediator of clozapine-induced LTP augmentation through enhanced dopaminergic activity. Augmentation of synaptic plasticity in the hippocampal-mPFC pathway via D(1) receptors appears to be responsible for the therapeutic effects of clozapine.
authors.affiliation: Department of Pharmacological Sciences, School of Pharmaceutical Science, Health Sciences University of Hokkaido, Ishikari-Tobetsu, 060-0293 Japan. mbird@hoku-iryo-u.ac.jp
authors.forename: Machiko
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shikanai
authors.forename: Hiroko
authors.initials: H
authors.lastname: Togashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Izumi
authors.forename: Takeya
authors.initials: T
authors.lastname: Kitta
authors.forename: Riki
authors.initials: R
authors.lastname: Hirata
authors.forename: Taku
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yoshioka
mesh_terms: D018686:Anesthetics, Intravenous / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001364:Awareness / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D009434:Neural Pathways / Q000187:drug effects*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D013569:Synapses / Q000187:drug effects; D014520:Urethane / Q000494:pharmacology
chemical_list: D018686:Anesthetics, Intravenous; D014150:Antipsychotic Agents; D017447:Receptors, Dopamine D1; D014520:Urethane; D003024:Clozapine; D006220:Haloperidol; D004298:Dopamine