Characterization of clozapine-induced changes in synaptic plasticity in the hippocampal-mPFC pathway of anesthetized rats.
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.
Matsumoto
Machiko
M
Department of Pharmacological Sciences, School of Pharmaceutical Science, Health Sciences University of Hokkaido, Ishikari-Tobetsu, 060-0293 Japan. mbird@hoku-iryo-u.ac.jp
Shikanai
Hiroki
H
Togashi
Hiroko
H
Izumi
Takeshi
T
Kitta
Takeya
T
Hirata
Riki
R
Yamaguchi
Taku
T
Yoshioka
Mitsuhiro
M
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
D018686:Anesthetics, Intravenous; D014150:Antipsychotic Agents; D017447:Receptors, Dopamine D1; D014520:Urethane; D003024:Clozapine; D006220:Haloperidol; D004298:Dopamine