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 D1 receptor antagonist SCH-23390 (10 μg/rat, i.c.v.), but not by the D2 receptor antagonist remoxipride (10 μg/rat, i.c.v.) or the 5-HT1A receptor antagonist WAY-100635 (20 μg/rat, i.c.v.). SCH-23390 (10 μg/rat, i.c.v.) by itself did not affect LTP induction. The D1 receptor agonist SKF-38393 (10 μg/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 D1 receptor as a mediator of clozapine-induced LTP augmentation through enhanced dopaminergic activity. Augmentation of synaptic plasticity in the hippocampal-mPFC pathway via D1 receptors appears to be responsible for the therapeutic effects of clozapine.