Background
Mechanisms underlying clozapine’s better clinical efficacy in schizophrenia remain
poorly understood. The prefrontal cortex (PFC) has been implicated as a primary site
for the therapeutic effects of clozapine; however, evidence for how clozapine influences
the activity of PFC neurons in behaviorally relevant contexts is lacking.
Methods
Ensemble single unit recording in awake rats was used to measure the activity of PFC
neurons in response to clozapine, its main metabolite N-desmethylclozapine (DMClz),
and the typical antipsychotic drug haloperidol during baseline conditions and after
treatment with the N-methyl-D-aspartate antagonist MK801. Behavioral stereotypy was
scored during recording.
Results
Clozapine and DMClz but not haloperidol had an activity-dependent influence on spontaneous
firing rate of PFC cells: they increased the activity of neurons with low baseline
firing rates and decreased the activity of neurons with higher firing rates. Clozapine
and DMClz but not haloperidol also reversed the effect of MK801 on PFC neuronal firing.
This reversal was strongly correlated with blockade of MK801-induced behavioral stereotypy.
Conclusions
These findings indicate that clozapine has the capacity to fine-tune spontaneous and
disrupted activity of PFC neurons. This effect might contribute, in part, to the therapeutic
efficacy of clozapine in schizophrenia.
Key Words
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Article info
Publication history
Published online: October 17, 2006
Accepted:
May 22,
2006
Received in revised form:
May 17,
2006
Received:
March 27,
2006
Identification
Copyright
© 2007 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
