Clozapine normalizes prefrontal cortex dopamine transmission in monkeys subchronically exposed to phencyclidine.
The mechanism responsible for the therapeutic effects of the prototypical atypical antipsychotic drug, clozapine, is still not understood; however, there is persuasive evidence from in vivo studies in normal rodents and primates that the ability to elevate dopamine neurotransmission preferentially in the prefrontal cortex is a key component to the beneficial effects of clozapine in schizophrenia. Theoretically, such an effect of clozapine would counteract the deficient dopaminergic innervation of the prefrontal cortex that appears to be part of the pathophysiology of schizophrenia. We have previously shown that following repeated, intermittent administrations of phencyclidine to monkeys there is lowered prefrontal cortical dopamine transmission and impairment of cognitive performance that is dependent on the prefrontal cortex; these biochemical and behavioral changes therefore model certain aspects of schizophrenia. We now investigate the effects of clozapine on the dopamine projections to prefrontal cortex, nucleus accumbens, and striatum in control monkeys and in those withdrawn from repeated phencyclidine treatment, using a dose regimen of clozapine that ameliorates the cognitive deficits described in the primate phencyclidine (PCP) model. In normal monkeys, clozapine elevated dopamine turnover in all prefrontal cortical, but not subcortical, regions analyzed. In the primate PCP model, clozapine normalized dopamine (DA) turnover in the dorsolateral prefrontal cortex, prelimbic cortex, and cingulate cortex. Thus, the present data support the hypothesis that the therapeutic effects of clozapine in this primate model and perhaps in schizophrenia may be related at least in part to the restoration of DA tone in the prefrontal cortex.
Elsworth
John D
JD
Neuropsychopharmacology Research Unit, Departments of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA. john.elsworth@yale.edu
Jentsch
J David
JD
Morrow
Bret A
BA
Redmond
D Eugene
DE
Roth
Robert H
RH
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D002522:Chlorocebus aethiops; D003024:Clozapine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006213:Hallucinogens / Q000633:toxicity*; D008297:Male; D008568:Memory / Q000187:drug effects; D010622:Phencyclidine / Q000633:toxicity*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*
D014150:Antipsychotic Agents; D006213:Hallucinogens; D010622:Phencyclidine; D003024:Clozapine; D004298:Dopamine