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Clozapine normalizes prefrontal cortex dopamine transmission in monkeys subchronically exposed to phencyclidine.
- Source :
-
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology [Neuropsychopharmacology] 2008 Feb; Vol. 33 (3), pp. 491-6. Date of Electronic Publication: 2007 May 16. - Publication Year :
- 2008
-
Abstract
- 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on the dopamine projections to prefrontal cortex, nucleus accumbens, and striatum in control monkeys and in those withdrawn from repeated phencyclidine treatment, using a dose regimen of clozapine that ameliorates the cognitive deficits described in the primate phencyclidine (PCP)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.
- Subjects :
- Animals
Brain Chemistry drug effects
Chlorocebus aethiops
Dopamine metabolism
Female
Male
Memory drug effects
Prefrontal Cortex metabolism
Psychomotor Performance drug effects
Antipsychotic Agents pharmacology
Clozapine pharmacology
Dopamine physiology
Hallucinogens toxicity
Phencyclidine toxicity
Prefrontal Cortex drug effects
Synaptic Transmission drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0893-133X
- Volume :
- 33
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 17507917
- Full Text :
- https://doi.org/10.1038/sj.npp.1301448