Subchronic phencyclidine administration increases mesolimbic dopaminergic system responsivity and augments stress- and psychostimulant-induced hyperlocomotion.
Previous studies have shown that repeated exposures to phencyclidine (PCP) induces prefrontal cortical dopaminergic and cognitive deficits in rats and monkeys, producing a possible model of schizophrenic frontal cortical dysfunction. In the current study, the effects of subchronic PCP exposure on forebrain dopaminergic function and behavior were further explored. Prefrontal cortical dopamine utilization was reduced 3 weeks after subchronic PCP administration, and the cortical dopaminergic deficit was mimicked by repeated dizocilpine exposure. In contrast, stress- and amphetamine-induced hyperlocomotion, behavior believed to be mediated by activation of mesolimbic dopamine transmission, was enhanced after PCP exposures. Furthermore, haloperidol-induced increases in nucleus accumbens dopamine utilization were larger in magnitude in PCP-treated rats relative to control subjects. These data are the first to demonstrate that repeated exposures to PCP causes prefrontal cortical dopaminergic hypoactivity and subcortical dopaminergic hyper-responsivity in rats, perhaps mimicking alterations in dopaminergic transmission that underlie the behavioral pathology of schizophrenia.
Jentsch
J D
JD
Neuropsychopharmacology Research Unit, Yale University School of Medicine, New Haven, Connecticut 208001, USA.
Taylor
J R
JR
Roth
R H
RH
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D003913:Dextroamphetamine / Q000494:pharmacology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004334:Drug Administration Schedule; D006220:Haloperidol / Q000494:pharmacology; D008032:Limbic System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D010622:Phencyclidine / Q000008:administration & dosage / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia; D013315:Stress, Psychological; D013997:Time Factors
D015102:3,4-Dihydroxyphenylacetic Acid; D016291:Dizocilpine Maleate; D010622:Phencyclidine; D006220:Haloperidol; D003913:Dextroamphetamine; D004298:Dopamine