title: Phencyclidine increases forebrain monoamine metabolism in rats and monkeys: modulation by the isomers of HA966.
abstract: The noncompetitive NMDA receptor antagonist phencyclidine (PCP) has psychotomimetic properties in humans and activates the frontal cortical dopamine innervation in rats, findings that have contributed to a hyperdopaminergic hypothesis of schizophrenia. In the present studies, the effects of the enantiomers of 3-amino-1-hydroxypyrrolid-2-one (HA966) on PCP-induced changes in monoamine metabolism in the forebrain of rats and monkeys were examined, because HA966 has been shown previously to attenuate stress- or drug-induced activation of dopamine systems. In rats, PCP (10 mg/kg, i.p.) potently activated dopamine (DA) turnover in the medial prefrontal cortex (PFC) and nucleus accumbens. Serotonin utilization was also increased in PFC. Pretreatment with either R-(+)HA966 (15 mg/kg, i.p.) or S-(-)HA966 (3 mg/kg, i.p.) partially blocked PCP-induced increases in PFC DA turnover, whereas neither enantiomer altered the effect of PCP on DA turnover in the nucleus accumbens or the PCP-induced increases in serotonin turnover in PFC. PCP (0.3 mg/kg, i.m.) exerted regionally selective effects on the dopaminergic and serotonergic innervation of the monkey frontal cortex, effects blocked by pretreatment with S-(-)HA966 (3 mg/kg, i. m.). Importantly, these data demonstrate that in the primate, PCP has potent effects on dopamine transmission in the frontal cortex, a brain region thought to be dysfunctional in schizophrenia. In addition, a role for S-(-)HA966 as a modulator of cortical monoamine transmission in primates is posited.
authors.affiliation: Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Jentsch
authors.forename: J D
authors.initials: JD
authors.lastname: Elsworth
authors.forename: D E
authors.initials: DE
authors.lastname: Redmond
authors.forename: R H
authors.initials: RH
authors.lastname: Roth
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002522:Chlorocebus aethiops / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D007536:Isomerism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010622:Phencyclidine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012565:Schizophrenic Psychology; D012701:Serotonin / Q000378:metabolism*; D013045:Species Specificity; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013681:Tegmentum Mesencephali / Q000187:drug effects / Q000378:metabolism
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D011760:Pyrrolidinones; D016194:Receptors, N-Methyl-D-Aspartate; D012701:Serotonin; C001369:1-hydroxy-3-amino-2-pyrrolidone; D010622:Phencyclidine; D004298:Dopamine