Brain extracellular levels of the putative antipsychotic CI-1007 and its effects on striatal and nucleus accumbens dopamine overflow in the awake rat.
The compound CI-1007 (R-(+)-1,2,3,6-tetrahydro-4-phenyl-1 [(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine maleate) has been identified as a partial dopamine agonist and putative antipsychotic in in-vitro and in-vivo neurochemical, neurophysiological and behavioural tests. By use of microdialysis in conjunction with high-performance liquid chromatography (HPLC) with electrochemical detection, the effects of the drug on brain dopamine release, previously observed in anaesthetized animals, were shown to occur in awake animals also. Detection of peripherally administered CI-1007 in the brain, i.e. evidence of the drug's ability to penetrate the blood-brain barrier, was achieved by use of in-vivo brain microdialysis in awake, freely moving rats and capillary HPLC in combination with tandem mass spectrometry (HPLC/MS/MS). Intravenous administration of CI-1007 (40 mg kg-1) significantly inhibits dopamine release in the nucleus accumbens, a region associated with dopamine hyperactivity in schizophrenia, while having a non-significant impact on the striatal dopamine neurotransmission which is critical to regular motor function. The differential neurochemical profile of the drug indicates its potential usefulness in treating positive disease symptoms and implies that its extrapyramidal side effects are lower than those of typical antipsychotics.
Iyer
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RN
Department of Chemistry, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Davis
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MD
Juneau
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PL
Giordani
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AB
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002845:Chromatography; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D013058:Mass Spectrometry; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014793:Visual Cortex / Q000187:drug effects* / Q000378:metabolism
D014150:Antipsychotic Agents; D018491:Dopamine Agonists; C090025:1,2,3,6-tetrahydro-4-phenyl-1-((3-phenyl-3-cyclohexen-1-yl)methyl)pyridine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine