title: Brain catechol-O-methyltransferase (COMT) inhibition by tolcapone counteracts recognition memory deficits in normal and chronic phencyclidine-treated rats and in COMT-Val transgenic mice.
abstract: The critical involvement of dopamine in cognitive processes has been well established, suggesting that therapies targeting dopamine metabolism may alleviate cognitive dysfunction. Catechol-O-methyl transferase (COMT) is a catecholamine-degrading enzyme, the substrates of which include dopamine, epinephrine, and norepinephrine. The present work illustrates the potential therapeutic efficacy of COMT inhibition in alleviating cognitive impairment. A brain-penetrant COMT inhibitor, tolcapone, was tested in normal and phencyclidine-treated rats and COMT-Val transgenic mice. In a novel object recognition procedure, tolcapone counteracted a 24-h-dependent forgetting of a familiar object as well as phencyclidine-induced recognition deficits in the rats at doses ranging from 7.5 to 30 mg/kg. In contrast, entacapone, a COMT inhibitor that does not readily cross the blood-brain barrier, failed to show efficacy at doses up to 30 mg/kg. Tolcapone at a dose of 30 mg/kg also improved novel object recognition performance in transgenic mice, which showed clear recognition deficits. Complementing earlier studies, our results indicate that central inhibition of COMT positively impacts recognition memory processes and might constitute an appealing treatment for cognitive dysfunction related to neuropsychiatric disorders.
authors.affiliation: aUCB Biopharma s.p.r.l., Neuroscience Therapeutic Area, Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium bLieber Institute for Brain Development Departments of cPsychiatry dNeurology eNeuroscience, Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore fClinical Brain Disorders Branch, National Institute of Mental Health, NIH, Bethesda, Maryland, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Detrait
authors.forename: Greg V
authors.initials: GV
authors.lastname: Carr
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Yves
authors.initials: Y
authors.lastname: Lamberty
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000008:administration & dosage / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000187:drug effects* / Q000235:genetics; D065098:Catechol O-Methyltransferase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D002396:Catechols / Q000494:pharmacology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy; D051379:Mice; D008822:Mice, Transgenic; D009570:Nitriles / Q000494:pharmacology; D009596:Nitrophenols / Q000008:administration & dosage / Q000494:pharmacology*; D010622:Phencyclidine / Q000008:administration & dosage / Q000633:toxicity; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects; D000077867:Tolcapone
chemical_list: D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D009570:Nitriles; D009596:Nitrophenols; C071192:entacapone; D000077867:Tolcapone; D002394:Catechol O-Methyltransferase; D010622:Phencyclidine; D004298:Dopamine