nitrophenols and Cognition-Disorders

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.

Topics: Animals; Benzophenones; Blood-Brain Barrier; Brain; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Cognition Disorders; Dopamine; Dose-Response Relationship, Drug; Male; Memory Disorders; Mice; Mice, Transgenic; Nitriles; Nitrophenols; Phencyclidine; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Recognition, Psychology; Tolcapone

Catechol-O-methyltransferase (COMT) modulates dopamine levels in the prefrontal cortex. The human gene contains a polymorphism (Val

Topics: Analysis of Variance; Animals; Benzophenones; Brain; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Choice Behavior; Cognition Disorders; Disease Models, Animal; Exploratory Behavior; Genotype; Maze Learning; Methionine; Mice; Mice, Transgenic; Nitrophenols; Polymorphism, Single Nucleotide; Reaction Time; Tolcapone; Valine

It is widely accepted that abnormal prefrontal cortex biology resulting in deficient cognition is a primary problem in schizophrenia and that all currently available antipsychotics fail to improve cognitive and negative symptoms originating from this deficit. Evidence from basic science has revealed the importance of prefrontal dopamine signaling for optimal prefrontal function. This article describes succinctly the progress made so far, taking into account the mechanisms involved in catechol-O-methyltransferase (COMT)-induced modulation of prefrontal dopamine signaling, the impact of COMT on cognitive function and the role of COMT gene polymorphisms. The potential role of the COMT inhibitor tolcapone to improve cognitive function in health and disease is also presented here. It will soon be understood if tolcapone represents one of the first hypothesis-driven, biology-based, genotype-specific, targeted treatments of cognitive and negative symptoms of schizophrenia.

Topics: Antipsychotic Agents; Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Cognition Disorders; Dopamine; Genetic Predisposition to Disease; Genotype; Humans; Nitrophenols; Polymorphism, Genetic; Schizophrenia; Schizophrenic Psychology; Signal Transduction; Tolcapone

Topics: Benzophenones; Bipolar Disorder; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Cognition Disorders; Comorbidity; Diagnosis, Differential; Enzyme Inhibitors; Gene Expression; Genotype; Humans; Nitrophenols; Pharmacogenetics; Schizophrenia; Telecommunications; Tolcapone