tolcapone and Memory-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

Repeated administration of tolcapone, an inhibitor of catechol-O-methyltransferase, was able to partially restore the memory deficits caused by bilateral cholinotoxin (AF64A) lesions in the basal magnocellular nuclei of Meynert. The 2-week tolcapone treatment (3 mg kg-1, once a day) was started 24 h before toxin infusion and the last injection was given 24 h before the first avoidance test. The beneficial action of tolcapone may be related to antioxidant properties of nitrocatechols.

Topics: Animals; Avoidance Learning; Benzophenones; Catechol O-Methyltransferase Inhibitors; Male; Memory; Memory Disorders; Nitrophenols; Rats; Rats, Wistar; Substantia Innominata; Time Factors; Tolcapone