Tolcapone enhances food-evoked dopamine efflux and executive memory processes mediated by the rat prefrontal cortex

Genetic variations in catechol-O-methyl transferase (COMT) or administration of COMT inhibitors have a robust impact on cognition and executive function in humans. The COMT enzyme breaks down extracellular dopamine (DA) and has a particularly important role in the prefrontal cortex (PFC) where DA transporters are sparse. As such, the beneficial cognitive effects of the COMT inhibitor tolcapone are postulated to be the result of increased bioavailability of DA in the PFC. Furthermore, it has been shown previously that COMT inhibitors increase pharmacologically evoked DA but do not affect basal levels in the PFC. The current study characterized the ability of tolcapone to increase DA release in response to behaviorally salient stimuli and improve performance of the delayed spatial win-shift (DSWSh) task. Tolcapone enhanced PFC DA efflux associated with the anticipation and consumption of food when compared to saline controls. Chronic and acute treatment with tolcapone also reduced the number of errors committed during acquisition of the DSWSh. However, no dissociable effects were observed in experiments designed to selectively assay encoding or recall in well-trained animals, as both experiments showed improvement with tolcapone treatment. Taken together, these data suggest a generalized positive influence on cognition. Furthermore, these data support the conclusion of Apud and Weinberger (CNS Drugs 21:535-557, 2007) that agents which selectively potentiate PFC DA release may confer cognitive enhancement without the unwanted side effects produced by drugs that increase basal DA levels in cortical and subcortical brain regions.